title: Persistent and anatomically selective reduction in prefrontal cortical dopamine metabolism after repeated, intermittent cannabinoid administration to rats.
abstract: Long-term abuse of delta-9-tetrahydrocannabinol (THC), the major psychoactive constituent of marijuana, produces behavioral and metabolic signs of frontal cortical dysfunction in humans; these effects persist even after short-term abstinence. Based on a preliminary finding that repeated administration of THC to rats reduces basal frontal cortical dopamine turnover (Jentsch et al. [1998] Neurosci Lett 246:169-172), we further investigated the effects of repeated administrations of THC or WIN 55,212-2 (WIN), a synthetic cannabinoid receptor agonist, on dopamine turnover in the prefrontal cortex, striatum, and nucleus accumbens. THC or WIN (twice daily for 7 or 14 days) caused a persistent and selective reduction in medial prefrontal cortical dopamine turnover; no significant alterations of dopamine metabolism were observed in the nucleus accumbens or striatum. Importantly, these dopaminergic deficits in the prefrontal cortex were observed after a drug-free period of up to 14 days. Thus, the cognitive dysfunction produced by heavy, long-term cannabis use may be subserved, in part, by drug-induced alterations in frontal cortical dopamine turnover.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Verrico
authors.forename: J David
authors.initials: JD
authors.lastname: Jentsch
authors.forename: Robert H
authors.initials: RH
authors.lastname: Roth
mesh_terms: D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D048588:Benzoxazines; D002186:Cannabinoids / Q000008:administration & dosage / Q000494:pharmacology*; D003342:Corpus Striatum / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000032:analysis / Q000378:metabolism*; D013759:Dronabinol / Q000008:administration & dosage / Q000494:pharmacology; D006213:Hallucinogens / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D000700:Analgesics; D048588:Benzoxazines; D002186:Cannabinoids; D006213:Hallucinogens; D009025:Morpholines; D009281:Naphthalenes; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D013759:Dronabinol; D004298:Dopamine