[Acute epidural hematoma following evacuation of chronic subdural hematoma with continuous closed system drainage]. The authors report a case of acute epidural hematoma occurring after evacuation of chronic subdural hematoma with continuous closed system drainage. Laboratory data of the patient including bleeding time were within normal limits. The cause of the postoperative intracranial hematoma was the rapid surgical decompression of the initial lesion, and we considered that it could be prevented if chronic subdural hematoma was treated using closed system drainage and slow decompression. But acute epidural hematoma occurred after this operative procedure and it was accelerated by evacuation of the chronic subdural hematoma through the drain. An emergent craniotomy and removal of the hematoma was performed, so the patient was discharged from hospital with satisfactory neurological recovery. A careful check of the evacuated hematoma volume is very important, and CT scanning should be immediately performed if postoperative hematoma is suspected.


[Malignant melanoma metastatic to the cavernous sinus and skull with an unknown primary origin: report of a case]. A rare case of malignant melanoma metastatic to the cavernous sinus and skull, with an unknown primary origin, is reported. A 46-year-old man noticed diplopia, lt. ptosis and swelling in the parietal and maxillary regions. The parietal skull tumor and the maxillary lymph node were excised and histological examination revealed malignant melanoma. Because of its roentogenological characteristics, the lesion of the cavernous sinus was also thought to be the site of metastasis of malignant melanoma. This case is rare because the initial symptom was cavernous sinus syndrome, and no involvement of brain parenchyma was observed.


[A case of Turner's syndrome associated with moyamoya disease]. A case of Turner's syndrome associated with Moyamoya disease in a 10-year-old female is presented. This patient had experienced two periods of syncope and transient right hemiparesis in 2 years. She was short in stature. She had cubitus vargus and mental retardation. The serum LH and FSH values were high. By chromosomal examination Turner's syndrome (karyotype: 45, X/46, X, i(Xq)) was diagnosed. An MRI (SE 2000/20) revealed abnormal vessels on the basal ganglia. Cerebral angiography showed occlusion of bilateral internal carotid arteries at the distal portion, bilateral posterior cerebral arteries at the proximal portion. Basal moyamoya well developed. EDAS (encephalo-duro-arterio-synangiosis) was performed bilaterally. We consider that this may be the first case report of Turner's syndrome associated with Moyamoya disease, and that there may be no relationship between Turner's syndrome and Moyamoya disease in this case.


[A case of intracranial multiple nonspecific granulomas related to rheumatic disease: with special reference to magnetic resonance imaging]. We encountered a rare case of a 48-year-old man with intracranial multiple granulomas secondarily caused by rheumatic disease. This was proven surgically after an 11-year course of remissions and deteriorations. In 1980, at the age of 32 years, the patient was first seen at the clinic of Neurology of the University Hospital, complaining of swelling and arthralgia of the joints of the knee, ankle, and wrist and with remittent fever and visual disturbance. The patient was diagnosed as having possible rheumatoid arthritis, and treated with administration of 30mg/day of prednisolone, which greatly improved the symptoms. The administration of 5 to 10mg/day of prednisolone had been continued after discharge from hospital. In 1985, visual acuity of the left eye decreased, and left facial hypesthesia developed. The patient was rehospitalized at the same clinic, and treated with 100mg/day of prednisolone, which again diminished the symptoms. Computed tomography(CT) on admission showed a high density mass with contrast enhancement in the left cavernous region. In addition to the left cavernous mass, a high density mass was detected by CT in the left parietal lobe, in 1987. Visual acuity of the left eye deteriorated in 1989. Because his response to prednisolone had decreased, the visual symptom was treated with gold sodium, which acted effectiveness. Symptoms deteriorated again in 1990. Early in 1991, CT and magnetic resonance imaging showed a new mass at the right frontal lobe, while the mass in the left cavernous region had increased in size. The patient was transferred to the clinic of Neurosurgery for surgical treatment.(ABSTRACT TRUNCATED AT 250 WORDS)


[Natural history for residual intracranial AVM: compared with that for conservatively treated AVM]. It is generally accepted that the most suitable treatment of AVM is surgical removal which does not cause neurological deficits. But in some cases, it is impossible to treat surgically because of size or location, so the patient is unfortunately discharged with some part of the nidus remaining. In this paper, we report the natural history of residual AVMs in which part of the nidus remained after initial therapy, and try to ascertain whether therapeutic reduction of the nidus is more effective in preventing intracranial hemorrhage than conservative treatment. Of 362 cases, residual AVMs were found in 35 cases, and were followed up for 9.2 years on average. Eighty cases treated with only conservative therapy were also followed up for 10.9 years on average. The annual risk of intracranial hemorrhage for residual AVMs was 2.9% and that for conservatively treated AVMs was 3.0%, not a significant difference. There was no difference between the two groups in mortality or ADL. We conclude that therapeutic reduction of the nidus was not effective in preventing intracranial hemorrhage.


[Effects of gamma-hydroxybutyrate on monoamine metabolism and protein synthesis after transient global cerebral ischemia]. The effects of gamma-hydroxybutyrate (GHB) on 1) monoamine metabolism, and 2) protein synthesis were examined in a gerbil stroke model. The monoamine metabolism was studied by occluding bilateral common carotid arteries for 15 minutes followed by GHB administered intravenously 3 hours later. Tissue monoamine concentration was examined up to 8 hours after recirculation. Three hours after GHB administration, dopamine (DA) had increased to almost twice that of the non-treated group, whereas homovanillic acid, a metabolite of DA, did not show any significant difference. These results may mean that GHB will facilitate DA synthesis but that it has no influence on its release. Therefore, a DA-mediated increase in cerebral blood flow in the cerebral cortex cannot be expected. Tryptophan, a precursor of 5-hydroxytryptamine (5HT), started to increase just after recirculation reaching a level of over four times that of the control value at 2 to 3 hours, and then starting to decrease in the non-treated group. This decline in tryptophan was markedly facilitated by GHB administration within 1 hour. On the other hand, 5HT administration within 1 hour. On the other hand, 5HT increased only very slightly in the cerebral cortex 1 hour after GHB administration, the change ratio being 1/30 of tryptophan. It can therefore be speculated, that the decrease in tryptophan brought about by GHB administration is due to the improvement in disturbed protein synthesis rather than to stimulation of 5HT synthesis. Protein synthesis was studied by administering GHB 2 minutes prior to a 5-minute temporal common carotid artery occlusion. Ninety minutes after recirculation animals were given a single dose of 14C-leucine and further 60 minutes were allowed to pass before sacrifice. Autoradiographs of the GHB-treated group were compared with those of the non-treated group. With GHB pretreatment, autoradiographs showed an increased uptake of 14C-leucine in at least the hippocampus, thalamus, and hypothalamus, and in two out of three animals, there was diffusely increased uptake. Thus, it is speculated that GHB is effective in improving the protein synthesis in the postischemic period. The favorable function of GHB during cerebral ischemia is regarded by many to be prevention of energy failure by reducing cerebral metabolism. On the other hand, the results derived from the present study suggest that GHB may improve protein synthesis in the postischemic period. Thus, we suggest that GHB is useful if given at the acute stage of cerebral ischemia such as during internal carotid artery or middle cerebral artery occlusion.


[Electrophysiological identification of the cochlear and vestibular nerves in the cerebellopontine angle: experimental study and clinical implication]. Electrical stimulation was applied on the surface of the eighth cranial nerve in the cerebellopontine angle of dogs and the evoked potentials were recorded with surface electrodes on the scalp. The shape of the evoked potentials recorded was different according to the portion of the nerve stimulated electrically. It was, therefore, possible to precisely identify the nerve stimulated from the surface recorded evoked potentials. This electrophysiological method may be helpful for the surgeon to precisely locate the cochlear and vestibular nerves in various operations in the cerebellopontine angle in human. Our preliminary experience of this monitoring method in acoustic neuroma excision was presented.


[Long-term prognosis of nonoperative acute epidural hematoma in children]. Computed tomography(CT) scan has revealed that certain acute epidural hematomas(AEH) don't need operative therapies. But, it is difficult to determine especially in childhood, whether AEH compressing the brain for a short-term would or would not effect the function of the central nervous system in the future. For this reason, the authors report the long-term prognosis of nonoperative AEH in children. Twelve children suffering from AEH were transported to our clinic. On admission, they had no neurological deficits and CT scan revealed hematomas that had maximum thickness of 5-19 mm without midline shift. With nonoperative therapy they were discharged and the hematomas disappeared within 3-12 weeks. After long-term follow-up (3-10 years), it was shown that they had no epileptic episodes, and no changes in their school study records. Also, the Yatabe-Guilford personality test revealed no abnormal data. These data suggest that children can be cured who suffer from AEH with no neural deficits, and in whom the maximum thickness of the AEH is less than 20 mm, and in whom there is no midline shift in CT scan, can be cured without undergoing an operation, and will have a good long-term prognosis.


[Analysis of long-term social rehabilitation of brain contusion]. 164 patients with brain contusion were evaluated with respect to social rehabilitation. 70 out of 134 patients (66.7%), said to have had good recovery or moderate disability by the Glasgow Outcome Scale (GOS), returned to full or partial employment. Factors such as age, Glasgow Coma Scale (GCS) at admission, duration of unawareness, fibrin and fibrinogen degradation product (FDP) were the most important in predicting social recovery. The Wechsler Adult Intelligence Scale (WAIS) was applied in 33 patients. The IQs of the patients who returned to their job fully tended to be higher than those who could not. In the majority of patients, impaired capacity for work was caused not only by physical deficits, but by mental retardation described as such as IQ score.


[Pitfalls of endovascular treatment for cerebral aneurysms]. Seventeen cases of unclippable aneurysms were treated by the endovascular balloon technique. Nine of them involved the anterior circulation, and eight involved the posterior circulation. Eleven of them were treated by parent artery occlusion with detachable balloons. Three were treated by endosaccular balloon embolization, and three cases combined with AVMs were occluded using ethylene vinyl alcohol copolymer (EVAL) including feeding arteries of the AVMs. Embolic complications occurred in one case of an IC bifurcation giant aneurysm treated by parent artery occlusion. Ischemic complications also appeared in two cases of aneurysms treated by endosaccular balloon embolization. In one case, the thrombus in the aneurysm propagated into the parent artery and occluded it later. In another case, the displaced balloon had obliterated the parent artery 6 hours after the embolization. Parent artery occlusion is a safe way to treat internal carotid giant aneurysms. However, endosaccular treatment still has some problems, i.e., 1) maintaining the balloon's position to preserve the parent artery, 2) balloon migration into the clot, 3) rupture of the aneurysm during or after treatment. Our studies indicate that endosaccular balloon embolization is still a high risk procedure and should be used only in selected cases, until new embolic agents, such as detachable coils, become available.


