Neuropharmacology 47 (2004) 345–358 www.elsevier.com/locate/neuropharm Cannabinoid physiology and pharmacology: 30 years of progress Allyn C. Howlett a,c, , Christopher S. Breivogel b , Steven R. Childers c , Samuel A. Deadwyler c , Robert E. Hampson c , Linda J. Porrino c a Neuroscience of Drug Abuse Research Program, Julius L. Chambers Biomedical/Biotechnology Research Institute at North Carolina Central University, Durham, NC 27707, USA b Department of Pharmaceutical Sciences, Campbell University School of Pharmacy, Buies Creek, NC 27506, USA c Department of Physiology/Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA Received 18 May 2004; received in revised form 23 July 2004; accepted 23 July 2004 Abstract D 9 -Tetrahydrocannabinol from Cannabis sativa is mimicked by cannabimimetic analogs such as CP55940 and WIN55212-2, and antagonized by rimonabant and SR144528, through G-protein-coupled receptors, CB 1 in the brain, and CB 2 in the immune system. Eicosanoids anandamide and 2-arachidonoylglycerol are the ‘‘endocannabinoid’’ agonists for these receptors. CB 1 recep- tors are abundant in basal ganglia, hippocampus and cerebellum, and their functional activity can be mapped during behaviors using cerebral metabolism as the neuroimaging tool. CB 1 receptors couple to G i/o to inhibit cAMP production, decrease Ca 2+ conductance, increase K + conductance, and increase mitogen-activated protein kinase activity. Functional activation of G-pro- teins can be imaged by [35S]GTPcS autoradiography. Post-synaptically generated endocannabinoids form the basis of a retro- grade signaling mechanism referred to as depolarization-induced suppression of inhibition (DSI) or excitation (DSE). Under circumstances of sufficient intracellular Ca 2+ (e.g., burst activity in seizures), synthesis of endocannabinoids releases a diffusible retrograde messenger to stimulate presynaptic CB 1 receptors. This results in suppression of c-aminobutyric acid (GABA) release, thereby relieving the post-synaptic inhibition. Tolerance develops as neurons adjust both receptor number and cellular signal transduction to the chronic administration of cannabinoid drugs. Future therapeutic drug design can progress based upon our current understanding of the physiology and pharmacology of CB 1 ,CB 2 and related receptors. One very important role for CB 1 antagonists will be in the treatment of craving in the disease of substance abuse. # 2004 Published by Elsevier Ltd. Keywords: Adenylyl cyclase; Anandamide; Antinociception; 2-Arachidonoylglycerol; Basal ganglia; Cognition; CP55940; Depolarization-induced suppression of inhibition (DSI); Dronabinol; Endocannabinoid; G-protein-coupled receptors; Hippocampus; Limbic system; Memory; Rimonabant; SR141716; Striatum; D9-Tetrahydrocannabinol; Voltage controlled Ca 2+ channels; WIN55212-2 1. Cannabinoid pharmacology 1.1. Plant-derived and synthetic cannabimimetic agents Ingestion of Cannabis sativa preparations such as marijuana (leaves and flowering tops) or ganja (resin) results in an intoxication characterized by sedation, cognitive dysfunction, failure to consolidate short-term memory, alteration in time assessment, perceptual changes, motor incoordination and poor executive function (see Abood and Martin, 1992; Dewey, 1986; Hollister, 1986; Pertwee, 1988 for review). Cannabinoid compounds isolated from the plant C. sativa comprise a familyoftricyclicringstructurescharacterizedbyaphe- nol ring having a 5-carbon alkyl chain meta to the hydroxyl, a central pyran ring, and a mono-unsaturated cyclohexyl ring (Fig. 1) (see Mechoulam, 1970; Agurell etal.,1986;Howlettetal.,2002 forreview).Cannabinoid receptor pharmacology as we now know it began 40 years ago when D 9 -tetrahydrocannabinol (D 9 -THC) (Fig. 1) was isolated and synthesized by Mechoulam’s laboratory, and demonstrated to be the primary psy- choactive constituent of marijuana (Mechoulam et al., 1967; Mechoulam and Gaoni, 1967). Other cannabinoid compounds, including cannabinol and cannabidiol, fail  Corresponding author. Tel.: +1-919-530-7032; fax +1-919-530- 7760. E-mail address: ahowlett@wpo.nccu.edu (A.C. Howlett). 0028-3908/$ - see front matter # 2004 Published by Elsevier Ltd. doi:10.1016/j.neuropharm.2004.07.030