A paradoxical regulation of the dopamine D3 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 D3 receptor in the shell of the nucleus accumbens were investigated in rats. In this brain area the D3 receptor is abundant and may mediate antipsychotic drug effects. The D3 receptor density and mRNA abundance were evaluated with 7-[3H]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 D3 receptor binding and mRNA in the nucleus accumbens. In contrast, a 2-week treatment with the neuroleptic haloperidol (20 mg/kg) had no effect on D3 receptor density and mRNA but enhanced D2 receptor density and mRNA level by > 50%. In addition, tolerance to the haloperidol-induced change of neurotensin mRNA mediated by the D2 receptor developed, but there was no tolerance to the opposite change mediated by the D3 receptor. Reserpine, a monoamine-depleting drug with antipsychotic activity, did not modify D3 receptor mRNA. These observations reinforce the idea that the D3 receptor may be an important target for neuroleptics whose antipsychotic actions, but not extrapyramidal motor actions, do not display tolerance. The D3 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 D1-like and D2-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 D3 receptor gene.