[Traumatic intracranial aneurysms after removal of tuberculum sellae meningioma: case report]. Two cases of traumatic aneurysms (TA) of the internal carotid artery (IC) due to removal of tuberculum sellae meningioma (TSM) are presented, and ideal treatment of those aneurysms is discussed. The tumor, compressing the IC laterally, was removed out without arterial injury in case 1. Though the patient's postoperative course was uneventful, frontal and intraventricular hemorrhage developed 2 months after the operation, and an IC dorsal aneurysm was detected. Preoperative angiograms showed no aneurysm, so it was considered to be a traumatic aneurysm due to the surgical procedure. The aneurysm was clipped at once, but postoperative angiograms showed recurrence of the aneurysm. IC balloon occlusion was carried out as the Matas test was negative. In case 2, a small tear in the IC was inadvertently made during recurrent TSM removal, which was wrapped with muscle using fibrin glue. 2 weeks after the operation, frontal hemorrhage developed. Angiograms revealed a small aneurysm of the IC, which was considered to be a traumatic aneurysm. IC balloon occlusion was performed as the Matas test was negative. These 2 patients have had no episodes of rerupture after the IC balloon occlusion. Tumors and main arteries are frequently adhesive, so arteries are easily injured during removal of meningiomas. Muscle wrapping was not enough to prevent TA formation. Neck clipping was not appropriate for treatment of TA, but IC balloon occlusion was an effective and excellent therapy for TA of IC.


[A report of four cases of intrathoracic meningocele]. Intrathoracic meningocele is regarded as an uncommon pathological entity frequently associated with von Recklinghausen's disease. In this paper, four cases of intrathoracic meningocele, treated between 1966 and 1986, are presented. There were three males and one female, all between the ages of 40 and 50. These were referred to our clinic for further evaluation of an asymptomatic lesion which had been seen on a routine chest roentgenogram. There was definite evidence of von Recklinghausen's disease in three cases: two males and one female. All four cases had no pain, dyspnea or neurological disorder. Chest and vertebral tomograms revealed masses in the posterior mediastinum and enlarged vertebral canals at the location of the lesion which varied from T-3 to T-11; three on the left side and one on the right side. None of them revealed scoliosis or kyphosis of the spine. In three cases, myelography was performed and showed an egg-shaped mass dorsolaterally. In two cases, metrizamide computed tomographic myelography was carried out and demonstrated deformity of the vertebral bone and passage of the contrast material through the enlarged vertebral canal into the paravertebral mass. Furthermore, magnetic resonance imaging was performed in two cases, and showed a homogeneous low signal intensity paravertebral mass communicating with the spinal canal on T1-weighted image. In two cases, the meningoceles were ligated or wrapped surgically. Postoperatively one presented a paraparesis and severe meningitis, and died; the other had an uneventful postoperative course. Two patients were followed conservatively without developing any symptoms or signs.(ABSTRACT TRUNCATED AT 250 WORDS)


[A ruptured aneurysm at the peripheral collateral circulation of the anterior choroidal artery in a patient with moyamoya disease: a case report]. This 42-year-old man experienced a sudden onset of occipital headache. Neurological examination revealed a moderately disturbed consciousness and a moderate left hemiparesis. CT scan disclosed a hugh hematoma in the right temporo parietal lobe without intraventricular hemorrhage. A cerebral angiography demonstrated typical findings of moyamoya disease and a small saccular aneurysm at the peripheral portion of the right anterior choroidal artery, which was dilated at the collateral circulation to the parietal lobe. The hematoma was removed at once by a craniotomy. He became alert but mild hemiparesis persisted. MRI disclosed a small signal-void lesion lateral to the trigone of the right lateral ventricle. The angiography repeated three weeks after the removal of the hematoma showed the unchanged size of the aneurysm. Direct surgery for the aneurysm was performed via the right parietal transcortical approach. The aneurysm was reached under the guidance of the intraoperative angiography. Trapping of the parent artery and the excision of the aneurysm were performed. On the basis of the presence of an internal elastic lamina at the neck of the aneurysm, the surgical specimen was histologically verified to be a true aneurysm. Since the collateral circulation was well preserved during surgery, no worsening of the neurological manifestation was observed. In view of the unfavorable prognosis for a moyamoya patient with this type of the aneurysm, which often results in a massive ventricular or intracerebral hemorrhage, surgery directed to the aneurysm itself should be considered.


[Penetrating injury of the common carotid artery: report of a case]. An eighty-year-old man slipped in the bathroom and received a deep slash wound in his left neck caused by a broken fragment of the bathroom door. A fragment of the glass stuck into his left neck. He was carried to our clinic after 20 minutes in a state of shock and showed right hemiparesis and aphasia. Following immediate orotracheal intubation and emergent therapy for shock, he was transferred to the operation theater for massive arterial bleeding from the wound. The left common carotid artery and internal jugular vein were exposed by extending the skin incision from the cervical wound along the anterior border of the left sternocleidomastoideus. The left common carotid artery and the internal jugular vein were simultaneously transected, and end-to-end anastomosis of the carotid artery was performed under the administration of 300 ml of Sendai Cocktail. The occlusion time of the left common carotid artery was approximately 50 minutes. Right hemiparesis and total aphasia did not change immediately after the surgery. The postsurgical CT scan showed an infarction in the posterior portion of the left middle and posterior cerebral arteries. However, after undergoing rehabilitation for a month, the patient could walk alone, and his aphasia improved. Many large series of penetrating injuries to the carotid artery were reported after World War II. Most casualties were younger males injured by gunshot. In middle cervical injury, the common carotid artery is the most vulnerable vessel, although other large vessels such as the external and internal carotid arteries as well as the internal jugular vein may be involved, often causing neurological deficits and shock.(ABSTRACT TRUNCATED AT 250 WORDS)


[Multiple cerebral infarction by blood-borne tumor emboli in carcinoma of the mid-pharynx: an autopsy case]. In May, 1989, a-54-year old man was admitted complaining of sore throat and tumor of the neck which had persisted for 2 months. Mid-pharyngeal tumor was diagnosed as poorly differentiated squamous cell carcinoma (stage, T3N2M0) and the patient was treated with radiation (Co 65Gy) from May 30 to July 24 and chemotherapy (UFT), which therapies were effective. On Aug. 16, sudden onset of consciousness disturbance and hemiparesis was revealed, and MRI showed small cerebral infarction. He died on Oct. 23, of pneumonia. Pathological diagnosis revealed a case of carcinoma of the mid-pharynx with wide-spread tumor embolism. Multiple cerebral and myocardial infarctions, thrombus in pulmonary arteries and congestion of kidneys with tumor emboli, due to "disseminated intravascular carcinomatosis" were noticed. A direct cause of death was dyspnea due to multiple lung metastases, pneumonia and tumor embolism in the pulmonary and coronary arteries.


Diencephalic GABAergic neurons in vitro respond to prolactin with a rapid increase in intracellular free calcium. In order to analyze the feedback action of prolactin (PRL) on the hypothalamus on the cellular level, we used primary cultures of rat embryonic diencephalon to measure the calcium response of individual neurons to PRL by means of fast fluorescence photometry. The cultures were subsequently stained with antibodies against the neuronal marker MAP-2, glutamic acid decarboxylase (GAD) or tyrosine hydroxylase (TH). PRL caused a rapid rise of intracellular free Ca2+ in a specific type of GABAergic neuron characterized by a spindle-shaped bipolar morphology and immunoreactivity to MAP-2 and GAD but not to TH. It is concluded that a subpopulation of hypothalamic GABAergic but not dopaminergic neurons react to PRL with a rapid increase in intracellular free Ca2+. These data are compatible with the assumption of a rapid negative feedback regulation of the secretion of PRL from the pituitary mediated by tuberoinfundibular GABAergic neurons.


Centrally administered insulin-like growth factor II fails to alter pulsatile growth hormone secretion or food intake. Insulin-like growth factor II (IGF-II) peptide, mRNA, and receptors are widely distributed in the central nervous system, yet the physiological role of IGF-II in brain remains largely unknown. In the present study, we examined the in vivo effects of central administration of recombinant human IGF-II on pulsatile GH secretion and food intake. The IGF-II preparation used was shown to stimulate 3H-thymidine incorporation in MG-63 human osteosarcoma cells in vitro. Free-moving adult male rats bearing chronic intracerebroventricular (icv) and intracardiac venous cannulae were icv administered 10 microliters of either IGF-II (in doses of 300 ng and 1 microgram) or the vehicle solution, and blood samples were obtained every 15 min for 6 h. Vehicle-injected control animals exhibited the typical pulsatile pattern of GH secretion with most peak GH values greater than 100 ng/ml and trough levels less than 1.2 ng/ml. Central administration of IGF-II, at both doses, failed to alter the spontaneous 6-hour GH secretory profile; there were no significant differences in either GH peak amplitude, GH trough level, GH interpeak interval, or mean 6-hour plasma GH level, compared to vehicle-injected controls. There was also no effect of icv administered IGF-II on mean plasma glucose or insulin levels. Compared to vehicle-injected control rats, the icv injection of IGF-II (at doses of 300 ng and 1 microgram) did not significantly alter 24-h food intake or body weight gain in normal feeding rats.(ABSTRACT TRUNCATED AT 250 WORDS)


Angiotensin II receptor development in the bed nucleus of the stria terminalis and other perihypothalamic brain regions of the female and male rat. Brain angiotensin II (AII) receptors play a role in the regulation of luteinizing hormone release. This action is thought to involve luteinizing hormone-releasing hormone containing neurons in the preoptic-anterior hypothalamic (POAH) area of the brain. Previous studies have demonstrated a discrete locus of AII receptor binding sites and responsiveness within the POAH to microinjections of AII in the adult female rat, corresponding to the ventral portion of the bed nucleus of the stria terminalis (BSTV). To further characterize the age- and sex-dependent AII receptor binding in the BSTV and other brain regions, in vitro receptor autoradiography using 125I-sarcosine1, isoleucine8 AII (125I-SI AII) was performed on 2-, 4- and 10-week-old female and male rat brains. Rats of both sexes displayed an age-dependent increase in 125I-SI AII binding in the BSTV, as well as in the suprachiasmatic nucleus (SCh). There was no detectable difference in binding within the BSTV between the female and male of any age group. Prepubertal ovariectomy did not impair the expression of 125I-SI AII binding in the BSTV or the SCh of adult female rats. The developmental expression of AII receptors in the BSTV and SCh may therefore play a role in sexual maturation and regulation of sexual function in the rat.


Pro-opiomelanocortin-containing neurons in rat median eminence. A significant number of pro-opiomelanocortin (POMC)-containing cells were detected in the rat median eminence (ME) by immunocytochemistry using an antibody raised against a synthetic peptide corresponding to the cleavage site between adrenocorticotropin and beta-lipotropin moieties. Distribution of POMC-positive cells was restricted to the internal zone of the anterior parts of the ME. Such cells were observed as early as the 14th day of gestation in the area of the primitive ME, long before glial fibrillary acidic protein-positive cells appeared postnatally in this structure. Dissociated cell cultures obtained from the ME of 1-day-old rats produced cells immunoreactive for neurofilaments and the POMC moiety. Such cells displayed a neuronal morphology: the cell body was oval (13-18 microns) with long and fine beaded fibers. These findings clearly demonstrate the early appearance of POMC neurons in the developmental ME, a target organ of the hypothalamic infundibular neurons.


