Biochemical, Anatomical and Behavioral Maraderization Allyn C
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The cannabinoid receptor: biochemical, anatomical and behavioral maraderization Allyn C. Howlett, Michelle Bidaut-Russell, William A. Devane, Lawrence S. Melvin, M. RossJohnson and Miles Herkenham Allyn C Howlett, The actions of the active principle of marihuana, t!,9- cannabinoid drug effects in vivo. Assessments of Michelle Bidaut- tetrahydrocannabinol, are mimicked by synthetic can- cannabinoid activity and structure-activity relation- Russell' and William nabinoid agonists showing high potency and enantio- ships for over 100 classical cannabinoids have been A. Devane" are at the selectivity in behavioral assays. These drugs have been compiled by Razdan", Evidence suggests that a Deparlmenfof used to characterize cannabinoid receptor binding, number of the characteristic behavioral effects of Pharmacology, biochemistry and pharmacology, leading to a better cannabinoids may result from their interaction with a Sf Louis University understanding of the effects of cannabinoids in the eNS stereoselective receptor site in the brain, Enantio- School of Medicine, 1402 South Grand of humans and experimental animals. mers of ~ 9_THC have been shown to differ in potency Boulevard St Louis, by ten-to 1oo-fold in depressing schedule-controlled MO 63104, USA, t!,9-Tetrahydrocannabinol (t!,9-THC) has been recog- responding in monkeys or in producing static ataxia in Lawrence S.Melvin nized as the major psychoactive component of mari- dogs/-", ~9-THC and cannabinoid analogs are also andM. Ross huana for over 25 years'. However, until recently a active in lowering body temperature and altering Johnson' are at PFizer mechanism by which ~9-THC and other natural and spontaneous activity in rodentsv". Levonantradol was Central Research. synthetic psychoactive cannabinoids produce their up to 30 times, and HCP-55940 was more than 50 Eastern Point Road, effects in vivo was not readily apparent. Because the times more potent than ~9-THC in these studies, Groton, a06340, cellular and biochemical mechanisms of action of whereas the dextro-isomers were poorly active or USA. and Miles psychoactive cannabinoids were not understood, inactive at the highest concentrations tested? (Table Herkenham is at the Unit of Functional neuroscientists were allowed great breadth to specu- D. Rodents also exhibit a typical immobility (or Neuroanatomy, late upon the influence that these compounds might catalepsy) in response to t!,9-THC and synthetic NIMH, Bethesda, have on neurons in the brain. Over the past two analogs (Table 1)9. MD 20892, USA. decades, a substantial multidisciplinary research effort In vitro studies using cultured neuroblastoma cells, has focused on examining the effects of cannabinoid neuroblastoma X glioma hybrid cells and brain slice compounds on biological and synthetic membranes, preparations demonstrated that one cellular action of ATPase and monoamine oxidase activities, eicosanoid cannabinoid drugs is the reversible inhibition of cAMP metabolism, hormone and neurotransmitter receptor production'v+", Further studies demonstrated that binding, and synaptosomal uptake of neuro- psychoactive cannabinoid compounds inhibit adenylate transmitters+'. Most of the in vitro cannabinoid cyclase activity via the G protein, Gj, suggesting a actions required concentrations of ~9-THC that were receptor-coupled mechanism 10. 12, 13. The inhibition of greater than estimated brain concentrations coinci- adenylate cyclase by natural and synthetic cannabi- dent with biological responses following in vivo noids is enantioselective, and the pharmacological administratiorr-". Furthermore, many in vitro effects profile for regulation of adenylate cyclase correlates of cannabinoids failed to show a structure-activity well with that observed for several animal models of relationship consistent with the in vivo behavioral cannabinoid activity14.15. These findings suggest that pharmacology+', Thus, it was difficult to attribute the the receptor characterized in cell lines is the same as behavioral effects of t!,9-THC to any single in vitro the receptor responsible for certain cannabinoid effect. actions in the CNS9,14.15(Table 1). Significant progress has been made in the cannabi- It is certainly possible that multiple signal transduc- noid field in recent years by using a class of high- tion mechanisms may be found to be linked to potency synthetic compounds originally developed for cannabinoid actions in the CNS. Arachidonic acid their analgetic properties". These compounds are accumulation in response to cannabinoid compounds typified by levonantradol, its active metabolite has been demonstrated in brain slice preparations 16. desacetyllevonantradol, and CP-55940 (Fig. 1). This However, studies