Zuzana Justinova1, Gianluigi Tanda, Patrik Munzar, Steven R Goldberg. 1. Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD 21224, USA.
Abstract
RATIONALE: Experimental evidence from animal studies suggests reciprocal functional interactions between endogenous brain cannabinoid and opioid systems. There is recent evidence for a role of the opioid system in the modulation of the reinforcing effects of synthetic cannabinoid CB1 receptor agonists in rodents. Since Delta(9)-tetrahydrocannabinol (THC), the natural psychoactive ingredient in marijuana, is actively and persistently self-administered by squirrel monkeys, this provides an opportunity to directly study involvement of opioid systems in the reinforcing effects of THC in non-human primates. OBJECTIVES: To study the effects of naltrexone, an opioid antagonist, on THC self-administration behavior in squirrel monkeys. METHODS: Monkeys pressed a lever for intravenous injections of THC under a ten-response, fixed-ratio (FR) schedule with a 60-s time-out after each injection. Effects of pre-session treatment with naltrexone (0.03-0.3 mg/kg intramuscularly, 15 min before session) for 5 consecutive days on self-administration of different doses of THC (2-8 microg/kg per injection) were studied. RESULTS: Self-administration responding for THC was significantly reduced by pretreatment with 0.1 mg/kg naltrexone for five consecutive daily sessions. Naltrexone pretreatment had no significant effect on cocaine self-administration responding under identical conditions. CONCLUSIONS: Self-administration behavior under a fixed-ratio schedule of intravenous THC injection was markedly reduced by daily pre-session treatment with naltrexone, but remained above saline self-administration levels. These findings demonstrate for the first time the modulation of the reinforcing effects of THC by an opioid antagonist in a non-human primate model of marijuana abuse.
RATIONALE: Experimental evidence from animal studies suggests reciprocal functional interactions between endogenous brain cannabinoid and opioid systems. There is recent evidence for a role of the opioid system in the modulation of the reinforcing effects of synthetic cannabinoid CB1 receptor agonists in rodents. Since Delta(9)-tetrahydrocannabinol (THC), the natural psychoactive ingredient in marijuana, is actively and persistently self-administered by squirrel monkeys, this provides an opportunity to directly study involvement of opioid systems in the reinforcing effects of THC in non-human primates. OBJECTIVES: To study the effects of naltrexone, an opioid antagonist, on THC self-administration behavior in squirrel monkeys. METHODS: Monkeys pressed a lever for intravenous injections of THC under a ten-response, fixed-ratio (FR) schedule with a 60-s time-out after each injection. Effects of pre-session treatment with naltrexone (0.03-0.3 mg/kg intramuscularly, 15 min before session) for 5 consecutive days on self-administration of different doses of THC (2-8 microg/kg per injection) were studied. RESULTS: Self-administration responding for THC was significantly reduced by pretreatment with 0.1 mg/kg naltrexone for five consecutive daily sessions. Naltrexone pretreatment had no significant effect on cocaine self-administration responding under identical conditions. CONCLUSIONS: Self-administration behavior under a fixed-ratio schedule of intravenous THC injection was markedly reduced by daily pre-session treatment with naltrexone, but remained above saline self-administration levels. These findings demonstrate for the first time the modulation of the reinforcing effects of THC by an opioid antagonist in a non-human primate model of marijuana abuse.
Authors: M Navarro; M R Carrera; W Fratta; O Valverde; G Cossu; L Fattore; J A Chowen; R Gomez; I del Arco; M A Villanua; R Maldonado; G F Koob; F Rodriguez de Fonseca Journal: J Neurosci Date: 2001-07-15 Impact factor: 6.167
Authors: Taco J De Vries; Judith R Homberg; Rob Binnekade; Halfdan Raasø; Anton N M Schoffelmeer Journal: Psychopharmacology (Berl) Date: 2003-04-01 Impact factor: 4.530
Authors: Zuzana Justinova; Regina A Mangieri; Marco Bortolato; Svetlana I Chefer; Alexey G Mukhin; Jason R Clapper; Alvin R King; Godfrey H Redhi; Sevil Yasar; Daniele Piomelli; Steven R Goldberg Journal: Biol Psychiatry Date: 2008-09-23 Impact factor: 13.382