Stimulation of prolactin secretion from rat pituitary by luteinizing hormone-releasing hormone: evidence against mediation by angiotensin II acting through a (Sar1-Ala8)-angiotensin II-sensitive receptor. In aggregate cell cultures of 15- to 20-day-old rat pituitary maintained in serum-free medium, luteinizing hormone-releasing hormone (LHRH) (10 nM) stimulated prolactin (PRL) release, confirming our previous results and those of others with serum-supplemented medium. Since angiotensin II (AII) stimulates PRL release and a renin-angiotensin system is expressed in gonadotrophs, LHRH stimulation of PRL release might be mediated by AII. To evaluate this hypothesis, the influence of (Sar1,Ala8)AII and (Sar1,Ile8)AII two peptide AII receptor antagonists, of DUP753, a nonpeptide and stable AII receptor antagonist, of a converting enzyme inhibitor, and of angiotensinogen on LHRH-induced PRL release was tested in various in vitro conditions of 15- to 20-day-old female rat pituitary. In aggregates maintained in serum-free medium with or without dexamethasone (DEX) and triiodothyronine (T3), or maintained in serum-supplemented medium, the effect of LHRH on PRL release was not affected by (Sar1Ala8)AII (0.1 microM), (Sar1,Ile8)AII (10 microM) or DUP753 (10 microM). Only a high dose (10 microM) of (Sar1,Ala8)AII attenuated the LHRH-induced PRL release. The latter attenuation was seen only with aggregates cultured in the DEX/T3 medium and not with aggregates cultured in the presence of serum. A dose of 1 or 10 nM (Sar1,Ala8)AII also failed to block the effect of LHRH used at 1 nM. In contrast, (Sar1,Ala8)AII dose dependently as well as DUP753 (10 microM) abolished the AII-induced PRL release. (Sar1,Ala8)AII also failed to affect the LHRH-induced PRL release in pituitary cell aggregates from 6-week-old male rats. However, in aggregates from both immature and 6-week-old rats, (Sar1,Ala8)AII provoked a small and statistically significant attenuation of the LHRH-induced PRL release when a 100 nM dose of LHRH was used. In freshly isolated hemipituitaries from 5-day-old rats, (Sar1,Ala8)AII (1 or 10 microM) did not affect the LHRH- (10 nM) induced PRL release. In single cells obtained by redispersion of aggregates and mounted in a Biogel P2 column, LHRH still stimulated PRL release. Again this effect could not be blocked by DUP753. Treatment of aggregate cell cultures with the angiotensin-converting enzyme inhibitor captopril or with angiotensinogen did not alter the LHRH-induced PRL release. It is concluded that AII is not the paracrine factor mediating the effect of LHRH at low nanomolar doses on PRL release, at least not through the classical AII receptor. The involvement of AII acting on a non-(Sar1,Ala8)AII-sensitive receptor cannot be excluded and warrants further investigation.


Opiate stimulation of prolactin secretion is reversed by ovarian hormone treatment. Previous studies have indicated that during the estradiol- and progesterone (P4)-induced surge in luteinizing hormone (LH), the effects of opiates on behavioral, autonomic and neuroendocrine functions are altered. In the present study, we further evaluated the apparent universality of alterations in opiate-mediated function during the LH surge by investigating the effects of morphine sulfate (MS) on prolactin (PRL) secretion during both the estradiol benzoate (EB) and the EB + P4-induced LH surges. All doses of MS tested (0.5, 2.0 and 5.0 mg/kg) resulted in significant increases in PRL secretion in nonestrogen-treated animals which did not show LH/PRL surges. During the LH/PRL surge induced by EB/P4 treatment, MS caused no change in the PRL secretion, while in EB/oil treated animals, a paradoxical and dose-dependent decrease in PRL secretion was observed. The suppression of PRL was 52, 68 and 80% of baseline respectively for the 3 doses of MS. Evaluation of the time dependence of MS on PRL secretion showed that the paradoxical suppression in EB/oil-treated animals was seen only during the LH/PRL surge, occurring at 17.30 h (7.5 h post P4 injection), and not before (12.30 h) or after (23.00 h) the steroid-induced LH/PRL surge. Finally, we assessed the role of pituitary dopamine receptors on the phenomenon of MS-induced PRL suppression in EB/oil rats. Domperidone (1mg/kg), a peripherally active D2 receptor antagonist, administered prior to the morphine challenge, attenuated the opiate-induced PRL suppression in EB/oil-treated animals suggesting that a dopaminergic mechanism is involved in this paradoxical response to morphine.(ABSTRACT TRUNCATED AT 250 WORDS)


Alterations in brain atrial natriuretic polypeptide levels in hypophysectomized rats. Twelve days after hypophysectomy depleted atrial natriuretic polypeptide (ANP) concentrations were measured in the plasma and in 8 of 18 microdissected brain nuclei of rats. Reduced ANP levels were found in brain structures (subfornical organ, organum vasculosum laminae terminalis, preoptic and hypothalamic periventricular nuclei, paraventricular nucleus, lateral hypothalamic area), which are directly involved in the central regulations of salt and fluid homeostasis, as well as in the medial amygdaloid nucleus and the locus ceruleus. ANP concentrations in the median eminence, medial preoptic and arcuate nuclei did not alter by hypophysectomy. Elevated ANP concentrations were measured only in the supraoptic nucleus of hypophysectomized rats.


Effects of sex and age on pyridostigmine potentiation of growth hormone-releasing hormone-induced growth hormone release. Previous studies have shown that pyridostigmine (PD) is capable of increasing the growth hormone (GH) response to GH-releasing hormone (GHRH) in young healthy subjects. In order to investigate the influence of age and sex on the PD potentiation of GHRH-induced GH release, we have studied the GH response to GHRH (50 micrograms i.v.) 1 h after oral administration of placebo or PD (60 mg) in 8 young healthy men (aged 19-28 years) and 8 age-matched young women (aged 18-25 years) during the follicular phase of the menstrual cycle, as well as in 8 postmenopausal women (aged 57-62 years) and 8 age-matched elderly men (aged 56-64 years). In the same subjects the effect of PD alone (60 mg p.o.) was also studied. Furthermore, in 6 postmenopausal women and 6 elderly men, the effect of a 30-mg PD oral dose on GH secretion and GH response to GHRH was evaluated with a similar protocol. The GH responses (mean +/- SE) to GHRH + placebo were similar in young men (peak 20.1 +/- 2 ng/ml, AUC 1,250 +/- 113 ng/ml/min) and women (peak 29.3 +/- 2.3 ng/ml, AUC 1,769 +/- 305 ng/ml/min). PD 60 mg was capable of significantly increasing the GH response to GHRH in young men (peak 43.5 +/- 5.1 ng/ml, AUC 3,734 +/- 472 ng/ml/min, p less than 0.005) but not in women (peak 39 +/- 2.3 ng/ml, AUC 2,479 +/- 205 ng/ml/min).(ABSTRACT TRUNCATED AT 250 WORDS)


Inhibin/activin subunits are costored with FSH and LH in secretory granules of the rat anterior pituitary gland. We recently reported that pituitary gonadotropes, major targets of circulating inhibins and activins, are also capable of synthesizing the inhibin (I) alpha- and inhibin/activin (I/A) beta B-subunits. In the present study, we examined the subcellular distribution of these subunits, with special attention given to determinating the extent to which they might be colocalized with the gonadotropins in secretory granules. Pituitaries from adult male rats were cryofixed, molecular distillation-dried, and resin-embedded. Immunogold staining methods were used to examine concurrently the distributions of an I/A subunit and FSH or LH. I/A subunits were detected only in cells that also labeled positively for a gonadotropin, and, in contrast to the gonadotropins, were sequestered almost exclusively within secretory granules. The I alpha-subunit colocalized with FSH in 31%, and with LH in 36%, of all positively stained granules. The I/A beta B-subunit was found with FSH or LH in about 25% of the granules. Approximately 52-69% of the granules contained FSH or LH alone; 7-18% were positive only for an I/A subunit, and this varied as a function of the particular gonadotropin with which costaining was carried out. Dual staining for the I alpha- and the I/A beta B-subunits indicated that at least 35% of all immunolabeled granules showed positive signals for both subunits. Coupled with methodological considerations to indicate that these estimates of the extent of colocalization are likely to be conservative, these data suggest that inhibin and activin are characteristically copackaged, and presumably coreleased, with the gonadotropins.


Characterization of prolactin receptors in human choroid plexus. The specific binding of 125I-human prolactin (hPRL) was studied in different areas of the human brain. Particularly high binding affinity of the hormone was found in the choroid plexus and this tissue was therefore selected for further studies. The hippocampus, the hypothalamus and the pituitary were among other regions containing prolactin-binding sites. In the choroid plexus the amount of PRL receptors was significantly higher in females than in males and was also found in both sexes to decrease with age. The binding affinity of 125I-hPRL to choroid plexus was 3.0 x 10(9) M-1 and the binding capacity was 10.3 pmol per mg protein. Following solubilization with Triton X-100 the PRL receptor fraction retained its hormone-binding properties and upon molecular sieve chromatography it behaved as a protein with a molecular mass of approximately 250,000. Cross-linking of 125I-hPRL to receptors from choroid plexus and subsequent sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis indicated a major hormone-binding unit of M(r) 44,000. This value is about 7,000 smaller than that reported earlier by us for the growth hormone receptors from the same tissue, following cross-linking to 125I-human growth hormone (hGH). By affinity column chromatography a complete separation of the hPRL and hGH binding units was achieved. It was thus shown that in choroid plexus the binding sites for GH and PRL occur as discrete entities.


