Hippocampus cannabinoid receptors

The cellular actions of cannabinoids clearly support the proposal that the cannabinoid receptor is inhibitory and, consequently, reduces the firing rate of target neurons. However, this is not wholly confirmed by electrophysiological measurements, which suggest that cannabinoid compounds can stimulate neurons in the hippocampus. This apparent discrepancy may be due to the ability of cannabinoids to inhibit the release of an inhibitory substance in the hippocampus and, thus, produce a net excitation. 

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). 

Both anandamide and 2-AG are inactivated by enzymatic hydrolysis (Goparaju et al. 1998). Fatty acid amide hydrolase (FAAH) is an enzyme that catalyses their hydrolysis. High concentrations of FAAH were found in the cerebellum, hippocampus and neocortex of rat brain, which are also rich in cannabinoid receptors. Further, there is a complementary pattern of distribution of FAAH and the CBl receptor. For example, in the cerebellum, FAAH is found in the cell bodies of Purkinje cells and the CBl receptor is found in the axons of granule cells and basket cells, which are presynaptic to Purkinje cells. 2-AG may also be inactivated by direct esterification into membrane phospholipids. Cannabinoid Receptors... 

Chronic exposure to THC causes a regulation of cannabinoid receptors, which appears to be region-specific (Zhuang et al. 1998). For example, while increases in cannabinoid receptor mRNA are seen in the cerebellum and hippocampus at 7 and 14 days of chronic treatment, decreases were seen in the striatum from days 2 to 14. However, levels returned to normal in all the regions by day 21, which coincides with reports of behavioral tolerance. 

Huang etal. assumed that N-arachidonoyl-dopamine (NADA) may exist as an endogenous capsaicin-like cannabinoid in mammalian nervous tissues and may possibly bind to the vanilloid receptor VRl. They found that NADA is indeed a natural endocannabinoid, in nervous tissues, with high concentrations found in the striatum, hippocampus, and cerebellum. They were also found in lower concentrations in the dorsal root ganglion. NADA binds to the cannabinoid receptors with a 40-fold selectivity for the CBi (K = 250 it 130 nM) over the CB2 receptors. 

Brain cannabinoid receptor. In humans, psychoactive cannabinoids produce euphoria, enhancement of sensory perception, tachycardia, antinociception, difficulties in concentration, and impairment of memory. The cognitive deficiencies persist after withdrawal. The toxicity of cannabis has been underestimated for a long time, since recent findings revealed that A-9-THG-induced cell death with shrinkage of neurons and DNA fragmentation in the hippocampus. The acute effects of cannabinoids, as well as the development of tolerance, are mediated by G protein-coupled cannabinoid receptors. The CBl receptor and its splice variant, CBl A, are found predominantly in the brain with highest densities in the hippocampus, cerebellum, and striatum. The CB2 receptor is found predominantly in the spleen and in hemopoi-... 

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. 

Autoradiographic localization of brain cannabinoid receptors using a labeled probe has revealed a unique distribution. Binding is most dense in the outflow nuclei of the basal ganglia, in the substantia nigra pars reticulata, the globus pallidus, the hippocampus, and cerebellum. 

A G protein-coupled cannabinoid receptor (CB1) is most numerous in the outflow nuclei of the basal ganglia, the substantia nigra, pars reticulata, globus pallidus, hippocampus, and brainstem. Positron emission tomographic (PET) studies have revealed increases in metabolism following THC in the same areas in which receptors are localized, suggesting that these receptors are closely involved in the clinical actions of the drug. 

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. 

Takahashi KA, Castillo PE (2006) The CB1 cannabinoid receptor mediates glutamatergic synaptic suppression in the hippocampus. Neurosci 139(3) 795-802 Takahashi RN, Pamplona FA, Fernandes MS (2005) The cannabinoid antagonist SR141716A facilitates memory acquisition and consolidation in the mouse elevated T-maze. Neurosci Lett 380(3) 270-75... 

Sjostrom PJ, Turrigiano GG, Nelson SB (2003) Neocortical LTD via coincident activation of presynaptic NMDA and cannabinoid receptors. Neuron 39 41 Somogyi P, Klausberger T (2005) Defined types of cortical interneurone structure space and spike timing in the hippocampus. J Physiol (Lond) 562 9-26 Spafford JD, Zamponi GW (2003) Functional interactions between presynaptic calcium channels and the neurotransmitter release machinery. Curr Opin Neurobiol 13 308-14 Staley K (1992) Enhancement of the excitatory actions of GABA by barbiturates and benzodiazepines. Neurosci Lett 146 105-7... 

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. 

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