the concept of volume transmission , introduced by luigi agnati and kjell fuxe in 1986 , designates is a form of communication in brain tissue in which modulators act across wide distances when their sites of release and removal are further apart than for  wired  transmission , characteristic of focused synaptic action ( fuxe et al . , 2010 ) . volume transmission affects large volumes of tissue and undergoes change more slowly than wired transmission . the concept of volume transmission in brain therefore overlaps with forms of paracrine and autocrine signaling . the canonical volume transmitters are monoamines , released from varicosities along the fibers of monoaminergic neurons and removed by transporters at sites reached after variable distances of diffusion . however , the list of potential agents of volume transmission is long , as any molecule that engages receptors , transporters , or enzymes far from a place of synthesis or release may qualify as a volume transmitter , including the archetypical wired transmitter glutamate ( okubo and iino , 2011 ) . another potential volume transmitter is l - dopa , which shares with lactate the ability to move across cellular membranes and reach cells far from the sites of generation ( gjedde et al . , 1993 ; ugrumov , 2009 ) . the g - protein - coupled 7tm receptor ( gpr ) family includes members that mediate specific actions of hydroxyl carboxylic acids ( hca ) , including gpr81 , also known as hca1 receptor ( blad et al . , 2011 ) , which serves lactate s downregulation of camp , as shown in adipocytes ( ahmed et al . , 2009 ) the gpr81 is prominent in adipose tissue , where it inhibits lipolysis , but it is known also to be expressed in a wider range of organs such as liver , kidney , skeletal muscle , spleen , and testis ( gantz et al . , 1997 ; ge et al . , 2008 ; liu et al . , 2009 ; rooney and trayhurn , 2011 ) evidence from in situ hybridization show a widespread distribution of gpr81 mrna in the brain , predominantly in neurons , including the principal neurons in cortex , hippocampus ( pyramidal and granule cells ) , and cerebellum ( granule cells ) , while labeling of astrocytes can not be excluded ( the allen institute for brain science , genstat , st . the receptor s reported affinities for l - lactate range from 1.3 to 5 mm ( cai et al . , 2008 ; liu et al . , 2009 ) , which is consistent with the range of lactate concentrations measured in brain tissue in vivo ( abi - saab et al . , 2002 ) . the binding of lactate to gpr81 attenuates the formation of camp , which in turn inhibits protein kinase a and hence glycogenolysis , leading to decreases of glucose-1-phosphate and glucose-6-phosphate ( g6p ) that affect glycolysis in the cytosol , as recently shown by kinetic modeling ( dinuzzo et al . , 2010 ) . the decrease of g6p affects its role as allosteric regulator of hexokinase ( hk ) , including the association of hk with the voltage dependent anion channel ( vdac ) in the outer mitochondrial membrane , with important consequences for the efficiency of oxidative phosphorylation of adp ( wilson , 2003 ; mailloux and harper , 2011 ) . the main thrust of this perspective is the importance of any physical separation of hk and pyruvate dehydrogenase ( pdh ) activities , which would lead to diffusion of lactate between the sites . as such , this concept is not limited to major compartments or cell types but applies equally well to subdivisions of cells , such as distal vs proximal dendrites and astrocytic processes vs cell bodies rather than to astrocyte / neuron differences ( figure 1 ) . in this illustration you can follow the two different mechanisms proposed : ( a ) lactate regulates the formation of camp via the lactate receptor gpr81 . ( c ) both the formation of camp and the adjustment of nadh / nad redox ratio can be linked to the maintenance of brain energy turnover and neurovascular coupling . the role of lactate in neurovascular coupling is included in the figure , but not dealt with in the text , which focuses on cellular effects of lactate in brain tissue . the roles of lactate as mediator of metabolic information rather than metabolic substrate answer a number of questions raised by the aerobic glycolysis of astrocytes and its controversial contribution to neuronal function . lactic and pyruvic acids interact through the actions of the cytosolic near - equilibrium lactate dehydrogenase ( ldh ) isozymes , which reflect the cytosolic nadh / nad ratios in cytosol . the cytosolic and the mitochondrial redox states are linked through a network of redox reactions and inner membrane transport processes , but the exact relation between cytosolic and mitochondrial nadh / nad ratios is not known . there are reports of mitochondrial ldh activity ( brooks , 2009 ) and therefore potential for coupling of lactate  pyruvate and nadh / nad ratios in the mitochondrial matrix . changes of the nadh / nad redox ratios trigger several intracellular responses , including expression of genes by modification of histone deacetylases , which profoundly affect the regulation of protein synthesis . for example sirtuins , gene - regulating histone deacetylases with effects on regulation of caloric intake , metabolism and age - related diseases ( finkel et al . , 2009 ) , are tightly redox regulated through the nadh / nad ratio ( gambini et al . , 2011 ) . genes activated by lactate through lactate - sensitive response elements include c - fos , c - jun , c - ets , hyal-1 , hyal-2 , cd44 , and caveolin-1 ( formby and stern , 2003 ) . the