The D3 dopamine receptor is a member of the family of D2-like dopamine receptors. Since the cloning and identification of the D3 receptor in 1990, considerable progress has been made towards understanding the function of this novel site. Although some avenues of investigation have yielded more definitive results than others, studies to date indicate the D3 receptor is localized preferentially in limbic brain areas and affects locomotion and perhaps reinforcement and reward. A subpopulation of the receptors appear to be autoreceptors which modulate dopamine synthesis, release, and neuronal activity. These observations have led to the hypothesis that the D3 receptor may be an appropriate target in the treatment of neuropsychiatric disorders such as schizophrenia and drug addiction. The role of D3 sites in disease, however, remains to be established. Genetic association of D3 receptor polymorphisms with neuropsychiatric disorders have been proposed. Alterations in expression of D3 sites may occur in some diseases. Although the study of this receptor is clearly in the early stages, these findings lay the foundation for future investigation. In this review, dopamine D3 receptor brain localization, cellular signaling mechanisms, and associated behavior will be discussed. The potential role of the D3 site in neuropsychiatric disorders and as a therapeutic target is also addressed.
The D 3 dopamine receptor has been proposed as a potential antipsychotic site. In this study, the effects of the D 3 -preferring compounds 7-OH-DPAT and nafadotride on levels of proneurotensin/neuromedin N (proNT/NThe D 3 dopamine receptor, cloned in 1990 by Sokoloff and colleagues, is similar in sequence and pharmacology to the D 2 receptor (Sokoloff et al. 1990). Although present in roughly 10-fold lower density than D 1 or D 2 receptors, the D 3 receptor is of particular interest because it is expressed primarily in brain regions such as the nucleus accumbens, olfactory tubercle, and islands of Calleja (Bouthenet et al. 1991;Bancroft et al. 1998), terminal fields of the mesolimbic dopamine projection that has been hypothesized to mediate psychotic symptoms (Stevens 1973). Unlike the D 2 receptor, only very low densities of D 3 receptors are detected in either the caudate nucleus or the pituitary, brain areas associated with the untoward neurological and endocrine effects, respectively, associated with most conventional antipsychotics. These observations suggest that the D 3 receptor, alone or in conjunction with other receptors, may be a target for novel antipsychotic drugs with an improved side effect profile (Sokoloff et al. 1990 Received October 13, 1998; revised February 8, 1999; accepted February 15, 1999. N EUROPSYCHOPHARMACOLOGY 1999 -VOL . 21 , NO . 2 7-OH-DPAT, Nafadotride Effects on ProNT/N mRNA 305Although it is well established that clinically efficacious antipsychotic drugs are dopamine antagonists (for review see Seeman 1981), it is likely that the therapeutic effects of these drugs are not mediated solely by dopamine receptors. Considerable evidence suggests that the peptide neurotransmitter neurotensin (NT) may also play a role in the pharmacological effects of antipsychotic drugs (for review see Nemeroff et al. 1992). Of note, the behavioral and physiological effects of NT in animals are similar to those produced by antipsychotic drugs. Moreover, NT concentrations in the cerebrospinal fluid (CSF) of some schizophrenic patients is lower than that of controls. Treatment of these patients with antipsychotic drugs is associated with increases in CSF NT concentrations to control levels. Similarly, both acute and chronic treatment with typical antipsychotic drugs, such as haloperidol, increase NT concentrations and density of proneurotensin/neuromedin N (proNT/N) mRNA, the mRNA encoding NT, in specific brain regions, most notably the nucleus accumbens and caudate nucleus, of the rat (Govoni et al. 1980;Merchant et al. 1991). These observations suggest that antipsychotic drugs produce an increase in regional NT concentrations that results, at least in part, from an increase in biosynthesis (Merchant et al. 1992a(Merchant et al. , 1994b.A previous study using the antipsychotic drug haloperidol suggests that, in contrast to D 2 blockade, blockade of D 3 receptors may decrease levels of proNT/N mRNA (Diaz et al. 1994). This observation suggests that blockade of D 3 sites may ultimately decrease...
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