Blockade of cannabinoid receptors by SR141716 selectively increases fos expression in rat mesocorticolimbic areas via reduced dopamine D2 function

• Published in: Neuroscience Vol. 91; no. 2; pp. 607 - 620
• Main Authors: ALONSO, R, VOUTSINOS, B, FOURNIER, M, LABIE, C, STEINBERG, R, SOUILHAC, J, LE FUR, G, SOUBRIE, P
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 01-06-1999
• Subjects: Animals; Biological and medical sciences; Brain - drug effects; Brain - physiology; Cannabinoids - antagonists & inhibitors; Dopamine - metabolism; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Genes, fos - drug effects; Limbic System - drug effects; Limbic System - physiology; Male; Medical sciences; Microdialysis; Neuropharmacology; Neurotensin - metabolism; Pharmacology. Drug treatments; Piperidines - pharmacology; Prefrontal Cortex - drug effects; Prefrontal Cortex - physiology; Psychodysleptics: hallucinogen; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Pyrazoles - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, Cannabinoid; Receptors, Dopamine D2 - drug effects; Receptors, Dopamine D2 - physiology; Receptors, Drug - antagonists & inhibitors; Receptors, Drug - physiology; Rimonabant; Rat; Neuroleptic; Dopamine receptor; Rodentia; Central nervous system; Neurotensin; Cannabinoid; Gene expression; Vertebrata; Mammalia; Animal; Brain (vertebrata); Immediate early gene; Biological receptor
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/S0306-4522(98)00675-7

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.