Abolition of prolactin surge induced by ovarian steroid hormones in the lactating rat. There are data indicating that stress-induced prolactin (PRL) release is blunted in the lactating rat like the release of other stress-associated hormones. In this experiment, the PRL release evoked by administration of estrogen, which is another principal stimulus for PRL release, was examined in ovariectomized lactating rats 8-15 days after delivery. Estradiol benzoate (EB, 20 micrograms) injections into ovariectomized nonlactating rats induced a PRL surge starting between 13:00 and 15:00 h with a peak at 17:00 h 2 days after the treatment, whereas the EB-induced PRL surge was absent in ovariectomized lactating rats separated from their pups at 09:00 h on the day or in mothers without separation from their pups. Injection of either thyrotropin-releasing hormone (TRH; 10 micrograms/kg) or pimozide (0.5 mg/kg) elevated serum PRL concentrations similarly in lactating and nonlactating rats when examined just before the beginning of the expected estrogen-induced PRL surge. Thus, the main cause for the reduced PRL response to estrogen in lactating rats seems not to be in the pituitary gland but in the brain. Progesterone, which is known to induce a PRL surge in ovariectomized estrogen-primed rats by acting on the mediobasal hypothalamus, also failed to evoke a PRL surge in lactating rats. Recovery from the inhibitory influence of suckling on PRL response to EB followed a time course similar to that observed in response to immobilization stress or to morphine injection; estrogen-induced PRL surge started to recover at 6 days and was almost fully recovered 8 days after weaning.(ABSTRACT TRUNCATED AT 250 WORDS)


Time-dependent changes in beta-endorphin-stimulated prolactin release during pregnancy. Endogenous opioid peptides (EOPs) stimulate prolactin (PRL) release in various physiological conditions in the rat. Moreover, EOPs are essential in initiating and maintaining the nocturnal PRL surges that occur over the first half of gestation in the rat. The purpose of this study was to investigate the potential role of the opioid beta-endorphin (beta-End) in mediating the nocturnal PRL surges. Day 8 pregnant rats received an infusion of 2.5, 10, 25 or 100 ng/microliters/min beta-End intracerebroventricularly (i.c.v.) for 15 min at 12.00 h, an intersurge period. PRL increased in a dose-dependent manner and from this, the largest dose was used in subsequent experiments to ensure maximal opioid receptor stimulation. The next experiment defined the temporal sensitivity of the neuroendocrine system regulating PRL surges to exogenous beta-End. Day 8 pregnant rats showed dramatic PRL responses to beta-End when given at midnight (presurge) or 12.00 h (intersurge), but greatly attenuated responses at 02.00 h (early surge) and 04.00 h (late surge). Animals treated at 06.00 h (postsurge) showed recovered responsiveness to beta-End. To determine what may account for the significantly lower PRL increases to beta-End during the surge, day 8 pregnant rats received 100 mg/microliters/min beta-End i.c.v. for 15 min at 10.00 h, and then again at 12.00 h. All animals showed PRL increases greater than 1,140 ng/ml at 10.00 h, but the subsequent response to beta-End at 12.00 h was reduced by 70%. In another experiment, beta-End was infused at midnight and the animals were monitored for a subsequent endogenous nocturnal PRL surge.(ABSTRACT TRUNCATED AT 250 WORDS)


Central oxytocin mediates inhibition of sodium appetite by naloxone in hypovolemic rats. Pituitary oxytocin (OT) secretion is inversely related to saline consumption in several experimental models of sodium appetite in rats. Because systemic OT administration does not inhibit sodium appetite, release of OT as a neurotransmitter within the brain, coincident with its secretion from the pituitary, may be related to inhibition of sodium ingestion. The present studies evaluated this possibility by increasing brain OT concentrations both exogenously and endogenously in rats with hypovolemia produced by subcutaneous administration of polyethylene glycol (PEG) solution. Intracerebroventricular (i.c.v.) administration of OT completely abolished intake of 0.5 M NaCl in PEG-treated hypovolemic rats, but did not significantly affect PEG-stimulated water intakes. Endogenous OT secretion was stimulated by systemic treatment with naloxone, which has been shown to increase peripheral and central OT levels. In both one-bottle (0.5 M NaCl) and two-bottle (water and 0.5 M NaCl) drinking tests, intraperitoneal naloxone completely abolished sodium appetite in association with markedly increased pituitary secretion of OT. This inhibition of sodium appetite could be prevented by i.c.v. pretreatment with a specific OT-receptor antagonist, although the antagonist by itself did not affect PEG-stimulated sodium intake. These findings therefore support previous reports which have found that sodium appetite in rats is inhibited by treatments that elicit pituitary release of OT, and provide more direct evidence that brain OT is causally involved in the inhibition of sodium appetite stimulated by such treatments in rats.


Exogenous androgen does not alter hypothalamic proopiomelanocortin gene transcript levels in the sexually immature male rat. To investigate possible mechanisms whereby the augmentation of hypothalamic proopiomelanocortin (POMC) messenger ribonucleic acid (mRNA) levels occurs with pubertal development, we employed the techniques of testosterone administration and in situ hybridization histochemistry in sexually immature male rats. Six animals from each of the following groups were studied: (1) untreated controls (CTRL); (2) empty capsule (SHAM); (3) testosterone capsule (TEST), and (4) untreated adults (ADLT). Capsules were implanted at 21 days of age. Groups 1-3 were sacrificed at 35 days of life; group 4 at 55 days. Ventral prostate and seminal vesicle weights were obtained to assess the biologic effect of testosterone. Hybridizations were performed on coronal brain slices through the region of the arcuate nucleus using a 35S-labeled oligonucleotide probe complementary to a 30-base sequence within POMC mRNA. Anatomically matched tissue sections (11 per animal, from the retrochiasmatic region rostrally to the premammillary nucleus caudally) were exposed to x-ray film, followed by densitometric analysis. The mean serum testosterone concentration of the TEST group was significantly greater than that of the ADLT animals; values for the CTRL and SHAM rats were undetectable. The accessory sex organ weights of the ADLT animals were greater than those of the TEST rats; both values were greater than those of the CTRL and SHAM groups which were indistinguishable. Increased levels of hypothalamic POMC mRNA were observed in the male rat after pubertal development.(ABSTRACT TRUNCATED AT 250 WORDS)


Differential hypothalamic arginine vasopressin response to glucocorticoid receptor antagonism in lean and obese Zucker rats. The obese Zucker rat (fa/fa) is an animal model for genetic obesity characterized by hyperphagia, hyperinsulinemia, and severe insulin resistance in peripheral tissues. Adrenal steroids seem to play an important role in the onset of fatty syndrome in these animals. There is strong evidence of abnormal regulation of the hypothalamic-pituitary-adrenal axis in obese Zucker rats. Considering the physiological function of arginine vasopressin (AVP) as an adrenocorticotropic hormone secretagogue, the present study was carried out to investigate the role of glucocorticoids in the control of hypothalamic AVP systems in lean and obese Zucker rats. In the first experiment, mifepristone (RU 38486), a glucocorticoid receptor antagonist, was administered for 4 days (10 mg/kg orally twice daily), and the expression of AVP mRNA in hypothalamic paraventricular and supraoptic nuclei was measured using in situ hybridization, and the concentrations of AVP in the pituitary gland and in the median eminence were quantified. Plasma corticosterone levels were also analyzed. Mifepristone treatment resulted in a threefold increase in plasma corticosterone levels in lean Zucker rats, but it did not change corticosterone secretion in obese animals. Mifepristone treatment decreased AVP mRNA levels in lean animals in the supraoptic nuclei, while in obese animals the AVP mRNA content was increased in the paraventricular nuclei. Mifepristone treatment significantly increased the concentration of AVP in the median eminence in lean rats and decreased it in obese animals. Mifepristone treatment did not change concentrations of AVP in the pituitary gland. In the second experiment, mifepristone was given for 4 days (10 mg/kg orally twice daily), and its effects on 24-hour food intake and plasma AVP concentrations were measured.(ABSTRACT TRUNCATED AT 250 WORDS)


A method to assess the development of muscle power in preterms after term age. The purpose of this paper is to report a detailed description of an instrument for evaluating the development of active and passive muscle power in preterms beyond term age. The instrument is constructed on a basis of age-specific items that assess these two components of muscle power and on the assumption that a persistent discrepancy between them serves to detect those preterms at most risk for disturbances in motor development. The application of the instrument is illustrated by reporting the individual trajectories of five case studies without any serious medical complications. It is concluded that if a marked discrepancy between active and passive power persists beyond the corrected age of 3 months, then this may be a sign of underlying pathology which will eventuate in abnormal postural outcomes and thereby disturbances in the control and coordination of movement. Having now provided a detailed description of how this instrument should be applied in postterm follow-up of preterm infants, we are currently examining its sensitivity and specificity on a much larger sample of similar subjects.


Battered child syndrome: cerebral ultrasound and CT findings after vigorous shaking. Child abuse by whiplash-shaking can lead to severe cerebral damage, neurological defects and mental retardation. Cerebral damage has been found with and without external evidence of head injury. We report the sonographic findings in two children after traumatization due to repetitive vigorous whiplash shaking. Cerebral sonography revealed cerebral edema at admission or within 48 hours thereafter. Follow-up studies demonstrated development of marked brain atrophy in both cases. The sonographic findings were confirmed by cranial computerized tomography. Doppler sonography was used to monitor cerebral perfusion by measuring intracranial blood flow. The clinical history of the patients demonstrates that cerebral sonography in combination with Doppler sonography not only serves as a diagnostic tool but also allows adjustment of therapy to the actual clinical status of the patient.


The natural history of acute disseminated leukoencephalitis. A serial magnetic resonance imaging study. The natural history of acute disseminated (leuko)encephalitis (ADE) in a 3-year-old girl who did not receive steroid therapy is reported. Serial MR studies disclosed: 1) white matter lesions resolved spontaneously, though very slowly, 2) active disease persisted for around three months and coincided with the onset of new subcortical lesions. These subcortical lesions were associated with hyperactivity, suggesting a possible etiologic correlation.


Acute encephalomyelitis: extending the neurological manifestations of acute rheumatic fever? The clinical course of a five-year-old boy who developed meningeal irritation, encephalomyelitis, and optic neuritis four weeks after Streptococcus pyogenes pharyngitis is detailed. The patient responded to therapy with corticosteroids and recovered fully. Review of the literature reveals that a wide range of neurological disorders have been described in association with rheumatic fever. We suggest that disseminated encephalomyelitis in this child most probably was related to the streptococcal infection and that the spectrum of post-infectious neurological disorders associated with Streptococcus pyogenes may be broader than is currently appreciated.


Kearns-Sayre syndrome with sideroblastic anemia: molecular investigations. The progressive syndrome of Kearns-Sayre has been studied at the clinical, biochemical and genetic levels in a patient. Clinical arguments suggest an evolution from Pearson's disease to Kearns-Sayre syndrome. The respiratory chain activities were low, and Southern blot analysis, together with gene sequencing, showed a heteroplasmic deletion of 7767 base pairs in a significant proportion of the mitochondrial DNA in different tissues. Protein synthesis studies on lymphoblasts did not reveal any translation of the new reading frame created by the deletion, although the corresponding deleted mitochondrial DNA sequence is transcribed.


Dominantly inherited hypoplasia of the vermis. A mother and her two daughters with presumed dominantly inherited, non-progressive, congenital cerebellar ataxia are reported. Magnetic resonance imaging revealed vermal hypoplasia in one case, and generalized hypoplasia of the cerebellum, predominating at the vermal level, in another case. These patients are identical to those previously published, except for a slowly progressive improvement of motor abilities observed during evolution.


The epidemiology of progressive encephalopathies in childhood. I. Live birth prevalence in west Sweden. Progressive encephalopathies in the west Swedish region were investigated in a population-based study. Cases were allocated to one of five main groups: 1) disorders covered by impairments in subcellular organelles, 2) disorders covered by deficiencies in the intermediate metabolism, 3) biochemically undefined neurometabolic disorders, 4) neuroimmunological disorders and 5) a symptom-orientated miscellaneous group. Progressive encephalopathies were identified in 76 of 132,138 children born alive in the study area during the 16-year-period 1970-85. This gives a live birth prevalence of 0.58 per 1000. In Sweden the size of the group corresponds to that of neural tube defects and that of congenital hydrocephalus. However, a vast number of different disorders are represented.


