Zuzana Justinova1, Gianluigi Tanda, Godfrey H Redhi, 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: Interest in therapeutic activities of cannabinoids has been restrained by the fact that they are most often mediated through activation of cannabinoid CB1 receptors, the same receptors that mediate the effects of delta9-tetrahydrocannabinol (THC) and are responsible for the abuse liability of marijuana. Persistent intravenous self-administration of THC by animals was first demonstrated in squirrel monkeys and shown to be mediated by CB1 receptors, but monkeys in the study had a history of cocaine self-administration, raising the possibility that persistent neurobiological adaptations might subsequently predispose animals to self-administer THC. OBJECTIVES: To demonstrate persistent intravenous self-administration of THC in drug-naive squirrel monkeys. METHODS: Monkeys with no history of exposure to other drugs learned to press a lever for intravenous injections (0.2 ml in 0.2 s) of THC under a 10-response, fixed-ratio schedule with a 60-s time-out after each injection. Acquisition of THC self-administration was rapid and the final schedule was reached in 11-34 sessions. Dose of THC was then varied from 1 to 16 microg/kg per injection with vehicle extinction following each dose of THC. RESULTS: THC maintained significantly higher numbers of self-administered injections per session and higher rates of responding than vehicle at doses of 2, 4 and 8 microg/kg per injection, with maximal rates of responding at 4 microg/kg per injection. Response rates, injections per session and total THC intake per session were two- to three-fold greater in monkeys with no history of exposure to other drugs compared to previous findings in monkeys with a history of cocaine self-administration. CONCLUSIONS: THC can act as an effective reinforcer of drug-taking behavior in monkeys with no history of exposure to other drugs, suggesting that self-administration of THC by monkeys provides a reliable animal model of human marijuana abuse.
RATIONALE: Interest in therapeutic activities of cannabinoids has been restrained by the fact that they are most often mediated through activation of cannabinoid CB1 receptors, the same receptors that mediate the effects of delta9-tetrahydrocannabinol (THC) and are responsible for the abuse liability of marijuana. Persistent intravenous self-administration of THC by animals was first demonstrated in squirrel monkeys and shown to be mediated by CB1 receptors, but monkeys in the study had a history of cocaine self-administration, raising the possibility that persistent neurobiological adaptations might subsequently predispose animals to self-administer THC. OBJECTIVES: To demonstrate persistent intravenous self-administration of THC in drug-naive squirrel monkeys. METHODS: Monkeys with no history of exposure to other drugs learned to press a lever for intravenous injections (0.2 ml in 0.2 s) of THC under a 10-response, fixed-ratio schedule with a 60-s time-out after each injection. Acquisition of THC self-administration was rapid and the final schedule was reached in 11-34 sessions. Dose of THC was then varied from 1 to 16 microg/kg per injection with vehicle extinction following each dose of THC. RESULTS:THC maintained significantly higher numbers of self-administered injections per session and higher rates of responding than vehicle at doses of 2, 4 and 8 microg/kg per injection, with maximal rates of responding at 4 microg/kg per injection. Response rates, injections per session and total THC intake per session were two- to three-fold greater in monkeys with no history of exposure to other drugs compared to previous findings in monkeys with a history of cocaine self-administration. CONCLUSIONS:THC can act as an effective reinforcer of drug-taking behavior in monkeys with no history of exposure to other drugs, suggesting that self-administration of THC by monkeys provides a reliable animal model of humanmarijuana 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: Francesca M Filbey; Joseph P Schacht; Ursula S Myers; Robert S Chavez; Kent E Hutchison Journal: Neuropsychopharmacology Date: 2009-12-09 Impact factor: 7.853
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