Chronic Treatment With Aripiprazole Prevents Development of Dopamine Supersensitivity and Potentially Supersensitivity Psychosis

Abstract

Background: Long-term treatment of schizophrenia with antipsychotics is crucial for relapse prevention, but a prolonged blockade of D2 dopamine receptors may lead to the development of supersensitivity psychosis. We investigated the chronic effects of aripiprazole (ARI) on dopamine sensitivity. Methods: We administered ARI (1.5 mg/kg/d), haloperidol (HAL; 0.75 mg/kg/d), or vehicle (VEH) via minipump for 14 days to drug-naive rats or to rats pretreated with HAL (0.75 mg/kg/d) or VEH via minipump for 14 days. On the seventh day following treatment cessation, we examined the effects of the treatment conditions on the locomotor response to methamphetamine and on striatal D2 receptor density (N = 4-10/condition/experiment). Results: Chronic treatment with HAL led to significant increases in locomotor response and D2 receptor density, compared with the effects of chronic treatment with either VEH or ARI; there were no significant differences in either locomotor response or D2 density between the VEH- and ARI-treated groups. We also investigated the effects of chronic treatment with HAL, ARI, or VEH preceded by HAL or VEH treatment on locomotor response and D2 density. ANOVA analysis indicated that the rank ordering of groups for both locomotor response and D2 density was HAL-HAL > HAL-VEH > HAL-ARI > VEH-VEH. Conclusions: Chronic treatment with ARI prevents development of dopamine supersensitivity and potentially supersensitivity psychosis, suggesting that by reducing excessive sensitivity to dopamine and by stabilizing sensitivity for an extended period of time, ARI may be helpful for some patients with treatment-resistant schizophrenia.

Antipsychotic-Induced Dopamine Supersensitivity Psychosis: Pharmacology, Criteria, and Therapy

“…The increase is similar to that induced by nigrostriatal lesions [7]. In animal models, increased D 2 density is associated with behavioral supersensitivity to dopamine stimulation manifested by TD-like symptoms [42,43], increased psychomotor activity in response to the dopamine agonists amphetamine and apomorphine [44,45,46], decreased efficacy in models of antipsychotic-like effects [9,10], and increased pursuit of reward cues in response to amphetamine [11,12,13]. Many of the older animal studies showing that chronic antipsychotic treatment produces dopamine D 2 receptor upregulation have used very high doses of antipsychotic/D 2 receptor occupancy.…”

“…Long-term administration of antipsychotics, through D 2 receptor blockade, increases D 2 receptor density in the striatum [42,43,44,45], either through an increase in D 2 receptor synthesis, a decrease in D 2 receptor degradation, or both. The increase is similar to that induced by nigrostriatal lesions [7].…”

“…In contrast, antipsychotics reduce internalization of D 2 receptors and produce an increase in brain D 2 receptor mRNA, a determinant of D 2 receptor density [66]. D 2 upregulation persists after discontinuation of antipsychotics [44] and produces alterations in intracellular systems, including G protein-coupled receptor kinase-6 (GRK-6) and β-arrestin 2, both of which are important for the internalization of D 2 receptors. In rats chronically treated with haloperidol, Oda et al [67] showed that the increase in the locomotor response to the indirect dopamine agonist methamphetamine was associated with a higher ratio of striatal GRK6 to β-arrestin 2.…”

“…Chronic treatment with aripiprazole was found to reverse dopamine supersensitivity in animal models, potentially by reducing upregulated D 2 receptors [44]. In vitro data suggest that aripiprazole is a functionally selective D 2 ligand rather than a simple partial agonist [180,181,182] and does not produce significant internalization of D 2 receptors.…”

Antagonist and partial agonist at the dopamine D2 receptors in drug-naïve and non-drug-naïve schizophrenia: a randomized, controlled trial

“…On the other hand, it has been reported that the density of D2-R in the striatum is not increased by administration of ARI in animal studies in contrast to administration of full antagonists [14]. Further, the density of D2-R that had once been increased by haloperidol administration is decreased to the level of the control group by administration of ARI [39].…”