Cerebral occipital calcifications in celiac disease. Bilateral occipital calcifications, occurring in celiac disease, are factors coming under a particular cerebral syndrome, which also includes epilepsy, migraine-like headache, visual troubles and mental deterioration. They seem to arise from hypofolatemia following gluten-induced enteropathy.


Sudden loss of hearing and vestibular function, muscular weakness, and multiple white matter lesions in preschool children. Sudden cochlear hearing loss, occurring successively or simultaneously in both ears, was observed in four unrelated preschool children. Vestibular testing could be carried out in three patients and showed complete bilateral loss of function. All patients had a mildly retarded motor development due to nonprogressive muscular weakness. On MR imaging all patients showed multiple periventricular and subcortical white matter lesions. These lesions were not clearly progressive in one patient examined repeatedly over 6 years. Virological, bacteriological, immunological, and metabolic examinations were normal in all patients. Muscle biopsy showed morphologically abnormal mitochondria in two and lipid storage in one patient. No indications have been found for a disturbed functioning of the muscle mitochondria. The identical pattern and course of the disease in these patients suggests a new nosological entity, the aetiology of which can only speculatively be attributed to a vascular process associated with a mitochondriopathy.


Central action of 5-HT3 receptor ligands in the regulation of sleep-wakefulness and raphe neuronal activity in the rat. Anxiolytic drugs, such as the benzodiazepines and the azapirones (ipsapirone, gepirone, buspirone), are well known to affect states of vigilance and to decrease the firing rate of serotoninergic neurones within the dorsal raphe nucleus in rats. In order to examine whether the newly developed 5-HT3 antagonists with potential anxiolytic properties act through similar mechanisms, the effects of several of such antagonists: MDL 72222, ICS 205-930, ondansetron and/or zacopride on both sleep-wakefulness and the discharge of serotoninergic neurones within the dorsal raphe nucleus were investigated in rats. When tested in a wide range of doses (0.05-10 mg/kg, i.p.), none of these drugs significantly affected the states of vigilance, except ondansetron, at 0.1 mg/kg, which increased paradoxical sleep for the first 2 hr after administration and MDL 72222, at 10 mg/kg, which reduced both paradoxical and slow wave sleep and increased wakefulness for the same initial period after treatment. In vivo, in chloral hydrate anaesthetized rats, as well as in vitro, in slices of brain stem, none of the 5-HT3 antagonists tested affected the firing rate of serotoninergic neurones. Similarly, no change in the electrical activity of serotoninergic neurones could be evoked in vitro by superfusion of the tissue with the 5-HT3 agonists, phenylbiguanide (10 microM) and 2-methyl-5-HT (1 microM). At a larger concentration (10 microM), the latter compound reduced the neuronal discharge probably through the stimulation of somatodendritic 5-HT1A autoreceptors since this effect, as that of ipsapirone, could be prevented by 10 microM l-propranolol. Comparison of these data with those obtained with benzodiazepines and 5-HT1A agonists of the azapirone series, supports the concept that different mechanisms are responsible for the anxiolytic-like properties of 5-HT3 agonists, compared to those of other anxiolytic drugs.


A post-synaptic depressant modulatory action of 5-hydroxytryptamine on excitatory amino acid responses in rat entorhinal cortex in vitro. The depressant action of 5-hydroxytryptamine (5-HT) in slices of entorhinal cortex of the rat has been examined. When single intracellular recordings of pyramidal cells in layers II/III of entorhinal cortex of the rat were made and drugs applied by iontophoresis, 5-HT evoked virtually no changes in passive membrane properties of the majority of cells studied. When short regular pulses of glutamate were applied to the neurones and 5-HT was ejected in addition, the depolarisations caused by glutamate were considerably reduced in amplitude. This attenuation persisted in medium containing cadmium chloride (200 microM) to block synaptic transmission. The magnitude of the response to 5-HT was dependent on the ejection current and this effect could not be mimicked by increasing ejections of Na+ or H+ ions. 5-Hydroxytryptamine had no apparent action on neuronal responses to iontophoretically ejected gamma-amino butyric acid (GABA). In later studies, the action of 5-HT was examined on epileptiform discharges, evoked in the presence of the GABA antagonist, bicuculline, in the same group of cells. Droplet application of 5-HT into the recording chamber, or perfusion of 10 microM 5-HT regularly attenuated the length of epileptiform bursts but, at this concentration, had no discernible effect on the resting membrane potential or membrane input resistance. The effect of 5-HT on the release of glutamate from slices of entorhinal cortex has also been examined using a fluorometric enzyme assay. Concentrations of 5-HT as large as 30 microM had no effect on the release of endogenous glutamate in these experiments.(ABSTRACT TRUNCATED AT 250 WORDS)


The putative 5-HT1A antagonist BMY 7378 blocks 8-OH-DPAT-induced changes in local cerebral glucose utilization in the conscious rat. It has previously been shown that the 5-HT1A agonist, 8-OH-DPAT, caused discrete changes in cerebral glucose utilization in the rat, as assessed by quantitative 2-deoxyglucose autoradiography. Here, the effect of the putative 5-HT1A antagonist, BMY 7378, on regional cerebral glucose utilization was examined, when injected alone and in rats treated with 8-OH-DPAT. In control rats, BMY 7378 (5 mg/kg, s.c.) markedly increased glucose utilization in the lateral habenular nucleus and moderately reduced glucose utilization in the hippocampal formation. Pretreatment with BMY 7378 (5 mg/kg) significantly attenuated the reductions in glucose utilization in the hippocampus, entorhinal, piriform and cingulate cortex, induced by 8-OH-DPAT (0.25 mg/kg). The 8-OH-DPAT-induced increase in glucose utilization in the copula pyramis, that is putatively associated with the appearance of the 5-HT behavioural syndrome, was also blocked by BMY 7378, as was the behavioural syndrome. In summary, BMY 7378 produced few of the discrete changes in cerebral glucose utilization that are seen with 8-OH-DPAT. However, many of the changes induced by 8-OH-DPAT were reversed by BMY 7378. These data are consistent with the hypothesis that the effects of 8-OH-DPAT on regional cerebral glucose utilization are mediated by 5-HT1A receptors.


Attenuation of defensive analgesia in male mice by 5-HT3 receptor antagonists, ICS 205-930, MDL 72222, MDL 73147EF and MDL 72699. Recent studies have shown that non-opioid defensive analgesia in male mice is potently inhibited by the 5-HT3 receptor antagonist, ondansetron. The present series of experiments was conducted to further explore the involvement of 5-HT3 receptor mechanisms in this particular form of adaptive inhibition of pain. The drug ICS 205-930 significantly attenuated the reaction at 1.25-2.5 micrograms/kg, with smaller and larger doses being ineffective. Both MDL 72222 and MDL 73147EF produced flat dose-response curves, with significant inhibition of defensive analgesia at minimum effective doses of less than or equal to 10 and 300 micrograms/kg, respectively. Although MDL 72699, the quaternary salt of MDL 72222, also inhibited the reaction, this effect was seen at comparatively large doses (0.5-1.0 mg/kg) only. None of the compounds tested had significant intrinsic effects of tail-flick latencies, over the dose ranges tested. These findings indicate that 5-HT3 receptor mechanisms may have an important modulatory role in certain forms of "stress" analgesia. Data are discussed in relation to the consistent profile of partial inhibition produced by 5-HT3 receptor antagonists in this model.


5-HT3 receptors in NG108-15 neuroblastoma x glioma cells: effect of the novel agonist 1-(m-chlorophenyl)-biguanide. The effect of the novel agonist, 1-(m-chlorophenyl)-biguanide (mCPBG) was examined on 5-HT3 receptors in NG108-15 mouse neuroblastoma x rat glioma hybrid cells, using whole-cell voltage-clamp and radioligand binding on intact cells. Electrophysiological studies showed that mCPBG is a partial agonist, with an EC50 of 3.1 microM. Displacement of the selective 5-HT3 receptor antagonist [3H]GR65630 by mCPBG revealed a Ki of 14.2 nM. The study suggests that mCPBG may have a high affinity for desensitized 5-HT3 receptors and also revealed some differences between 5-HT3 receptors in NG108-15 and N1E-115 cells.


N-methyl-D-aspartate receptors in the retina: 3-[(+/-)-2-carboxypiperazin- 4-yl]-propyl-1-phosphonic acid (CPP) binding studies. 3-[(RS)-2-Carboxypiperazin-4-yl]-propyl-1-phosphonic acid (CPP) has been known for some years as one of the most selective antagonists at the N-methyl-D-aspartate (NMDA) receptor in the brain. The characteristics of the binding of [3H]CPP to chick retinal membranes were studied from the biochemical and pharmacological point of view. Magnesium induced a dose-dependent increase in the binding of [3H]CPP (EC50 = 4 microM). In the absence of this ion, a single population of receptors was found (KB = 431 nM; Bmax = 9.5 pmol/mg protein), which was not modified by the addition of 1 mM MgCl2. An additional, high affinity site (KB = 59 nM; Bmax = 2.2 pmol/mg protein) became evident in the latter condition. Saturation curves of the binding of [3H]CPP, using 1 mM AMPA [(RS)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate] or L-aspartate, as displacers in the presence of Mg2+, showed a KB = 200 and 395 nM, respectively. The relative potency of some analogues of excitatory amino acids, for displacing bound CPP in the absence of Mg2+, was AMPA = APH greater than L-glutamate = CPP; Mg2+ significantly increased the potency of AMPA, APH and L-glutamate. These results showed that CPP bound to high affinity (Mg(2+)-dependent) and low affinity sites and that AMPA and L-aspartate compete with this compound only at the low affinity sites. These findings suggest that either the binding of CPP in the retina shows different properties from those described in the brain or alternatively, that AMPA is not as specific for the quisqualate receptor in this organ.


Antidiuretic effects of purinoceptor agonists injected into the hypothalamic paraventricular nucleus of water-loaded, ethanol-anesthetized rats. The effects of injection of various purinoceptor agonists into the hypothalamic paraventricular nucleus in water-loaded and ethanol-anesthetized rats were investigated. Adenosine triphosphate (ATP), beta,gamma-methyleneadenosine 5'-triphosphate (AMP-PCP) and beta,gamma-imidoadenosine 5'-triphosphate (AMP-PNP) potently decreased the outflow of urine in a time- and dose-dependent manner. The ED50 values were approx 70 and 37 nmol for ATP and AMP-PCP, respectively. Adenosine diphosphate (ADP), AMP and adenosine reduced the outflow of urine much less than ATP. Adenosine triphosphate induced concomitant increases in the osmotic pressure of the urine and in the level of arginine-vasopressin (AVP) in plasma. The antidiuretic effect of ATP was blocked by prior injection of quinidine (a P2-purinoceptor antagonist) into the paraventricular nucleus, but not by the prior injection of theophylline (a P1-purinoceptor antagonist). The effect of ATP was also blocked by intravenous injection of an AVP(V1V2)-receptor antagonist, d(CH2)5-D-Tyr(Et)VAVP. The results suggest that ATP injected into the paraventricular nucleus may stimulate a purinoceptor, releasing AVP and inducing the antidiuretic effect through renal AVP(V2) receptors.