dna binding of the transcription factor fos jun heterodimer ap-1 depends on a specific cysteine residue being in the reduced sate ( abate et al . , in addition , pyruvate , which interacts closely with lactate as dictated by the nadh / nad ratio , is a gene regulator through histone deacetylase inhibition ( thangaraju et al . both the ldh isozymes and the monocarboxylic acid transporters ( mct ) of the blood  brain barrier and cell membranes of brain tissue mediate near - equilibrium transfer of lactate ( bergersen et al . , 2001 ; bergersen , 2007 ) when unidirectional fluxes exceed net fluxes by several orders of magnitude . therefore ldh and mct proteins thus , changes of pyruvate and lactate concentrations in one place lead to similar changes of lactate concentrations across large volumes of brain tissue over long times . in turn , any effects of changes of lactate on the nadh / nad ratio in one place lead to similar effects in widely distributed populations of cells ( cf . cerdn et al . , 2006 ; ramrez et al . , 2007 ; rodrigues et al . , 2009 ) in fact , the transfer of lactate is so efficient that it is difficult to observe any differences of lactate concentrations across cell membranes in brain tissue ( gjedde and marrett , 2001 ; ido et al . , 2001 , 2004 ; 2002 ) , such that significant cellular compartmentation of lactate is unlikely to exist under normal conditions , except briefly . the high concentration of mct2 at the psd of fast excitatory synapses co - localized with glutamate receptors ( bergersen et al . , 2001 , 2005 ) suggests a particular need for lactate transfer at these synapses perhaps involved in volume transmission signaling . in addition to moving through brain tissue by facilitated transfer across plasma membranes of all cells through mct1 , mct2 , and mct4 , and by diffusion through the extracellular space , lactate spreads through the astroglial network in which individual astrocytes are connected by gap junctions ( dienel , 2011 ; mathiesen et al . , 2011 ) . one puzzle is the kinetic differences among the isozymes of ldh ( obrien et al . , 2007 ) , the physiological role of which at near - equilibrium is not yet understood ( ross et al . , 2010 ; quistorff and grunnet , 2011 ; ross , 2011 ) , but may be related to the proposed function of lactate as a volume transmitter in cytosolic and perhaps mitochondrial environments with widely differing nadh / nad+ ratios ( figure 1 ) . the purported changes of lactate concentrations and the consequent redistribution of lactate happen whenever and wherever sites of generation and metabolic conversion of pyruvate are unmatched or physically separated . pyruvate is the main end product of aerobic glycolysis , which is controlled by the concerted action of the hk and phosphofructokinase ( pfk ) enzyme complex , while the fate of pyruvate is determined by the pdh complex in mitochondria . the two enzyme complexes are the main flux - generating determinants of brain energy metabolism as controlled by allosteric effectors , and both therefore define the path that is open to the respective so - called  pathway substrates ,  glucose in the case of the hk  pfk complex , pyruvate in the case of the pdh complex ( gjedde , 2007 ) . the temporal and spatial integration of the activities of these enzyme complexes is then the key to the dynamics of lactate inside and among the cells of brain tissue . both the oxygen  glucose index ( ogi ) and the oxygen extraction fraction ( oef ) decline during the temporary departures from steady - state associated with functional activation of brain regions , attributed to increased aerobic glycolysis ( madsen et al . . the declines are signs of focal disintegration of the hk  pfk and pdh activities , resulting in increased lactate pyruvate ratios , redistribution of lactate and adjustment of nadh / nad ratios within the sphere of action of the redistributed lactate . this process seems to be so efficient that it leaves no oxygen deficit or abnormal atp , adp , or amp levels , even in seizures ( larach et al . extracellular lactate concentrations increase during neuronal and synaptic activation in vivo , as determined by microdialysis ( uehara et al . 2011 ) , and proton magnetic resonance spectroscopy minutes after stimulation ( prichard et al . , 1991 ; sappey - marinier et al . , 1992 ; maddock et al . , 2006 ) , following a transient decrease 5 s after stimulation ( mangia et al . , 2003 ) . these observations are consistent with adjustments that follow the perturbation of an existing steady - state and the subsequent return to a potential new steady - state , depending on conditions , such as the intensity of the continuing neuronal activation . the lactate dynamics are uniquely dependent on the shifts among these steady- and non - steady - states of brain energy metabolism . the observations that the ogi declines during the non - steady - state of the early stages of functional brain activation , signifies increased lactate production in the tissue as a whole , evidently due to increased glucose consumption relative to oxygen consumption . the observations are consistent with changes of glucose consumption that match the changes of blood flow during activation , while changes of oxygen consumption generally do not ( gjedde et al . , 2002 ; recent evidence also shows that the changes of glucose consumption exceed the changes of oxygen consumption at specific regional locations ( vaishnavi et al . , 2010 ) , rather than everywhere , creating the gradients of lactate concentration