A paradoxical regulation of the dopamine D3 receptor expression suggests the involvement of an anterograde factor from dopamine neurons.

Abstract

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 ofin 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 -aminobutyric acid receptor agonist reducing dopamine neuron activity, but not by sustained blockade of Dil-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.The dopamine (DA) D3 and D4 receptors, two receptors displaying similarities with the DA D2 receptor, have been recently identified. Their high sequence homology (1, 2), similar coupling to guanine nucleotide binding proteins (3-5), and recognition by antipsychotic drugs (1, 2, 6, 7) have raised questions regarding the functional significance of this diversity.Receptor diversity may allow a single neurotransmitter to exert distinct influences on various target neurons. In this respect, D3 and, even more, D4 receptors seem to be expressed in much more restricted brain areas and in distinct neuronal populations as compared to the D2 receptor (1, 2, 8). The D4 receptor, however, seems to mediate, like the D2 receptor, inhibition of adenylyl cyclase (5). In the case of the D3 recepThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.tor, the signaling system in cerebral neurons remains to be identified but its stimulation may trigger responses opposite to tho...

Long-Term Effects of S(+)N-n-Propylnorapomorphine Compared with Typical and Atypical Antipsychotics: Differential Increases of Cerebrocortical D2-Like and Striatolimbic D4-Like Dopamine Receptors

“…Neither D 2 nor D 3 receptor upregulation was detected in CPu or ACC after long-term treatment with clozapine or (ϩ)-NPA, and fluphenazine evidently increased D 2 but not D 3 binding (Tables 4 and 5 (Table 5), consistent with previous findings after antipsychotic treatment (Levésque et al 1995;). Lack of a response of D 3 receptors to repeated treatment with DA antagonists may reflect their inability to upregulate in response to prolonged blockade, perhaps paralleling their limited or inconsistent interactions with G-proteins and second- (Sokoloff et al 1990;Baldessarini and Tarazi 1996).…”

Loss of Dopamine D2 Receptors in Alzheimer's Disease with Parkinsonism But Not Parkinson's or Alzheimer's Disease

“…Murray et al 1994). Studies in the rat indicate D 3 receptors may be regulated by loss of DA afferents differently from the D 2 receptor and produce a reduction in number (Lévesque et al 1995). We have recently demonstrated that striatal DA loss in PD also alters D 3 receptors in a manner opposing that of D 2 receptors and, thus, make it difficult to differentiate between these effects in this study (Ryoo et al 1998).…”

Distribution of Dopamine D3 Receptor Expressing Neurons in the Human Forebrain Comparison with D2 Receptor Expressing Neurons

“…Thus, brain areas with relatively high densities of D 3 receptors may be under tonic regulatory influence of the brain dopaminergic system, even if the dopaminergic innervation is sparse. D 2 and D 3 receptors may elicit opposing responses in neurons Lévesque et al 1995;Surmeier et al 1996), and may respond differently to loss of DA or antipsychotic treatment (reviewed in Joyce and Meador-Woodruff 1997). Our data provide initial insight into details of distribution and co-expression of DA D 2 and D 3 receptors in the human brain.…”