Blockade of cannabinoid receptors by SR141716 selectively increases Fos expression in rat mesocorticolimbic areas via reduced dopamine D-2 function

The present study investigated, in rats, whether blockade of cannabinoid CB 1 receptors may alter Fos protein expression in a manner comparable to that observed with antipsychotic drugs. Intraperitoneal administration of the s elective CB1 receptor antagonist, SR141716, dose-dependently (1.0, 3.0 and 10 mg/kg) increased Fos-like immunoreactivity in mesocorticolimbic areas (p refrontal cortex, ventrolateral septum, shell of the nucleus accumbens and dorsomedial caudate-putamen), while motor-related structures such as the co re of the nucleus accumbens and the dorsolateral caudate-putamen were unaff ected. In the ventrolateral septum, taken as a representative structure, th e Fos-inducing effect of SR141716 (10 mg/kg) was maximal 2 h after injectio n and returned to near control levels by 4 h. Within the prefrontal cortex, SR141716 increased the number of Fos-positive cells predominantly in the i nfralimbic and prelimbic cortices, presumptive pyramidal cells being the ma jor cell types in which Fos was induced, The D-1-like receptor antagonist, SCH23390 (0.1 mg/kg), did not prevent the Fos-inducing effect of SR141716 in any brain region examined (prefrontal c ortex, nucleus accumbens, ventrolateral septum and dorsomedial caudate-puta men), although SCH23390 significantly reduced Fos expression induced by coc aine (20 mg/kg) in all these regions. By contrast, the dopamine D-2-like ag onist, quinpirole (0.25 mg/kg), counteracted SR141716-induced Fos-like immu noreactivity in the ventrolateral septum, the nucleus accumbens and the dor somedial candate-putamen, while no antagonism was observed in the prefronta l cortex, Microdialysis experiments in awake rats indicated that SR141716, at doses which increased Fos expression (3 and 10 mg/kg), did nor alter dop amine release in the shell of the nucleus accumbens. Finally, SR141716 incr eased the levels of neurotensin-like immunoreactivity in the nucleus accumb ens, 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 aty pical neuroleptic drugs. (C) 1999 IBRO. Published by Elsevier Science Ltd.