Clozapine and dopamine D3 receptor antisense reduce cocaine- and amphetamine-regulated transcript expression in the rat nucleus accumbens shell

Cocaine- and amphetamine-regulated transcript (CART) is a neuropeptide highly expressed in the hypothalamus and nucleus accumbens. Hypothalamic CART has been associated with food intake and body weight control, but in the nucleus accumbens the role of CART remains elusive. New generations of antipsychotic drugs show a good efficacy over psychotic symptoms but they induce an important weight gain. The mechanism underlying this unexpected side effect is still unknown. The present results show, for the first time, that acute and chronic treatment with the atypical neuroleptic clozapine, but not the conventional neuroleptic haloperidol, reduced the expression of CART mRNA in the shell of the nucleus accumbens. CART mRNA is colocalized with both dopamine D-2 and D-3 receptor transcripts in the nucleus accumbens shell. However, a dopamine D-3 receptor, but not D-2, antisense oligonucleotide administration reduced CART expression in this brain area. These results suggest that the dopamine D-3 receptor, but not the D-2, is involved in the control of CART expression in the nucleus accumbens and that it may participate in the modulation of CART mRNA levels by clozapine. The modulation of CART, an anorexigenic neuropeptide, in the dopamine mesolimbic pathway may potentially play a role in dysregulated food intake induced by some antipsychotic drugs. (C) 2003 Wiley-Liss, Inc.