Evaluating long-term consequences of adolescent antipsychotic exposure

Abstract

Antipsychotic drugs (APDs) are being used increasingly to treat a variety of conditions in adolescence. Accordingly there has been a dramatic increase in the prescription of APDs to adolescents over the past twenty years. Adolescence is an important postnatal developmental period in which major maturation changes occur in both brain structures and multiple neurotransmitter systems. Therefore, adolescence may represent a period of sensitivity to environmental perturbations including exposure to such pharmacological agents. The specific neurobiological consequences of APDs on the adolescent brain are however still poorly understood. The aim of the work presented in this thesis is to investigate how APD administration in adolescence can affect the immature adolescent brain, using a rodent model of adolescence.In this thesis, I examined chronic risperidone treatment (1.3 mg/kg/day for 21-22 days) in adolescent rats (postnatal day (PND) 36-PND56/57) with respect to short-and long-term neurobiological changes. Short-term alterations were measured either during or proximal to chronic treatment. Long-term effects were measured after a lengthy drug-free interval of 36 -60 days.Risperidone-induced neurobiological effects in adolescents were compared with those in adult rats (PND80-PND100/101) treated with the same risperidone regimen. Risperidone was chosen for detailed examination given this is the atypical APD that is most commonly prescribed to adolescents in the clinic. Behavioural effects were assessed using two well-validated tests for APD action, namely suppression of the conditioned avoidance response (CAR) and the horizontal bar test for catalepsy. Risperidone-induced changes in brain structures and metabolism of the nucleus accumbens (NAc) were examined with clinical comparable methods namely magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy ( 1 H MRS), respectively.Neurochemical alterations and gene expression in the NAc and the striatum were assessed with high performance liquid chromatography (HPLC) and real-time polymerase chain reaction respectively.My data reveal that, during chronic risperidone treatment, adolescent rats were less sensitive to risperidone-induced increases in catalepsy (when tested in horizontal bar test) and escape failures (when tested in CAR paradigm), both of which are striatum-dependent behaviours. By contrast, adult rats were observed to develop a progressive increase in these behaviours during chronic risperidone treatment. Accompanying these behavioural findings, increased levels of dopamine metabolites were observed selectively in the striatum of rats treated with risperidone in adolescence.Increased dopamine metabolites represent increased turnover of dopamine and/or increased dopamine availability, which both suggest increased dopaminergic signalling. Increased dopamine neurotransmission in adolescent-treated rats may overcome the behavioural effects of dopaminergic blockade by risperidone. When assessed after an equivalent drug-free interval o...