A late appearance by the dopamine D‐3 receptor

The D-3 dopamine receptor was first cloned in 1990 and was shown to be present largely in limbic regions of the brain, with much lower levels expressed in striatal areas. Many neuroleptic drugs, as well as dopamine agonists, were shown to interact with D-3 receptors and in some cases with a higher affinity than for D-2 receptors (including haloperidol and clozapine, but see McCormick et al.). In subsequent years, the D-3 receptor was targeted as a site of action for potential novel antipsychotic drugs, but this aspiration has yet to be achieved. More recently, alterations in D-3 receptor density were examined in relation to Parkinson’s disease (PD) in tissues from 6hydroxydopamine (6-OHDA) lesioned rat and 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)treated primates, and in post-mortem tissues from individuals dying with PD. Some studies found a proliferation of D-3 receptors in the striatum after exposure to levodopa and specifically in animals that developed abnormal involuntary movements (AIMs) or dyskinesia, although no consensus was reached. Subsequently D-3 antagonists or partial agonists were shown to suppress levodopa-induced dyskinesia in MPTP-treated primates and to prevent dyskinesia induction. These studies served to establish a link between the D-3 receptor and involuntary movements, at least in PD. As with dyskinesia in PD, the genesis of tardive dyskinesia (TD) occurring as a result of exposure to antipsychotic drugs has proved difficult to unravel. The late occurrence of dyskinetic movements, classically affecting the oro-buccal-facial-lingual areas, was initially associated with typical neuroleptic agents, but it is now known to occur with second-generation atypical antipsychotics, although to a lesser degree. The exception to this rule is clozapine, whose actions have never been explained or mimicked. The classical explanation for TD has been that D-2 receptor sensitization takes place, but this has never been totally satisfactory. Some similarities have been seen in markers of striatal output pathway function that are changed in response to chronic administration of antiparkinsonian drugs in 6-OHDA lesioned rats and normal rats treated chronically with classical antipsychotic drugs. This suggests that despite opposing actions on postsynaptic striatal dopamine receptors, dopamine agonist and antagonist compounds might induce common changes linked to dyskinesia induction, and that brings us back to the role that D-3 receptors might play in the induction of TD. One problem has been the veracity of the studies needed to explore the pathophysiology of TD in terms of time required for drug treatment to lead to induction and expression of late onset dyskinesia. However, the chronic administration of neuroleptic drugs to both Old and New World monkeys has long been known to lead to the late onset of dyskinetic movements. Cebus apella (capuchin monkeys) are considered more susceptible to the development of TD, and one reason may relate to the Ser9Gly polymorphism that they carry in the D-3 receptor gene, which has been suggested as a susceptibility factor for the development of TD in some populations. This may be highly relevant to the studies now reported by Mahmoudi and colleagues, in which they have compared the effects of haloperidol and clozapine administration for up to 36 months on the expression of D-1, D-2, and D-3 receptors and markers of striatal output pathway activity in Cebus apella. In their study, the administration of haloperidol for 36 months resulted in mild dyskinetic movements, which they described in a previous publication. Dyskinesia appeared with a latency of some 19 months in some animals but not in others, so providing one essential control group for the effect of drug treatment alone. In clozapine-treated animals, no dyskinetic movements were seen, although, as the authors point out, the 6-month period of treatment may not have been sufficiently long. A -----------------------------------------------------------*Correspondence to: Professor Peter Jenner, NDRG, Hodgkin Building, King’s College, London SE1 1UL, United Kingdom, E-mail: peter.jenner@kcl.ac. uk