A PARADOXICAL REGULATION OF THE DOPAMINE D-3 RECEPTOR EXPRESSION SUGGESTS THE INVOLVEMENT OF AN ANTEROGRADE FACTOR FROM DOPAMINE NEURONS

The effects of interruption of dopaminergic transmission or sustained blockade of dopamine receptors by neuroleptics on the dopamine D-3 receptor in the shell of the nucleus accumbens were investigated in rats. In this brain area the D-3 receptor is abundant and may mediate antipsychotic drug effects. The D-3 receptor density and mRNA abundance were evaluated With 7-[H-3] hydroxy-N,N-di-n-propyl-2-aminotetralin and by quantitative PCR or image analysis of in situ hybridization signals, respectively. Unilateral dopamine neuron degeneration by 6-hydroxydopamine or sections triggered, after a few days, a marked decrease (up to 50%) in D-3 receptor binding add mRNA in the nucleus accumbens, In contrast, a 2-week treatment With the neuroleptic haloperidol (20 mg/kg) had no effect on DJ receptor density and mRNA but enhanced D-2 receptor density and mRNA level by >50%, In addition, tolerance to the haloperidol-induced change of neurotensin mRNA mediated by the D-2 receptor developed, but there was no tolerance to the opposite change mediated by the D-3 receptor, Reserpine, a monoamine-depleting drug with antipsychotic activity, did not modify D-3 receptor mRNA. These observations reinforce the idea that the D-3 receptor may be an important target for neuroleptics whose antipsychotic actions, but not extrapyramidal motor actions, do not display tolerance, The D-3 receptor mRNA level was also decreased by a unilateral injection in dopamine cell body areas of colchicine, a drug blocking the anterograde axonal transport, or by baclofen, a type A gamma-aminobutyric acid receptor agonist reducing dopamine neuron activity, but not by sustained blockade of D-1-like and D-2-like, neurotensin, or cholecystokinin receptors, We therefore propose that an anterograde factor present in mesolimbic dopaminergic neurons, but distinct from dopamine and known peptide cotransmitters, plays a positive role on transcription of the D-3 receptor gene.