title: Blockade of cannabinoid receptors by SR141716 selectively increases Fos expression in rat mesocorticolimbic areas via reduced dopamine D2 function.
abstract: The present study investigated, in rats, whether blockade of cannabinoid CB1 receptors may alter Fos protein expression in a manner comparable to that observed with antipsychotic drugs. Intraperitoneal administration of the selective CB1 receptor antagonist, SR141716, dose-dependently (1.0, 3.0 and 10 mg/kg) increased Fos-like immunoreactivity in mesocorticolimbic areas (prefrontal cortex, ventrolateral septum, shell of the nucleus accumbens and dorsomedial caudate-putamen), while motor-related structures such as the core of the nucleus accumbens and the dorsolateral caudate-putamen were unaffected. In the ventrolateral septum, taken as a representative structure, the Fos-inducing effect of SR141716 (10 mg/kg) was maximal 2 h after injection and returned to near control levels by 4 h. Within the prefrontal cortex, SR141716 increased the number of Fos-positive cells predominantly in the infralimbic and prelimbic cortices, presumptive pyramidal cells being the major cell types in which Fos was induced. The D1-like receptor antagonist, SCH23390 (0.1 mg/kg), did not prevent the Fos-inducing effect of SR141716 in any brain region examined (prefrontal cortex, nucleus accumbens, ventrolateral septum and dorsomedial caudate-putamen), although SCH23390 significantly reduced Fos expression induced by cocaine (20 mg/kg) in all these regions. By contrast, the dopamine D2-like agonist, quinpirole (0.25 mg/ kg), counteracted SR141716-induced Fos-like immunoreactivity in the ventrolateral septum, the nucleus accumbens and the dorsomedial caudate-putamen, while no antagonism was observed in the prefrontal cortex. Microdialysis experiments in awake rats indicated that SR141716, at doses which increased Fos expression (3 and 10 mg/kg), did not alter dopamine release in the shell of the nucleus accumbens. Finally, SR141716 increased the levels of neurotensin-like immunoreactivity in the nucleus accumbens, but not in the caudate-putamen. Collectively, the present results show that blockade of cannabinoid receptors increases Fos- and neurotensin-like immunoreactivity with characteristics comparable to those reported for atypical neuroleptic drugs.
authors.affiliation: Sanofi Recherche, Department of Neuropsychiatry, Montpellier, France.
authors.forename: R
authors.initials: R
authors.lastname: Alonso
authors.forename: B
authors.initials: B
authors.lastname: Voutsinos
authors.forename: M
authors.initials: M
authors.lastname: Fournier
authors.forename: C
authors.initials: C
authors.lastname: Labie
authors.forename: R
authors.initials: R
authors.lastname: Steinberg
authors.forename: J
authors.initials: J
authors.lastname: Souilhac
authors.forename: G
authors.initials: G
authors.lastname: Le Fur
authors.forename: P
authors.initials: P
authors.lastname: Soubrié
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D002186:Cannabinoids / Q000037:antagonists & inhibitors; D004298:Dopamine / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D016762:Genes, fos / Q000187:drug effects*; D008032:Limbic System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D017551:Microdialysis; D009496:Neurotensin / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043882:Receptors, Cannabinoid; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000502:physiology*; D011955:Receptors, Drug / Q000037:antagonists & inhibitors / Q000502:physiology*; D000077285:Rimonabant
chemical_list: D002186:Cannabinoids; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D017448:Receptors, Dopamine D2; D011955:Receptors, Drug; D009496:Neurotensin; D000077285:Rimonabant; D004298:Dopamine