Upregulation of dopamine D3, not D2, receptors correlates with tardive dyskinesia in a primate model

Abstract

Background-Tardive dyskinesia (TD) is a delayed and potentially irreversible motor complication arising in patients chronically exposed to centrally-active dopamine D 2 receptor antagonists, including antipsychotic drugs and metoclopramide. The classical dopamine D 2 receptor supersensitivity hypothesis in TD, which stemmed from rodent studies, lacks strong support in humans.

Neuroleptic-Induced Oral-Facial Tardive Dyskinesia in a Prepuberal Boy with an Attention-Deficit Hyperactivity Disorder

“…Recent articles have shown a relationship between the chronic administration of Haloperidol and an increment of the number of D 3 receptors in the striatonigral neurons and the anterior caudateputamen area, especially in animals that developed tardive dyskinesia [5]. Also, the dopamine D 1 receptors were reduced in the anterior putamen, the basal ganglia related with involuntary movements [6].…”

“…If this is a problem in elderly people, it is even a more serious event when it is administrated in children, since adverse effects in humans have been published [2,5,9] and the effect in children has not been established, even though there are evidences in changes in gene expressions of midbrain neurons due to haloperidol administration [6]. For all these reasons we do not recommend haloperidol for the treatment of Attention-Deficit Hyperactivity Disorder in children, at least until new studies have been done.…”

Identification and management of tardive dyskinesia: A case series and literature review

“…The most prominent traditional explanatory models have been attributed to dopamine D 2 receptor supersensitivity, which has been recently confirmed by primate model research suggesting for the first time that upregulated striatal D 3 receptors correlate with TD and that the D 3 receptor could provide a novel target for medication intervention in TD [17]. Other findings have implicated other causes such as GABA depletion, disturbed balance between dopamine and cholinergic systems, neurotoxicity and oxidative stress, changes in synaptic plasticity and defective neuroadaptive signaling [10][11][12].…”

“…Spontaneous Dyskinesia in antipsychotic naive patients with schizophrenia ranges from 4 to 40%, depending on the age and duration of the illness. Once developed, TD seems very persistent, the course of TD might be mediated by the affinity for the dopamine D 2 and D 3 receptors [12,17]. Prevalence of TD is estimated to be 20-50% of all patients treated with antipsychotics, with prevalence increasing with advanced age [18,19].…”

Current drug treatments targeting dopamine D3 receptor

“…A number of animal studies supports a critical role of D3R in dyskinesia. Tardive dyskinesia induced by haloperidol in nonhuman primates correlates with upregulated D3R in striatum (Mahmoudi et al, 2014); moreover, lentiviralinduced D3R overexpression in the dorsal striatum leads to the appearance of dyskinetic behavior (Cote et al, 2014). On the other hand, genetic deletion of the D3R decreases LID without interfering with the antiparkinsonian effect of L-DOPA (Solis et al, 2015), while striatal injection of oligonucleotides antisense targeting D3R blocks the behavioral sensitization to the A C C E P T E D M A N U S C R I P T…”