Repeated administration of aripiprazole produces a sensitization effect in the suppression of avoidance responding and phencyclidine-induced hyperlocomotion and increases D₂ receptor-mediated behavioral function

Abstract

The present study investigated how repeated administration of aripiprazole (a novel antipsychotic drug) alters its behavioral effects in two behavioral tests of antipsychotic activity and whether this alteration is correlated with an increase in dopamine D2 receptor function. Male adult Sprague-Dawley rats were first repeatedly tested with aripiprazole (3, 10 and 30 mg/kg, subcutaneously (sc)) or vehicle in a conditioned avoidance response (CAR) test or a phencyclidine (PCP) (3.20 mg/kg, sc)-induced hyperlocomotion test daily for five consecutive days. After 2–3 days of drug-free retraining or resting, all rats were then challenged with aripiprazole (1.5 or 3.0 mg/kg, sc). Repeated administration of aripiprazole progressively increased its inhibition of avoidance responding and PCP-induced hyperlocomotion. More importantly, rats previously treated with aripiprazole showed significantly lower avoidance response and lower PCP-induced hyperlocomotion than those previously treated with vehicle in the challenge tests. An increased sensitivity to quinpirole (a selective D2/3 agonist) in prior aripiprazole-treated rats was also found in the quinpirole-induced hyperlocomotion test, suggesting an enhanced D2/3-mediated function. These findings suggest that aripiprazole, despite its distinct receptor mechanisms of action, induces a sensitization effect similar to those induced by other antipsychotic drugs and this effect may be partially mediated by brain plasticity involving D2/3 receptor systems.

Sex differences in aripiprazole sensitization from adolescence to adulthood

“…The dose of aripiprazole (10 mg/kg) was determined based on previous studies in our lab (Gao et al, 2015; Li et al, 2005) and reports in the literature (Carli et al, 2011; Cosi et al, 2006; Li et al, 2004). This dose of aripiprazole was chosen because it results in 85% occupancy, respectively, at one hour post-injection (Natesan et al, 2006), but does not cause catalepsy (Hirose et al, 2004).…”

“…One dose of OLZ (.5 mg.kg) and one dose of CLZ (5 mg/kg) were tested. It has been demonstrated that repeated OLZ treatment causes sensitization, whereas repeated CLZ causes tolerance in both adolescent and adult rats (Gao, Qin & Li, 2015). These doses were tested to determine how ARI sensitization would affect OLZ and CLZ exposure.…”

“…Studies have shown that neurotransmitter release, changes in neuroreceptor levels, receptor-mediated second messenger activities, cell electrophysiology, and behaviors can be affected by antipsychotic treatment (Gao, Qin, & Li, 2015). These changes can result in either an augmentation (sensitization) or decrease (tolerance) of the effects of the drug.…”

“…Moreover, it is likely that these changes are biological and developmentally mediated and thus will impact behavioral and neurochemical response to antipsychotics. For example, previous work in our laboratory has shown that repeated aripiprazole treatment disrupted avoidance responding and inhibition of PCP-induced hyperlocomotion, demonstrating induced sensitization behavioral effects (Gao & Li, 2015). Undoubtedly, these results emphasize the need for more research designed to examine the impact of chronic administration of antipsychotic drugs and likely sex and developmental differences that would impact overall efficacy of treatment.…”

“…This paradigm has been validated in previously conditioned place avoidance (CAR) and PCP-induced hyperlocomotion work. For example, repeated administration of ARI produced a sensitization effect in normal adult male rats in the CAR model (Gao et al, 2015). Additionally, it has been shown that repeated OLZ treatment causes sensitization, whereas repeated CLZ treatment causes tolerance (a decreased disruption of avoidance response) in both adolescent and adult rats (Shu et al, 2014).…”