Long-lasting sensitization induced by repeated risperidone treatment in adolescent Sprague-Dawley rats: a possible D2 receptor mediated phenomenon?

Abstract

Rationale Risperidone use in children and adolescents for the treatment of various neuropsychiatric disorders (e.g. schizophrenia, autism, disruptive behavior, etc.) has increased substantially in recent decades. However, its long-term effect on the brain and behavioral functions is not well understood. Objective The present study investigated how a short-term risperidone treatment in adolescence impacts antipsychotic response in adulthood in the conditioned avoidance response and PCP-induced hyperlocomotion tests. Methods Male adolescent Sprague-Dawley rats (postnatal days [P] 40-44 or 43-48) were first treated with risperidone (0.3, 0.5 or 1.0 mg/kg, sc) and tested in the conditioned avoidance or PCP (3.2 mg/kg, sc)-induced hyperlocomotion model daily for 5 consecutive days. After they became adults (~P 76-80), they were challenged with risperidone (0.3 mg/kg, sc) to assess their sensitivity to risperidone re-exposure. A quinpirole (a D2/3 receptor agonist, 1.0 mg/kg, sc)-induced hyperlocomotion test was later conducted to assess the risperidone-induced functional changes in D2 receptor. Results In the risperidone challenge test in adulthood, adult rats previously treated with risperidone in adolescence made significantly fewer avoidance responses and exhibited significantly lower PCP-induced hyperlocomotion than those previously treated with vehicle. They also appeared to be more hyperactive than the vehicle-pretreated ones in the quinpirole-induced hyperlocomotion test. Prepulse inhibition of acoustic startle or fear-induced 22 kHz ultrasonic vocalizations in adulthood was not altered by adolescence risperidone treatment. Conclusions Adolescent risperidone exposure induces a long-term increase in behavioral sensitivity to risperidone that persists into adulthood. This long-lasting change might be due to functional upregulation of D2-mediated neurotransmission.

Evaluating long-term consequences of adolescent antipsychotic exposure

“…This APDinduced sensitized suppression of CAR in adolescence persists until adulthood (PND76-92). This long-lasting increased drug response in CAR has been demonstrated with adolescent treatment with olanzapine (Qiao et al 2013), risperidone (Qiao et al 2014a), asenapine (Shu et al 2014b) and haloperidol (Gao and Li 2014). The exception was clozapine which induces an opposite effect, a tolerance-like state with less suppression of the avoidance response in rats with prior adolescent exposure.…”

“…Another study from the same group has shown that adult rats who had adolescent exposure to risperidone (0.3 or 1 mg/kg/day from PND44 to PND48) showed an increased sensitivity to motor effects of a challenge dose (0.3 mg/kg) of this APD (Qiao et al 2014a). However, the rats in these studies were examined for the effects of APDs on repeated phencyclidine-induced hyperlocomotion during adolescence.…”

“…For instance, rats treated in adolescence with risperidone (1 mg/kg/day for 5 days via subcutaneous injections (SC)) (Qiao et al 2014a) ). This study however did not examine psychostimulant induced locomotor response.…”

“…Several studies have shown that rats treated with atypical APDs such as olanzapine, clozapine and risperidone during adolescence have normal PPI when tested either at 24 hours after APD exposure or even after a lengthy drug washout period (Qiao et al 2014a;Qiao et al 2013;Shu et al 2014a).…”

“…Treatment in adolescence with both atypical APDs such as olanzapine (Qiao et al 2013), risperidone (Qiao et al 2014a) and asenapine (Gao and Li 2013) and typical APDs i.e. haloperidol (Gao and Li 2014) have all been shown to induce a sensitization-like CAR suppression response to a later challenge dose of these same APDs after drug washout.…”