title: Enhancement of endocannabinoid neurotransmission through CB1 cannabinoid receptors counteracts the reinforcing and psychostimulant effects of cocaine.
abstract: Cannabinoids, in contrast to typical drugs of abuse, have been shown to exert complex effects on behavioural reinforcement and psychomotor function. We have shown that cannabinoid agonists lack reinforcing/rewarding properties in the intracranial self-stimulation (ICSS) paradigm and that the CB1 receptor (CB1R) agonist WIN55,212-2 attenuates the reward-facilitating actions of cocaine. We sought to determine the effects of the endocannabinoid neurotransmission enhancer AM-404 (1, 3, 10, 30 mg/kg) on the changes in ICSS threshold and locomotion elicited by cocaine and extend the study of the effects of WIN55,212-2 (0.3, 1, 3 mg/kg) on cocaine-induced hyperlocomotion. AM-404 did not exhibit reward-facilitating properties, and actually increased self-stimulation threshold at the highest dose. Cocaine significantly reduced self-stimulation threshold, without altering maximal rates of responding. AM-404 (10 mg/kg) attenuated this action of cocaine, an effect which was reversed by pretreatment with the selective CB1R antagonist SR141716A. WIN55,212-2 decreased locomotion at the two highest doses, an effect that was blocked by SR141716A; AM-404 had no effect on locomotion. Cocaine caused a significant, dose-dependent increase in locomotion, which was reduced by WIN55,212-2 and AM-404. SR141716A blocked the effects of WIN55,212-2 and AM-404 on cocaine-induced hyperlocomotion. SR141716A alone had no effect on ICSS threshold or locomotion. These results indicate that cannabinoids may interfere with brain reward systems responsible for the expression of acute reinforcing/rewarding properties of cocaine, and provide further evidence that the cannabinoid system could be explored as a potential drug discovery target for the treatment of psychostimulant addiction and pathological states associated with psychomotor overexcitability.
authors: Laboratory of Behavioral Neuroscience, Department of Psychology, School of Social Sciences, University of Crete, Rethymnon, Crete, Greece.
authors: Styliani
authors: S
authors: Vlachou
authors: Fygaleia
authors: F
authors: Stamatopoulou
authors: George G
authors: GG
authors: Nomikos
authors: George
authors: G
authors: Panagis
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D048588:Benzoxazines / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000502:physiology*; D000697:Central Nervous System Stimulants / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D003042:Cocaine / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D063388:Endocannabinoids; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D009281:Naphthalenes / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects*; D012201:Reward; D000077285:Rimonabant; D012653:Self Stimulation; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
chemical_list: D001095:Arachidonic Acids; D048588:Benzoxazines; D063385:Cannabinoid Receptor Modulators; D000697:Central Nervous System Stimulants; D063388:Endocannabinoids; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D003042:Cocaine; D000077285:Rimonabant; C107594:N-(4-hydroxyphenyl)arachidonylamide