Cortex cannabinoid receptors

Cannabinoid receptors are expressed throughout the cerebral cortex and the hippocampus, and a subpopulation of these cells appear to show an unusually high level of activity. It is possible that cells in these areas modulate the sensory effects of cannabis, particularly the effects on perception, task performance and memory. In addition, the anticonvulsant properties of cannabis are believed to be mediated here. Parts of the hypothalamus show high levels of receptor sites for cannabinoids this may be related to hypothermia effects. High levels in the cerebellum may be related to mediating the property of cannabinoids that produces the reduction in ataxic (muscle co-ordination) symptoms in certain disorders (Herkenham et al., 1991). 

Cannon CM, Palmiter RD (2003) Reward without dopamine, J Neurosci 23 10827-10831 Carboni E, Bortone L, Giua C, Di Chiara G (2000) Dissociation of physical abstinence signs from changes in extracellular dopamine in the nucleus accumbens and in the prefrontal cortex of nicotine dependent rats. Drug Alcohol Depend 58 93-102 Castane A, Valjent E, Ledent C, Parmentier M, Maldonado R, Valverde O (2002) Lack of CBl cannabinoid receptors modifies nicotine behavioural responses, but not nicotine abstinence. Neuropharmacology 43 857-867... 

In 1988, the same group reported the existence of a cannabinoid receptor in rat brain. High affinity and stereoselectivity — essential criteria for a pharmacologically distinct cannabinoid receptor — in the brain was demonstrated. Several years later, the cDNA of the cannabinoid receptor was isolated from a rat cerebral cortex cDNA library and expressed in Chinese hamster ovary cells.This G-protein-coupled receptor was isolated from a human brain stem cDNA library. The deduced amino acid sequence encoded a protein of 472 residues, which shares 97.3% identity... 

The psychological effects of cannabis are due to cannabinoids such as A -tetrahydrocannabinol (THC) which interact with specific cannabinoid receptors in the brain (Devane et al.,1988 Matsuda et al., 1990). The functions of these receptors are not known but high concentrations are present in sensory and limbic areas, and THC also increases dopamine release from the nucleus accumbens and frontal cortex (Tanda et al., 1987) and decreases the release of acetylcholine (Trzepacz, 2000). 

To date, little postmortem work has been done in human cannabis abusers. Preclinical studies indicate that chronic treatment with 5 -THC markedly reduces CBj receptor binding in all brain areas containing this receptor (cerebellum, hippocampus, cortex, globus pal-lidus, striatum), and enhances the cAMP pathway (Rubino et ah, 2000). Other preclinical work has shown that the cannabinoid receptor reserve is larger than that for most other G protein-coupled receptor systems (Gifford et ah, 1999). This means that at occupancies as low as 0.13%, 50% of maximal inhibition of Ach release is achieved. 

Cannabinoid receptors, the binding sites for THC from marijuana, are prevalent in the brain and concentrated in areas like the basal ganglia, hippocampus, cerebellum, and cerebral cortex (indicated in pink on this illustration). THC interrupts the normal communication between neurotransmitters and results in changes of behavior and physical effects controlled by these areas of the brain. 

Daniel H, Crepel F (2001) Control of Ca(2+) influx by cannabinoid and metabotropic glutamate receptors in rat cerebellar cortex requires K(+) channels. J Physiol 537(Pt 3) 793-800 Davis MI, Ronesi J, Lovinger DM (2003) A predominant role for inhibition of the adenylate cy-clase/protein kinase A pathway in ERK activation by cannabinoid receptor 1 in N1E-115 neuroblastoma cells. J Biol Chem 278(49) 48973-80 Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258 1946-9... 

Antonelli, T., Tomasini, M. C., Tattoli, M., Cassano, T., Finetti, S., Mazzoni, E., Trabace, L., Carratu, M. R., Cuomo, V., Tanganelli, S., and Ferraro, L. (2006). Prenatal exposure to the cannabinoid receptor agonist WIN 55,212-2 and carbon monoxide reduces extracellular glutamate levels in primary rat cerebral cortex cell cultures. Neurochem. Int. 49, 568—576. 