that serve to redistribute lactate inside as well as outside cells and across the blood the regional variation of the ogi ( vaishnavi et al . , 2010 ) may possibly be related to different ratios of cell types ( low in cortex with numerous astrocytes , high in cerebellum with numerous neurons ) . any separation of the sites of lactate generation and lactate metabolism inside or among cells therefore must result in shuttling of lactate among its sites of generation and metabolism . thus , the temporal and spatial mismatches of lactate generation and metabolism arise because different cellular and subcellular compartments react differently to activating stimuli ( gjedde et al . , 2005 ; vaishnavi et al . , it has been shown by mr spectroscopy that blood lactate is an efficient substrate for the brain , and especially for neurons , both in rat ( bouzier et al . , 2000 ; hassel and brthe , 2000 ) and in humans ( boumezbeur et al . , 2010 ) . the increased lactate also has effects on brain metabolism , which are characterized by reduction of the cerebral ogi in the context of a state known as  central fatigue  ( dalsgaard , 2006 ; dalsgaard and secher , 2007 ; rasmussen et al . , central fatigue precedes the muscle fatigue that also relates to increased lactate ( van hall , 2010 ) . the mechanism responsible for the onset of central fatigue is not known with certainty but appears to be related to decreased oxygen delivery , which in turn may be due to increased lactate in brain tissue and possible effects on lactate s receptor gpr81 ( rasmussen et al . , 2010 ; the downregulation of camp formation by binding of lactate to gpr81 offers a novel explanation of central fatigue and  over - training  distress ( lehmann et al . , 1993 ) , and possibly in part the asthenia seen in advanced cancer , a condition that is known to be characterized by chronically increased blood lactate levels ( koppenol et al . , 2011 ) . chronically increased lactate levels similarly are held to be characteristic of old age and dementia , based on the properties of a mtdna mutator mouse model ( ross et al . , 2010 ) . these effects contrast with the upregulation of camp by noradrenaline with effects such as arousal and enhanced brain performance ( berridge , 2008 ) . many other observed effects of lactate on neuronal function may result from enzyme- or receptor - mediated responses rather than from the direct actions of lactate as a metabolic substrate . for example , the observation that lactate administration protects against ischemia ( schurr et al . however , this is not readily explained by metabolic effects , as lactate metabolism can not raise energy turnover under ischemic conditions , although after ischemia and in the penumbra of vascular occlusion , the availability of lactate for oxidation may assist in alleviating ischemia induced damage ( schurr et al . , 2001 ; berthet et al . , similarly , the observed protective effect of lactate on glutamate toxicity in the brain ( ros et al . , 2001 ) may be due to receptor - mediated inhibition , rather than the simple satisfaction of the metabolic demands of neurons exposed to high concentrations of glutamate ( schurr et al . , 1999 ) . in microdialysis of the cerebral cortex , excitotoxic concentrations of glutamate raised lactate at the expense of glucose in the dialysate . the addition of l - lactate caused the lesion to become smaller and abolished the decrease of glucose . replacing l - lactate with the non - physiological d - lactate isomer expanded the lesion and raised l - lactate in the dialysate above the level observed with glutamate alone ( ros et al . , 2001 ) , consistent with the claim that endogenously produced lactate is neuroprotective by means of receptor interaction . the suppression of noradrenalin and adrenalin releases by blood lactate clamps at 4 mm ( fattor et al . , 2005 ) also suggests a receptor mechanism , consistent with the postulated reduction of camp formation by grp81 activation . interestingly , also -adrenoceptor blockers , which presumably act by reducing intracellular camp , are neuroprotective in stroke and other brain injuries , and also lower extracellular glutamate levels , which may further limit excitotoxic cell damage ( goyagi et al . , 2011 ) . the proposed role of lactate as a mediator of information on changing nadh / nad ratios among the cells of brain tissue has implications for the understanding of regulation of brain energy metabolism , including the communication between cytosol and mitochondria in large populations of cells ( xu et al . , 2007 ) . lactate s inhibition of camp formation through g - protein - coupled receptors may be a factor in the development of central fatigue . an action of lactate may therefore be to  smooth  the non - steady - states that underlie the mismatches of glycolysis and oxidative phosphorylation , induced by needs for aerobic glycolysis that satisfy the short time constants of atp turnover required for maintenance of rapid de- and repolarizations . the redistribution of lactate by the volume transmission is both temporal and spatial and potentially reaches large volumes of tissue , aided by the extended syncytium of astrocytic networks connected by gap junctions . the role of lactate as informant of metabolic states rather than substrate of metabolism solves a number of puzzles that contribute to the controversy surrounding the understanding of astrocytic metabolism and its contribution to neuronal function . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest .