Effects of repeated and acute aripiprazole or haloperidol treatment on dopamine synthesis in the dorsal striatum of young rats: comparison to adult rats

Abstract

The purpose of the present study was to determine whether repeated treatment with the D2 partial agonist aripiprazole or the D2 antagonist haloperidol alters dopamine (DA) synthesis characteristics in the dorsal striatum of young rats. To this end, rats received a daily pretreatment regimen of aripiprazole or haloperidol on postnatal days (PD) 10-20 and were tested 24 or 72 h later after an acute injection of vehicle, aripiprazole, haloperidol, or quinpirole (a D2 agonist). For comparison purposes, adult rats were pretreated with an 11-day regimen of saline or haloperidol on PD 70-80 and DA synthesis was measured after acute drug treatment on PD 83. Dorsal striatal DA synthesis was determined by measuring L-dihydroxyphenylalanine accumulation after NSD-1015 treatment. In a separate experiment, the ability of repeated drug treatment to up-regulate dorsal striatal D2 receptors was assessed in young and adult rats 72 h after drug discontinuation. The major findings of this study were that: (a) acute treatment with haloperidol and aripiprazole increased DA synthesis while quinpirole reduced it; (b) pretreatment with haloperidol and aripiprazole blunted the synthesis-modulating effects of acutely administered dopaminergic drugs; and (c) DA synthesis of young and adult rats was affected in a qualitatively similar manner by DA agonist, antagonist, and partial agonist drugs. In conclusion, results from the present study suggest that synthesis-modulating autoreceptors in the dorsal striatum are functionally mature by the end of the preweanling period and DA synthesis declines to near basal levels during the course of repeated aripiprazole treatment.

Repeated aripiprazole treatment causes dopamine D2 receptor up-regulation and dopamine supersensitivity in young rats

“…While there are an abundance of studies assessing the efficacy and side-effect profiles of aripiprazole in children and adolescent patients (Fraguas et al, 2011; Kirino, 2012), very few preclinical studies have examined the effects of repeated aripiprazole treatment using developmental animal models. Most notably, Der-Ghazarian et al (2010) reported that an 11-day regimen of aripiprazole (10 mg/kg once daily) administered to rats on postnatal day (PD) 10–20 caused a short-term decline in the sensitivity of synthesis-modulating autoreceptors. This decrease in autoreceptor sensitivity was apparent one day, but not three days, after conclusion of the drug pretreatment regimen, and was similar to the pattern of effects produced by the D2 receptor antagonist haloperidol.…”

Early Antipsychotic Treatment in Juvenile Rats Elicits Long-Term Alterations to the Dopamine Neurotransmitter System

“…Whilst previous studies investigating the long-term effect of juvenile APD use on DA synthesis markers in the adult brain have to our knowledge not been completed, several studies investigating the immediate and long-lasting effects of APD treatment with aripiprazole, olanzapine and risperidone on DA synthesis markers, precursors, and NT levels in young [37,43] and adult [43,44,45,46,47,48,49,50] rodent models have demonstrated differing effects.…”

“…Additionally, decreased TH levels in the PFC were also uncovered in the male cohort following early aripiprazole and olanzapine treatment. Previous investigations into the effect of the partial D 2 agonist aripiprazole over acute and short-term durations in the adult rodent have uncovered increases to DA markers indicative of an increased DA synthesis and/or production in the PFC of male rats [43,44,45,46,47]. However, studies into the effects of short-term aripiprazole treatment on DA production in the VTA have revealed an opposite effect, with reductions in DA firing observed [48,50].…”

“…Female rats that received early olanzapine drug treatment exhibited increased D 2 receptor binding density in the PFC, NAc and CPu when compared to the control group. Previous investigations into the effects of APD treatment on DA D 2 receptor levels in an animal model have also uncovered either similar significant increases to D 2 receptor expression following treatment, or no change to D 2 receptor expression across both male and female cohorts [36,37,38,40,43,57,60,61,62]. Whilst studies into the effects of both short and long-term APD treatment with olanzapine and risperidone on D 2 receptor densities have found increases in regions including the PFC, CPu, NAc and hippocampus, both immediately following cessation of treatment [38,57] and after long-term time periods [18,37,38,57], the effects of treatment with the partial agonist drug aripiprazole, over short and long-term treatment periods, have found conflicting results.…”

“…Whilst studies into the effects of both short and long-term APD treatment with olanzapine and risperidone on D 2 receptor densities have found increases in regions including the PFC, CPu, NAc and hippocampus, both immediately following cessation of treatment [38,57] and after long-term time periods [18,37,38,57], the effects of treatment with the partial agonist drug aripiprazole, over short and long-term treatment periods, have found conflicting results. APD treatment in both young and adult rat models have been found to result in no immediate alterations to D 2 receptor density in striatal brain regions [43,60,61], whilst a more recent investigation in young rats uncovered an increased expression of D 2 receptor levels in the CPu following a short-term treatment period [36]. Surprisingly, despite the well-document high affinity and mechanism of action of APDs through DA D 2 receptors, no alterations to D 2 receptor levels were observed in the male cohort in any of the investigated regions in the present study.…”