suggest that this is not due to a review describes the recent efforts to elucidate the receptor-regulated phospholipase C or phospholipase neurochemical properties and neuroanatomical local- A2, but rather to the inhibition of arachidonic acid ization of a unique receptor for these cannabinoid acylation on membrane lipids17. compounds and speculates on the role that this receptor plays in the effects of cannabinoid com- Localization and functional significance of pounds on behavior. cannabinoid receptors in the brain Synthesis of a potent radiolabeled ligand, [3H]CP- Cannabinoid pharmacology and the cAMP 55940, led to the development of membrane hom- second messenger system ogenate and tissue section binding assays for the Several animal models are currently used to study characterization and localization of the cannabinoid receptor in brain 18. 19 (Devane, W. A., PhD Thesis, St Louis University, 1989). The [3H]CP-55940 binding • Current addresses: Michelle Bidaut-Russell, Department of site is saturable, has high affinity and enantioselec- Psychiatry, St louis University School of Medicine, 1221 SouTh tivity for agonist ligands, and exhibits characteristics Grand Boulevard, St Louis, MO 63104, USA; William A. Devane, Department of Natural Products, Faculty of Medicine, Hebrew expected for a neuromodulator receptor associated University, Jerusalem 91120, Israel; M. RossJohnson. Glaxo, lnc., with a G protein'< 19. As shown in Table I, the relative 5 Moore Drive, Research Triangle Park, NC 27709, USA. potencies with which cannabinoid compounds inhibit 420 TINS, Vol. 13, No. 10, 1990 [3H]CP-55 940 binding parallels the abilities of these the cerebellar molecular layer~s. A9-THC compounds to produce behavioral effects in Receptors are also dense in the animals18,19. A similar structure-activity profile exists cerebral cortex, the neostriatum for receptor binding and the regulation of adenylate and in the remainder of the hippo- cyclase in vitro (Table I) 18,19. High-affinity ligands for campal formation. Comparatively a variety of neurotransmitter, neuromodulator and little binding is observed in the hormonal classes, including adrenergic, cholinergic, brain stem and spinal cord 12,18. dopaminergic, serotonergic, opioid, GABAergic, glu- Current work is addressing the tamatergic, steroid, and prostanoid agonists and roles of cannabinoid receptors in Levonantradol R = COCH3 antagonists, fail to displace [3H]CP-55 940 binding at receptor-rich regions such as the OH Desacetyllevonantradol R : H this receptor 12,18. [3H]CP_55 940 binding is also found basal ganglia. There is evidence in the nervous systems of lower vertebrate species implicating the basal ganglia in the (Table II; Devane, W. A., PhD Thesis, St Louis cataleptic response to cannabinoids seen in rodents22 and in the poten- University, 1989). The cannabinoid receptor appears o to be conserved across species in that the Kd values tiation by Ag-THC and levonan- are similar, and the non-hydrolysable GTP analog tradol of reserpine-induced hypo- guanylyl-[3-y-imidodiphosphate reduces the binding kinesia in a model of Parkinson's CP 55,940 (Devane, W. A., Phi) Thesis, St Louis University, disease in rats and primates ~3. OH 1989). Cannabinoid drugs attenuate the It should be noted that a cannabinoid binding site in Dl-dopaminergic stimulation of o rat brain homogenates has been described using the cAMP production as do D2-dop- ligand [3H]-5'-trimethylammonium AS-THCTM. It is aminergic agonists and opioid clear that this binding site is not the same as that for agonists in striatal slices24. This [3H]CP-55 940, because the density of these two sites suggests that opioid and canna- HO in various brain regions is not similar, and the binoid receptors may be co-local- structure-activity profile for displacement in equilib- ized on the same population of cells rium studies differs. The relative affinities of cannabi- that respond to dopamine. Anatom- Fig. 1. The chemical structures of noid compounds for the [3H]-5'-trimethylammonium ical evidence for this comes from AgTHC and synthetic cannabinoid AS-THC binding site does not correlate well with the observation that cannabinoid, compounds. threshold for behavioral responses in the Rhesus D1- and D2-dopaminergic recep- monkey2°. 5'-Trimethylammonium AS-THC does not tors in the striatum, globus pallidus exhibit biological activity in typical animal behavioral and substantia nigra pars reticulata are lost following models of cannabinoid action21, and thus, the pharma- ibotinic acid lesions of the striatumzS. cological relevance of this binding site remains in Desacetyllevonantradol regulates cAMP production question. in brain regions exhibiting high receptor binding Autoradiography using [3H]CP-55940 reveals a density. Populations of cells in the cortex, hippocam- heterogeneous