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4. Cannabis the drug
4.2 The cannabinoid receptor
The desire to identify a specific biochemical pathway responsible for the expression of the psychoactive effects of cannabis has prompted a prodigious amount of cannabinoid research (Martin, 1986). Early studies found that radioactively labelled THC would non-specifically attach to all neural surfaces, suggesting that it produced its effects by perturbing cell membranes (Martin, 1986). However, the work of Howlett and colleagues (Howlett et al 1986; 1987; 1988) showed that cannabinoids inhibit the enzyme that synthesizes cyclic AMP in cultured nerve cells, and that the degree of inhibition was correlated with the potency of the cannabinoid. Since many receptors relay their signals to the cell interior by changing cellular cyclic AMP, this finding strongly suggested that cannabinoids were not just dissolving non-specifically in membranes. After eliminating all the known receptors that act by inhibiting adenylate cyclase, it was concluded that cannabinoids acted through their own receptor. The determination and characterisation of a specific cannabinoid receptor in brain followed soon after (Devane et al, 1988), paving the way for its distribution in brain to be mapped (Bidaut-Russell et al, 1990; Herkenham et al, 1990).
It is now accepted that cannabis acts on specific cannabinoid receptors in the brain, conclusive evidence for which was provided by the cloning of the gene for the cannabinoid receptor in rat brain (Matsuda et al, 1990). A cDNA which encodes the human cannabinoid receptor was also cloned (Gerard et al, 1991) and the human receptor was found to exhibit more than 97 per cent identity with the rat receptor. Cannabinoid receptors have also been found in the nervous system of lower vertebrates, including chickens, turtles and trout (Howlett et al, 1990) and there is preliminary evidence that they exist in low concentration in fruit flies (Bonner quoted in Abbott, 1990; Howlett, Evans and Houston, 1992). This phylogenetic distribution suggests that the gene must have been present early in evolution, and its conservation implies that the receptor serves an important biological function.
The localisation of cannabinoid receptors in the brain has elucidated the pharmacology of the cannabinoids. Herkenham and colleagues (Herkenham, et al 1990; 1991a; 1991b; 1992) used autoradiography to localise receptors in fresh cut brain sections of a number of species, including humans. Dense binding was detected in the cerebral cortex, hippocampus, cerebellum and in outflow nuclei of the basal ganglia, particularly the substantia nigra pars reticulata and globus pallidus. Few receptors were present in the brainstem and spinal cord. Bidaut-Russell and colleagues (Bidaut-Russell et al, 1990) located cannabinoid receptors in greatest abundance in the rat cortex, cerebellum, hippocampus and striatum, with smaller but significant binding in the hypothalamus, brainstem and spinal cord.
High densities of receptors in the hippocampus and cortex suggest roles for the cannabinoid receptor in cognitive functions. This is consistent with evidence in humans that the dominant effects of cannabis are cognitive: loosening of associations, fragmentation of thought, and confusion on attempting to remember recent occurrences (Hollister, 1986; Miller and Branconnier, 1983). High densities of receptors in the basal ganglia and cerebellum suggested a role for the cannabinoid receptor in movement control, a finding which is also consistent with the ability of cannabinoids to interfere with coordinated movements.
Cannabis has a mild effect on cardiovascular and respiratory function in humans (Hollister, 1986) which is consistent with the observation that the lower brainstem area has few cannabinoid receptors. The absence of sites in the lower brainstem may in fact explain why high doses of THC are not lethal. Cannabinoid receptors do not appear to reside in the dopaminergic neurons or the mesolimbic dopamine cells that have been suggested as a possible "reward" system in the brain.
These mappings of receptors have been broadly confirmed in recent work by Matsuda and colleagues (1992, 1993) using a histochemistry technique to neuroanatomically localise cannabinoid receptor mRNA. Labelling intensities were highest in forebrain regions (olfactory areas, caudate nucleus, hippocampus) and in the cerebellar cortex. Clear labelling observed in the rat forebrain suggests several potential sites in the human brain that could mediate an impairment of memory function (Miller and Branconnier, 1983), such as the hippocampus, medial septal complex, lateral nucleus of the mamillary body, and the amygdaloid complex. Similarly, labelling was detected clearly in rat forebrain regions that correspond to those that could mediate cannabis-induced effects on human appetite and mood (namely, the hypothalamus, amygdaloid complex, and anterior cingulate cortex). It should be borne in mind that the regions where cannabinoid receptors occur may have long projections to other areas, contributing to the multiplicity of effects of the cannabinoids.
Since THC is not a naturally occurring substance within the brain, the existence of a cannabinoid receptor implied the existence of a naturally occurring or "endogenous" cannabinoid-like substance. Devane and colleagues (1992) recently identified a brain molecule which binds to the receptor and mimics the action of cannabinoids. The molecule, arachidonylethanolamide, which is fat soluble like THC, has been named "anandamide" from a Sanskrit word meaning "bliss". Anandamide has been found to act on cells that express the cannabinoid receptor, but it has no effect on identical cells which lack the receptor. Further research is necessary to determine which neurons are responsible for producing anandamide molecules and to determine what their role is.
The unique psychoactivity of cannabinoids may be described as a composite of numerous effects which would not arise from a single biochemical alteration, but rather from multiple actions (Martin, 1986). Thus, the diverse pharmacological actions of the various cannabinoids implies the existence of receptor subtypes. Cannabinoid receptor cDNA can be used to search for other members of the hypothesised receptor family (Snyder, 1990). If the receptors with the potential for mediating the therapeutic uses of cannabis are different from those responsible for their psychoactive effects, cannabinoid receptor cDNA cloning and new synthetic cannabinoids modelled on anandamide may help to uncover the receptor subtypes and develop drugs to target them, thus fulfilling the ancient promise of "marijuana as medicine". If, however, it were the case that there was only one type of cannabinoid receptor, then the psychoactive and therapeutic effects would be inseparable. The evidence against this proposition mounts with the recent cloning of a cannabinoid receptor in spleen that does not exist in brain (Munro et al, 1993).