Cannabis receptor studies

Endocannabinoids. Figure 1 Chemical structures of the two most studied endocannabinoids, anandamide and 2-arachidonoylglycerol, of Cannabis sativa psychoactive principle, A9-tetrahydrocannabinol, and of the CB-i receptor antagonist/inverse agonist, rimonabant. 

A -THC, the main psychoactive component of cannabis, is a moderately potent partial agonist of the CBi and CB2 receptors, while cannabidiol has little affinity for either receptor (Table 6.7). The term classical cannabinoids is used to describe cannabinoid receptor modulators structurally related to (67), which have a tricyclic dibenzopyran core. While several other structural types of cannabinoid receptor modulators have been discovered in recent years, the classical cannabinoids are still by far the most extensively studied group in terms of SAR and pharmacology. 

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. 

Some people claim that the effects of low doses of salvinorin are similar to Cannabis and have suggested the possibility that like THC, salvinorin A might bind to the anandamide receptor site (CBl). This site had not been looked at in the NovaScreen study, so in 1998, Siebert submitted a sample of salvinorin A to Dr. Raphael... 

Schmetzer et al. [27] performed a joint CoMFA and Yak study for 31 cannabi-noids acting on the CB1 receptor. Starting from a ligand-based pharmacophore model, a classical CoMFA investigation was accomplished yielding a correlation... 

Urigiien, L., Perez-Rial, S., Ledent, C., Palomo, T., and Manzanares, J. (2004). Impaired action of anxiolytic drugs in mice deficient in cannabinoid CB1 receptors. Neuropharmacology 46, 966-973. Vandrey, R. G., Budney, A. J., Moore, B. A., and Hughes, J. R. (2005). A cross-study comparison of cannabis and tobacco withdrawal. Am.J. Addict. 14, 54-63. 

Several studies have investigated how cannabis use and/or the endocannabinoid system itself may be associated with schizophrenia. Although the endogenous cannabinoid system might be implicated in schizophrenia, relatively few studies have analyzed receptor expression or binding in postmortem brain. 

Using in situ radioligand binding, another study reported an increased CB1 density in DLPFC, an effect that was not dependent on previous cannabis use (Dean et al., 2001). In addition, an increased CB1 receptor density in the striatum has been reported, which may have been associated with recent cannabis intake (Dean et al., 2001). Postmortem studies of cannabinoid receptor expression, in particular for the CB1 receptor in PCC, ACC and DLPFC support the involvement of the cannabinoid system in the pathophysiology of schizophrenia. 

Dean B, Sundram S, Bradbury R, Scarr E, Copolov D. 2001. Studies on [3H] CP-55940 binding in the human central nervous system Regional specific changes in density of cannabinoid-1 receptors associated with schizophrenia and cannabis use. Neuroscience 103 9-15. 

Two subtypes of G protein-coupled receptors for cannabis s psychotropic component, A -tetrahydrocannabinol (THC), have been cloned to date, the cannabinoid CBi and CB2 receptors (Howlett et al. 2004). Yet, five different types of endogenous agonists for these cannabinoid receptors have been identified so far (Fig. 1). These compounds, named endocannabinoids by analogy with THC (Di Marzo and Fontana 1995), are all derived from long-chain polyunsaturated fatty acids. In particular (1) the anandamides are amides of ethanolamine with polyunsaturated fatty acids with at least 20 carbon atoms and three 1,4-diene double bonds. The C20 4 homologue in this series, V-arachidonoylethanolamine (AEA) (Devane et al. 1992), also known simply as anandamide, has been most studied. 

Cannabidiol (CBD) is a non-psychotropic component of cannabis with possible therapeutic use as an anti-inflammatory drug. Recent studies on both enantiomers of CBD showed enantioselectivity in their interaction with cannabinoid and vanniloid (VRl) receptors as well as on the cellular uptake and enzymatic hydrolysis of anandamide (Bisogno et al. 2001). 

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. 

The papers listed in Table 3 and discussed in the preceding paragraph represent in vitro studies, and the question arises whether similar results are also obtained in vivo. This was examined in a series of studies on rats subjected to in vivo microdialysis the ligands under study were administered intraperitoneally or intravenously. Cannabinoids indeed decrease acetylcholine release in the dorsal hippocampus (Mishima et al. 2002). In the studies by Tzavara et al. (2001,2003a), in which cannabinoid agonists were not studied themselves, the CBi receptor inverse agonist SR 141716, which elicits effects opposite in direction to those of cannabi-... 

The anecdotal reports of effects of smoking cannabis on cognitive processes has naturally prompted investigation into the effects of cannabinoids on synaptic plasticity, and in particular long-term potentiation (LTP). To summarise 17 years of effort, it has been easy to show that cannabinoids have effects on LTP, and most commonly suppress it, but far more difficult to define the mechanisms by which this occurs. Emerging themes are that the commonly reported inhibition of LTP by synthetic cannabinoids may be mediated by non-CBi receptors, and that the function of the endogenous cannabinoid system may be to facilitate induction of LTP. The vast majority of studies have focussed on synaptic plasticity in the CAI region of the rat hippocampal slice and we will start our review there. 

---