Oxytocin modulates behavioural adaptation to repeated treatment with cocaine in rats. Behavioural adaptation to and the effects of the neurohypophyseal peptide, oxytocin, on repeated treatment with cocaine were investigated in rats. The content of immunoreactive oxytocin in the plasma, hypothalamus and different limbic structures in the brain were also studied after treatment with cocaine, identical to that used in the behavioural experiment. Repeated administration of cocaine (7.5 mg/kg, s.c.) produced a behavioural tolerance to the stereotyped sniffing-inducing effect of the challenge doses (1.875, 3.75 and 7.5 mg/kg, s.c.) of cocaine on the fifth day, which was demonstrated by parallel shifting of the dose-response and time-effect curves of the test doses of cocaine. The development of tolerance was inhibited by pretreatment with oxytocin (0.05 micrograms, (s.c.), administered before each daily injection of cocaine. A smaller dose of oxytocin (0.005 micrograms, s.c.) had no effect in this model. A decreased amount of immunoreactive oxytocin was detected in the plasma, in the hypothalamus and in the hippocampus, after repeated treatment with cocaine. Replacement of oxytocin by local injection (100 pg) into the ventral hippocampus, before each daily administration of cocaine, prevented the development of tolerance to cocaine. These results suggest that endogenous oxytocin, localized in limbic-forebrain areas, may have an important regulatory role in the development of behavioural changes induced by the repeated administration of cocaine.


Phylogenetic tree analysis of G protein-coupled 5-HT receptors: implications for receptor nomenclature. The nomenclature system used to characterize 5-hydroxytryptamine receptor subtypes remains controversial. To date, the majority of nomenclature systems have been on the differential pharmacological properties of the receptors. However, the availability of molecular biological data allows for a nomenclature system based on the structural properties of the receptors. The evolutionary relationships between the known G protein-coupled 5-HT receptor subtypes were determined by a phylogenetic tree analysis. The data indicate that 2 major classes of G protein-coupled 5-HT receptors have evolved. Each of the 2 branches differentiate into additional 5-HT receptor subtypes. The most recent branching of 5-HT receptor subtypes occurs at the level of individual species. These data also indicate that the degree of structural similarity (e.g. 93% identify between human and rat 5-HT1B receptors) does not necessarily correlate with pharmacological similarity. Phylogenetic tree analysis allows for a nomenclature framework that can be easily expanded to incorporate additional 5-HT receptor subtypes that have yet to be identified.


(+/-)-1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane(DOI) and alpha-methyl-5-HT: 5-HT2 receptor agonistic action on phosphatidylinositol metabolism in the rat fronto-cingulate and entorhinal cortex. In the present study, the effects of 5-HT and two 5-HT1c/5-HT2 receptor agonists, (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and alpha-methyl-serotonin (alpha-Me-5-HT) on phosphoinositide hydrolysis were compared, to determine whether DOI and alpha-Me-5-HT were full agonists. Consistent with the results obtained from previous studies, both (+/-)-DOI and alpha-Me-5-HT stimulated turnover of phosphoinositide in a concentration-dependent manner. However, the response obtained with these 5-HT1c/5-HT2 receptor agonists was only 30-40% of that of 5-HT. The stimulation of hydrolysis of phosphoinositide, produced by both 5-HT2 receptor agonists, was potently antagonized by ritanserin (a 5-HT1c/5-HT2 receptor antagonist) and alpha-phenyl-1-(2-phenylethyl)-4-piperine methanol [(+)-MDL 11,939, a 5-HT2 receptor antagonist] but not by granisetron (BRL a 5-HT3 receptor antagonist), suggesting that the action of DOI and alpha-Me-5-HT was primarily mediated by 5-HT2 receptors. When the effect of increasing the concentration of 5-HT on turnover of phosphoinositide was measured in the presence of a 1 microM concentration of the 5-HT3 receptor antagonist granisetron, the response obtained was similar to the response produced by the 5-HT2 receptor agonists, DOI and alpha-Me-5-HT. These results confirm the previous finding that 5-HT stimulates hydrolysis of phosphoinositide by interacting with 5-HT1c/5-HT2 and 5-HT3 receptors. Moreover, they suggest that DOI and alpha-Me-5-HT are full agonists at the 5-HT2 receptor, coupled to hydrolysis of phosphoinositide in the cortex of the rat.


5-HT1-like receptor agonists enhance wakefulness. The effects of four 5-HT1-like receptor agonists (8-OH-DPAT, RU 24969, BEA 1654 and 5-carboxamidotryptamine) and some putative 5-HT1-like receptor antagonists on vigilance were examined in an attempt to clarify the role of 5-HT1-like receptors in the sleep-waking pattern of rats. Both 8-OH-DPAT (0.5-2.0 mg/kg, s.c.) and RU 24969 (0.5-2.0 mg/kg, s.c.) increased wakefulness and the latencies of slow wave and rapid eye movement (REM) sleep. The slow wave and REM sleep were correspondingly decreased or completely abolished. The two other 5-HT1-like receptor agonists had either a slight (BEA 1654, 1.0-5.0 mg/kg, s.c.) or no (5-carboxamidotryptamine, 0.5-2.0 mg/kg, s.c.) effect on sleep pattern. The arousal effect of 8-OH-DPAT was further potentiated in rats pretreated with reserpine (2.5 mg/kg, i.p.; 18 hr before 8-OH-DPAT). The non-selective 5-HT1-like and 5-HT2 receptor antagonist, methiothepin (2.0 mg/kg, i.p.) and the beta-adrenoceptor antagonist propranolol (16.0 mg/kg, s.c.), which is a putative antagonist at 5-HT1A and 5-HT1B receptor subtypes, significantly potentiated the arousal effect of RU 24969. The putative 5-HT1A and 5-HT1B receptor antagonist, cyanopinolol (4.0 mg/kg, s.c.), mixed 5-HT1A receptor agonist/antagonist MDL 72832 (1.0 mg/kg, s.c.) and the alpha 1-adrenoceptor antagonist prazosin (2.0 mg/kg) did not affect the vigilance, altered by RU 24969. These results suggest that the arousal effect of 5-HT1-like receptor agonists is probably not mediated by any of the subtypes of 5-HT1-like receptors or by an activation of a noradrenergic system.


Stimulatory and inhibitory effects of serotonergic hallucinogens on spinal mono- and polysynaptic reflex pathways in the rat. The effects of two 5-HT-related hallucinogens on rat spinal mono- and polysynaptic reflex pathways in the rat were investigated. 5-Methoxy-N,N-dimethyltryptamine (5-MeODMT, 1 and 100 micrograms/kg, i.v.), an indolealkylamine agent, produced a dose-dependent decrease in the monosynaptic reflex, whereas 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, 1-100 micrograms/kg), a phenylalkylamine agent, produced a dose-dependent increase in the monosynaptic reflex. Both agents increased the polysynaptic reflex. The 5-HT2 receptor antagonists ketanserin (100 micrograms/kg) and ritanserin (100 micrograms/kg) blocked the effects of DOI on the monosynaptic reflex but only partially blocked the 5-MeODMT-induced effect on the monosynaptic reflex. These antagonists inhibited the change in polysynaptic reflex, induced by DOI but not by 5-MeODMT. Neither propranolol (1 mg/kg) nor 3-tropanyl-3,5-dichlorobenzoate (MDL 72222, 1 mg/kg) antagonized the effect of either agent. 5-Methoxy-N,N-dimethyltryptamine and DOI increased the excitability of motoneurons and this effect was inhibited by ketanserin. These results indicate that the two types of hallucinogens possess both common and distinct characteristics, with regard to their action on the spinal reflex: (1) both increase the activity of motoneurons through 5-HT2 receptors but (2) only 5-MeODMT has an inhibitory action on the pathway of the monosynaptic reflex.


Blockade of dopamine autoreceptors by haloperidol and the apparent dynamics of potassium-stimulated endogenous release of dopamine from and reuptake into striatal suspensions in the rat. A study was made to determine what effects the blockade of dopamine (DA) autoreceptors has on the dynamics of depolarization-stimulated release of DA from suspensions of the striatum. A rotating disk electrode voltammetric technique and a first order kinetic model were used to measure and quantify time-resolved depolarization-induced release of DA from and reuptake into the same striatal suspension. Multiphasic dose-response relationships between the magnitudes, rates and apparent rate constants of release of DA and the concentration of the autoreceptor antagonist, haloperidol, were observed. At small concentrations of haloperidol, less than or equal to 0.1 microM, the magnitude of release of DA and apparent release rate constants were increased, however, the duration of release, the initial rate of release and the rate constants of reuptake of DA were unaffected. At larger concentrations of haloperidol, greater than 1.0 microM, release of DA was prolonged and reuptake was decreased. The rate constants for release of DA correlated with the magnitude of release of DA at all of the concentrations of haloperidol studied. The concentrations of haloperidol in tissue were estimated and then correlated with functionally significant systemic doses of haloperidol by direct comparison to published data, relating total concentrations of haloperidol in tissue with systemic doses and their behavioral effects. At these doses, haloperidol was found to increase the release rate constant and magnitude of release of DA, without altering the duration of release or the timing of reuptake. Thus, at presumed functionally significant doses, autoreceptor antagonism resulted in a modulation of the amplitude of release of DA only.


The effect of antidepressant drugs on the locomotor hyperactivity induced by MK-801, a non-competitive NMDA receptor antagonist. It was found earlier that imipramine, amitriptyline and citalopram enhanced the locomotor hyperactivity induced by MK-801, a non-competitive NMDA receptor antagonist, in rats. Now, three other antidepressants: (+)-oxaprotiline, an inhibitor of the uptake of noradrenaline, (-)-oxaprotiline, an enantiomer devoid of any effect on the uptake of noradrenaline and fluoxetine, an inhibitor of the uptake of 5-hydroxytryptamine, have been examined in male Wistar rats. All those antidepressants, given in a single dose, increased the MK-801-induced locomotor hyperactivity. That increase was completely antagonized by haloperidol and partly by SCH 23390 and (+/-)-sulpiride; prazosin was inactive. Repeated administration of antidepressants produced a similar but more potent (than acute one) enhancement of the action of MK-801. Also, in that case haloperidol and SCH 23390 produced the strongest antagonistic effect; (+/-)-sulpiride and prazosin had a distinctly less potent action. Another effect of MK-801, anticonvulsant activity (electroshock-induced convulsions), was not increased by the antidepressants studied. These results indicate that antidepressants with a different pharmacological profile, increased the MK-801-induced locomotor hyperactivity, this effect being probably indirectly mediated, at least in part, by a dopamine mechanism.


Behavioral and neurochemical effects of continuous infusion of cocaine in rats. The ability of continuous intravenous infusion of cocaine (60 mg/kg per day for 11 or 12 days; by osmotic minipump) to alter responses to acute injection of cocaine (20 mg/kg, i.p.; given 24 hr after termination of the infusion by minipump) was tested in conscious, tethered Sprague-Dawley rats. Extracellular levels of cocaine, dopamine and metabolites of dopamine in the striatum were determined by in vivo microdialysis. Locomotor activity and stereotyped behavior were evaluated simultaneously during dialysis sampling. Prior infusion of cocaine blunted the ability of acute challenge with cocaine to increase the efflux of dopamine in the striatum, locomotor activity and stereotypy. Increases in extracellular levels of homovanillic acid in the striatum were significantly greater in cocaine-infused rats than vehicle-infused controls, both prior to and after acute injections of cocaine. However, no differences between these two groups were observed in levels of cocaine in the striatum after acute challenge. Extracellular levels of dopamine in the striatum correlated significantly (P less than 0.05) with stereotypy in both groups but with locomotor activity only in cocaine-infused rats. The results indicate that behavioral tolerance occurred after continuous intravenous infusions of cocaine, that this was correlated with neurochemical tolerance to acute cocaine challenge and that alterations in the metabolism of cocaine did not account for the observed behavioral responses.


The effect of 3-amino-1,2,4-triazole on voluntary ethanol consumption: evidence for brain catalase involvement in the mechanism of action. The effects of the catalase inhibitor, 3-amino-1,2,4-triazole (AT), on maintenance of voluntary consumption of ethanol was tested in male Long-Evans rats. AT produced a dose-dependent reduction in ethanol intake but did not affect total fluid consumption. AT also produced a dose-dependent inhibition of brain catalase lasting throughout the drinking period. These results suggest a role for brain catalase in determining the level of ethanol intake in rats.


Transfer of [3H]leucine across the blood-brain barrier at high blood-side oxytocin concentrations in normal and morphine-dependent rats. The effects of circulating oxytocin on permeability of the blood-brain barrier (BBB) to L-[3H]leucine were studied in anaesthetized rats using the intracarotid, single pass, bolus injection technique. After bolus intracarotid oxytocin injection (10(-9) M), there were no differences in [3H]leucine uptake, compared with controls, in any of eight brain regions with a 'tight' BBB (olfactory bulb, frontal cortex, visual cortex, corpus striatum, hippocampus, thalamus, hypothalamus and colliculi) or in BBB-free, 'leaky' structures (pineal gland, choroid plexus, neuro-intermediate pituitary, anterior pituitary). [3H]leucine uptake by the 'leaky' structures was 2.4x and 2.6x uptake by 'tight' regions in the oxytocin and control groups respectively. In morphine-dependent rats, naloxone increased oxytocin secretion 28-fold within 5 min, but did not affect [3H]leucine uptake for any BBB-protected brain region or BBB-free 'leaky' structure. Accumulation of [3H]leucine was 8.3x and 7.0x greater in the 'leaky' structures than in the 'tight' regions in the naloxone and control groups respectively; [14C]inulin accumulation by each 'tight' region (measured simultaneously with [3H]leucine to determine the vascular space) was not affected by naloxone. It is concluded that even very high blood plasma concentrations of oxytocin do not affect BBB permeability for leucine. It is unlikely that altered BBB permeability, at least for amino acids, contributes to CNS changes during naloxone-provoked morphine withdrawal.


CSF enkephalins in diabetic neuropathy.

CSF enkephalins in diabetic neuropathy. CSF methionine and leucine enkephalins were measured by high performance liquid chromatography and radioimmunoassay in diabetic patients with painful neuropathy (n = 22) and painless neuropathy (n = 5), and non-diabetic subjects with low back pain (n = 11). Wide variations in CSF enkephalin levels were found and they were often below the limit of detection (less than 0.1 pmol/l) in the diabetic and non-diabetic groups. The origin of CSF enkephalins is unknown and CSF levels may not reflect tissue concentrations. In conclusion, CSF enkephalin levels are difficult to interpret and do not provide useful information on the function of enkephalinergic pathways.


Prolactin response to anesthetic stress and beta-endorphin is altered in female rats treated neonatally with monosodium glutamate. MSG (4 mg/g, sc) or saline was administered to neonatal female rats on days 1, 3, 5, 7 and 9. Study 1) Prl levels were assessed at 30, 60 and 75 days after birth to monitor possible development of hyperprolactinemia. No hyperprolactinemia was observed at any time studied. Study 2) MSG and control rats were administered pentobarbital anesthesia at 2 months of age. At 20, 60 and 90 min following anesthesia, plasma was collected for assay of Prl. 20 min prior to the 90 min bleeding, BE (5 micrograms/5 ul) was stereotaxically administered, into the third ventricle. MSG-treated rats had an attenuated Prl response to the stress of anesthesia (bleeding 1). Prl levels in control and MSG-treated rats were similar at 60 min post-anesthesia (bleeding 2) which represented a return of Prl levels to baseline after stress-induced elevation of Prl. Control and MSG-treated rats exhibited an increase in plasma Prl following intracerebroventricular BE; however, the amplitude of this response was markedly attenuated in the MSG-treated animals (bleeding 3). Thus, an observed loss of TH-positive neurons in the arcuate nucleus of the hypothalamus following MSG treatment and the attenuated response of Prl to anesthesia-stress and BE administration suggests that Prl secretion in response to these agents is operative through inhibition of the TIDA system. Furthermore, these studies show that the Prl response to these agents (anesthetic and BE) is intact but sub-operational in MSG-treated rats.


Cerebrospinal fluid endothelin-1 in Alzheimer's disease and senile dementia of Alzheimer type. We have measured the endothelin-1 concentrations in the cerebrospinal fluid samples from 5 patients with Alzheimer's disease (AD), 6 patients with senile dementia of Alzheimer type (SDAT) and 7 patients with other diseases without dementia (disease control: DC). The cerebrospinal fluid endothelin-1 level was significantly lower in AD than in DC. No correlation was observed between cerebrospinal fluid endothelin-1 concentration and any other factors such as age, duration from onset, systolic blood pressure, cerebrospinal fluid protein level or plasma endothelin-1 concentration in AD or SDAT. These results suggest a possible alteration of the endothelin-1 system in the central nervous system in Alzheimer's disease.


Effects of cocaine on the contents of neurohypophyseal hormones in the plasma and in different brain structures in rats. The effects of acute and chronic cocaine treatments on the levels of the neurohypophyseal hormones oxytocin (OXT) and vasopressin (AVP) in the plasma and in different brain structures in rats were measured by radioimmunoassay (RIA). Acute cocaine treatment had no effect on the level of OXT in the plasma or in the amygdala, but increased OXT contents were measured in the hypothalamus and in the hippocampus. The OXT levels in the basal forebrain structures (including the septum and the nucleus accumbens) were decreased by a single dose of cocaine. The acute injection of cocaine increased the level of AVP in the plasma, and decreased contents of OXT were measured in the amygdala and in the basal forebrain. Repeated treatment with cocaine decreased the level of OXT in the plasma, hypothalamus and hippocampus. The AVP contents were decreased in all of the brain structures investigated, but no change was caused in the plasma level of AVP by repeated injections of cocaine. These results demonstrate complex, region-specific interactions between cocaine and the neurohypophyseal hormones in the brain and in the periphery underlying the alteration in behavioral and autonomic functions caused by acute and chronic cocaine exposure.


Disturbance of spatiotemporal footfall contact patterns in the rat by TRH analogue CG3703. Administration of TRH or its analogues to a rat changes the dynamics of locomotion resulting in shorter stance times and causes postural disturbances, including hunched back and pelvic girdle elevation. Locomotor disturbance, induced by a variety of methods, results in changes to the footfall patterns during the stance phase of locomotion. The present work investigated whether these postural and locomotor dynamic disturbances in the CG3703 treated rat were associated with changes to the pattern of paw/floor contact during locomotion. It was found that in treated animals the area of hindpaw contact increased while that of the forepaw decreased from control values. The pattern of contact changed, with hindpaw stance being shifted towards more distal elements while in the forepaw a reduction in the deployment of proximal elements without any compensating increase in distal contact was seen. These results are discussed in the context of the effects of TRH analogues on sensory and motor processing in the CNS.


Interleukin-6 and corticotrophin-releasing hormone mRNA are modulated during differentiation of human neuroblastoma cells. Two cell clones [BE(2)-C and BE(2)-M17] derived from the human neuroblastoma cell line SK-N-BE(2) express corticotrophin-releasing hormone as well as interleukin-6 mRNA. Both genes are overexpressed, although with a different time course, following exposure to 5 microM retinoic acid, in parallel to the induction of neuroblastic differentiation. On the contrary, we are unable to detect interleukin-1 beta mRNA in these cell lines. Both cytokines are known to increase hypothalamic CRH mRNA. The production of cytokines and neuropeptides by neuroblastoma cells indicate a complex dialogue between tumour cells and anti-tumour immunity.


Effects of intracerebroventricular administration of calcitonin gene-related peptide on passive avoidance behaviour in rats. The effects of different doses of calcitonin gene-related peptide (CGRP) on passive avoidance behaviour were studied in male rats following its intracerebroventricular (i.c.v.) administration. Treatment with doses of 200 ng, 300 ng, 500 ng or 1 microgram was performed prior to learning, immediately and 6 h after the learning session and 30 min before the 24 h retention test. CGRP enhanced the avoidance latency in a dose-dependent manner at each time studied, with the exception of 6 h after the learning session. It is concluded that CGRP might be able to lengthen the passive avoidance latency by facilitating learning and memory formation.


Comparison of the effects of neurotensin and vasopressin on the adrenal cortex of dexamethasone-suppressed rats. Neurotensin (NT) and vasopressin (AVP) share some similarities as far as their actions on the adrenal weight and secretion are concerned. The present study aimed to compare the in vivo chronic effect of these two peptides on the adrenal cortex of dexamethasone (Dx)-treated rats. NT or AVP were ip. infused at a rate of 2 micrograms/rat/d for 7 d. In the animals concomitantly treated with 15 micrograms Dx/100 g/d for 7 d, both NT and AVP partially prevented adrenal atrophy. AVP enhanced plasma aldosterone concentration (PAC), but not that of corticosterone (PBC). On the other hand, NT did not affect either PAC or PBC. In rats treated with 35 micrograms Dx/100 g/d for 14 d, neither NT nor AVP administered for the last 7 d exerted any effect on the adrenal weight. However, also under these conditions of profound adrenal atrophy AVP was still able to notably raise PAC, while NT was ineffective. Our findings indicate that the mechanism underlying the aldosterone secretagogue action of AVP does not require, unlike that of NT, the presence of ACTH. Moreover, in light of many recent literature data they could suggest the possibility that in vivo NT acts on the rat adrenal cortex via AVP.


Comparison of the clinical presentation of symptomatic arteriovenous malformations (angiographically visualized) and occult vascular malformations. The authors compared the clinical presentations of angiographically apparent arteriovenous malformations (AVMs) and angiographically occult vascular malformations (AOVMs) of the brain in 188 consecutive patients treated when computed tomography and magnetic resonance were available. There were 133 patients (70.7%) with AVMs and 55 patients (29.2%) with AOVMs. AOVMs tended to occur more frequently in male patients and in the posterior fossa and to present earlier clinically than AVMs, but differences were not significant. One distinctive feature was the greater size of AVMs, as compared with AOVMs. Presentation by hemorrhage occurred in 64.3% of the patients with AVMs and in 61.8% of those with AOVMs. Malformations of both types located in the posterior fossa presented with hemorrhage more frequently (84.2% of AVMs and 78.5% of AOVMs) than similar lesions lying above the tentorium (60.8% of AVMs and 56% of AOVMs). Bleeding was more severe in patients with AVMs than in those with AOVMs, as indicated by the higher mortality associated with hemorrhage (7.5 vs. 3.6% of the cases) and the more frequent and marked decrease in the level of consciousness observed at admission (34 vs. 16.2% of drowsy or comatose patients). Brain hematomas caused by AVMs were on average bigger than those caused by AOVMs (58.8 and 20% of large hematomas, respectively), and intraventricular and subarachnoid hemorrhages were also more common and profuse in patients with AVMs. However, AOVMs bled subsequently more times than AVMs (61.7 vs. 15.6%), before they were diagnosed and treated, leading to a higher nonoperative morbidity (16.3 vs. 13.6%).(ABSTRACT TRUNCATED AT 250 WORDS)


Involvement of the external carotid arteries in moyamoya disease: neuroradiological evaluation of 66 patients. Arterial stenoses and/or occlusions in moyamoya disease are mainly localized intracranially, although some instances of stenotic lesions of the extracranial arteries have been reported in some autopsy cases. We have reviewed the angiograms of 66 patients with moyamoya disease to investigate whether stenotic lesions are present in the external carotid artery and its branches. We noticed that 13 patients had stenoses in the branches of the external carotid artery, although no occlusions were recognized. This result indicates that the arterial stenoses and/or occlusions are not confined to the intracranial arteries and that systemic factors contribute to the pathogenesis of moyamoya disease. This result also suggests that studies on specimens of the superficial temporal artery, which can be obtained easily at surgery, may reveal the molecular mechanism of intimal thickening.


Surgical treatment of moyamoya disease in pediatric patients--comparison between the results of indirect and direct revascularization procedures. Either encephaloduroarteriosynangiosis (EDAS) or superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis combined with encephalomyosynangiosis (EMS) has been performed on most of the children with moyamoya disease in our department. EDAS alone was done in the parietal region of 13 sides in 10 patients, and STA-MCA anastomosis with EMS in the parietal region was done on 7 sides in 6 patients. The surgical results of these two different procedures were then compared. Postoperative collateral formation was observed on external carotid angiograms, and the improvement of clinical symptoms was monitored for 1 year after the bypass procedure. STA-MCA anastomosis with EMS was found to be superior to EDAS in both the development of collateral circulation (P less than 0.05) and postoperative clinical improvement (P less than 0.01). EDAS can be done easily and safely on small children with moyamoya disease, but STA-MCA anastomosis with EMS is considered to be more appropriate, whenever possible.


Neurinomas presenting as spontaneous intratumoral hemorrhage. Massive intratumoral or subarachnoid hemorrhage from neurinomas is very rare. The authors report on six patients, four men and two women, with neurinomas that presented as spontaneous intratumoral hemorrhage. The average age of the patients was 56.8 years (range, 31-74 years). Neurinomas originated from the acoustic nerve in four patients and from the trigeminal nerve in two. Four cases were accompanied by the sudden occurrence of clinical symptoms such as headache, double vision, and hemisensory or motor disturbance. The maximum diameter of the tumors ranged from 2.8 to 3.8 cm (average, 3.1 cm). Histological examinations showed massive hemorrhage and increased vascularity, with dilated, thin-walled vessels, in all cases. The size of the tumor and the increase in vascularity with dilated, thin-walled vessels within neurinomas are important pathogenetic factors of hemorrhage. When sudden onset of symptoms or rapid worsening of chronic symptoms occurs in neurinomas, intratumoral or subarachnoid hemorrhage should be considered as a possible cause, and magnetic resonance imaging can be an important tool in obtaining correct diagnosis.


Proliferative characteristics of juvenile pilocytic astrocytomas determined by bromodeoxyuridine labeling. Bromodeoxyuridine (BUdR) labeling studies were performed to characterize the biological and clinical behavior of 50 juvenile pilocytic astrocytomas (JPAs) from 47 patients. Each patient received an i.v. infusion of BUdR before tumor resection; the excised tumor specimens were stained by the immunoperoxidase method with anti-BUdR monoclonal antibody to determine the BUdR labeling index (LI), or percentage of S-phase cells. The BUdR LI ranged from 0.22 to 4.3% (less than 1% in 34 and greater than or equal to 1% in 16; mean +/- SE, 1.05 +/- 0.13%). Tumors from younger patients often had higher LIs, but as the age of the patients increased, the frequency of tumors with LIs greater than or equal to 1% decreased. Tumors from male patients had higher LIs than those from female patients (1.36 +/- 0.20% [SE] vs. 0.75 +/- 0.13%; P less than 0.01), and tumors in the cerebellum had higher LIs than those in the hypothalamus (1.39 +/- 0.24% vs. 0.87 +/- 0.15%; P less than 0.05). The LI did not correlate with the gross appearance of the tumor (solid or cystic) or with outcome after the initial diagnosis. Overall, there was no difference in the LIs of primary and recurrent tumors. Four tumors (3 primary and 1 recurrent) that recurred after subtotal resection had a higher mean LI than 32 tumors that did not recur after subtotal resection (2.6 +/- 0.7% vs. 0.74 +/- 0.09%; P less than 0.005). None of 14 totally resected tumors (mean LI, 1.3 +/- 0.2%) has recurred.(ABSTRACT TRUNCATED AT 250 WORDS)


Transcranial color-coded real-time sonography in the evaluation of intracranial neoplasms and arteriovenous malformations. Transcranial color-coded real-time sonography (TCCS) was performed in 57 patients with primary intracranial brain tumors (n = 49) or arteriovenous malformations (n = 8) to evaluate its diagnostic potential. In 46 patients (81%), lesions could be identified employing this technique. In 7 patients, transcranial ultrasound examination was not feasible because of bone thickness; in the remaining 4 patients, the tumor was indistinguishable from adjacent brain tissue despite sufficient insonation, suggesting that these neoplasms are isoechogenic. The sonographic features of brain tumors were very similar: a hyperechogenic matrix of the lesion was interspersed by hypoechogenic pixels. Larger hypoechogenic areas (0.5-1 cm) gave evidence of tumor necrosis. Differences between the findings of TCCS and computed tomography concerning tumor size were found in 7 patients, in whom TCCS revealed an area of smaller extension within the corresponding hypodense area on the computed tomographic scan. Perifocal brain edema could not be detected by ultrasound examination. In 13 patients, a thin, hypoechogenic peritumoral halo was disclosed that did not correlate with perifocal brain edema identified by computed tomography and that may have been due to compression of adjacent parenchyma. In patients with arteriovenous malformations, TCCS permitted the identification of the main feeders, the nidus, and the draining venous system by color-coded depiction of intravascular blood flow. In conclusion, TCCS is an additional method for initial diagnosis and highly suitable for follow-up in tumor patients and provides valuable information about tissue characteristics and blood flow.


The prognostic value of somatosensory and motor evoked potentials in comatose patients. Somatosensory and motor evoked potentials (SEP and MEP) were examined in a total of 213 patients in traumatic (n = 140) and nontraumatic (n = 73) coma. It was the aim of this study to compare the prognostic value of MEP elicited by both electrical and magnetoelectric transcranial stimulation with the use of SEP alone. According to the presence or absence of responses and the duration of central conduction time, SEP and MEP obtained during Days 1 through 3 after the onset of coma were divided into four categories and correlated with the outcome of the patients, as assessed by the Glasgow Outcome Scale. Our results clearly show that in terms of prognostic value, SEP are superior to MEP, with normal findings indicating a favorable outcome and absent responses an unfavorable outcome. On the other hand, patients with normal electromyographic responses after both electrical and magnetoelectric stimulation had favorable and unfavorable outcomes about equally. Thus, unlike SEP, normal MEP do not allow any prognostic conclusions. Only the bilateral absence of MEP in response to electrical stimulation was a definitely unfavorable prognostic sign because all of these patients died. In contrast, with magnetoelectric stimulation, neither normal nor absent responses allowed any prognostic conclusions. Therefore, the prognostic value of electrically evoked motor responses is limited, and magnetoelectric stimulation cannot be recommended in this context.


Severe head injury in children: experience of the Traumatic Coma Data Bank. The outcome at discharge, 6 months, and 1 year after they had sustained severe head injuries was investigated in children (0-15 yr old at injury) who were admitted to the neurosurgery service at one of four centers participating in the Traumatic Coma Data Bank. Of 103 eligible children, the quality of recovery was assessed by the Glasgow Outcome Scale (GOS) at 6 months after injury in 92 patients (86% of series) and at 1 year in 82 patients (73% of series). The lowest post-resuscitation Glasgow Coma Scale score and pupillary reactivity were predictive of the 6-month GOS as were their interaction. Analysis of the first computed tomographic scan disclosed that bilateral swelling with/without midline shift was related to a poor outcome as was the presence of mass lesions. Comparison of age-defined subgroups of patients revealed that outcome was poorest in the 0- to 4-year-old patients, as reflected by their mortality, which increased to 62% by 1 year. Distinctive features of the injuries in the 0- to 4-year-olds included evacuated subdural hematomas (20% of patients) and hypotension (32% of patients). The most favorable outcome was attained by 5- to 10-year-olds (2/3 had a good recovery by 1 yr), whereas the GOS distribution of adolescents was intermediate between the children and adults. In summary, the GOS data reflect heterogeneity in the quality of outcome after severe head injury depending on age, neurological indices, and computed tomographic scan diagnostic category.


Management of symptomatic chronic extra-axial fluid collections in pediatric patients. The records of 103 pediatric patients having symptomatic chronic extra-axial fluid collections treated at Children's Hospital of Los Angeles from 1977 to 1988 were reviewed. Patients were treated with observation, serial percutaneous needle drainage, drainage through burr holes, drainage into a closed external drainage system, or subdural to peritoneal shunt. If the initial treatment was not effective, additional forms of treatment were instituted. Shunts, ultimately used in 73% of the patients, proved to be the most effective treatment. Of the group with shunts, the extra-axial fluid was unilateral in 20% and bilateral in 80%. In those patients with bilateral effusions, no difference in efficacy of shunts was seen in patients treated with bilateral versus unilateral shunts. Of the 75 patients with shunts, 12% required a shunt revision for progressive or recurrent symptoms. Shunt infections occurred in 3% of the patients, necessitating removal of the shunt and treatment with antibiotics. Eosinophilia in the subdural fluid was associated with shunt obstruction requiring revision. The shunt was never removed in 51% of patients with no untoward effects. This study demonstrates that the most efficacious treatment of symptomatic chronic extra-axial fluid collections in children is a unilateral subdural to peritoneal shunt. The shunt need not be removed after resolution of the fluid collections.