Koethe D, Llenos IC, Dulay JR, Hoyer C, Torrey EF, et al. 2007. Expression of CB(1) cannabinoid receptor in the anterior cingulate cortex in schizophrenia, bipolar disorder, and major depression. J Neural Transm 114 1055-1063. 

Newell KA, Deng C, Huang XF. 2006. Increased cannabinoid receptor density in the posterior cingulate cortex in schizophrenia. Exp Brain Res 172 556-560. 

The primary active component of cannabis is A9-tetrahy-drocannabinol (THC), which is responsible for the greater part of the pharmacological effects of the cannabis complex. A8-THC is also active. However, the cannabis plant contains more than 400 chemicals, of which some 60 are chemically related to A9-THC, and it is evident that the exact proportions in which these are present can vary considerably, depending on the way in which the material has been harvested and prepared. In man, A9-THC is rapidly converted to 11-hydroxy-A9-THC (5), a metabolite that is active in the central nervous system. A specific receptor for the cannabinols has been identified it is a member of the G-protein-linked family of receptors (6). The cannabinoid receptor is linked to the inhibitory G-protein, which is linked to adenyl cyclase in an inhibitory fashion (7). The cannabinoid receptor is found in highest concentrations in the basal ganglia, the hippocampus, and the cerebellum, with lower concentrations in the cerebral cortex. 

A THC tetrahydrocannabinol is the major psychoactive ingredient in the Cannabisplant. A THC is responsible for both the psychiahic and therapeutic effects obtained from marijuana. Its receptor, the cannabinoid receptor, is located mainly tat the presynaptic gap. The areas of the brain most affected are the basal ganglia, cerebellum, cerebral cortex, and the hippocampus. The acute effects consist of degradation in short term memory, changes in sensory perception, reduced concenhation, disturbances in motor abilities, hypothermia, increased blood pressure and heart rate, and reduced pain perception. 

Cannabinoids exert their effect by interaction with specific endogenous cannabinoid receptors. Neuronal cannabinoid receptors are termed CBi receptors and have been found in rat, guinea pig, dog, monkey, pig, and human brains and peripheral nerves. A second cannabinoid receptor, the CB2 receptor, was identified in macrophages in the spleen and is also present in other immune cells. The distribution of CBj receptors is very similar to that of the distribution of injected THC and includes cerebral cortex, limbic areas (including hippocampus and amygdala), basal ganglia, cerebellum, thalamus, and brainstem. 

The mechanisms involved in THC s central nervous system (CNS) and cardiovascular effects have not been well delineated. Specific cannabinoid receptors in the cerebral cortex may be responsible for the pharmacologic effects of THC. THC also has immunosuppressive effects and results in depression... 

Ferraro L, Tomasini MC, Gessa GL, Bebe BW, Tanganelli S, Antonelli T (2001) The cannabinoid receptor agonist WIN 55,212-2 regulates glutamate transmission in rat cerebral cortex an in vivo and in vitro study. Cerebral Cortex 11 728-733... 

Denovan-Wright EM, Robertson HA (2000) Cannabinoid receptor messenger RNA levels decrease in a subset of neurons of the lateral striatum, cortex and hippocampus of transgenic Huntington s disease mice. Neuroscience 98 705-713... 

The CBi cannabinoid receptor is the major mediator of the psychoactive effects of cannabis and its derivatives. In addition, this G protein-coupled receptor transduces many of the effects of the endogenous cannabinoids. Understanding the distribution of CBi receptors has proved helpful to both predict and understand the effects of cannabinoids. For example, the high CBi receptor levels found in cortex, basal ganglia, and cerebellum coincide with the prominent effects cannabinoids have on functions subserved by these brain regions. By comparison, the low levels present in the medullary nuclei responsible for regulating respiration are consistent with the modest effects cannabinoids have on respiratory drive. Furthermore, the strong presynaptic localization of the receptor found in ultra-structural studies underscores its major role as a modulator of neurotransmitter release. 

Fig. 7. Effects of cannabinoids on synaptic transmission in the cerebellar cortex. CBi receptor-mediated inhibition of neurotransmission was demonstrated at several synapses in the cerebellar cortex. In addition to the proven sites of inhibition, inhibition is very probable at additional sites (based on the localisation of the CBi receptor). In addition to synaptic inhibition, activation of CBi receptors can also directly decrease the firing rate of interneurons (not shown)...

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