Behavioural and Biochemical Effects of Subchronic Treatment with Raclopride in the Rat: Tolerance and Brain Monoamine Receptor Sensitivity

Abstract:Male Sprague‐Dawley rats were treated with the dopamine (DA) D2receptor blocking agent raclopride 0.5 or 8.0 mg kg−1subcutaneously (1.0 and 16.0 μmol kg−1, respectively), twice daily for 21 days. The animals treated with raclopride gained weight at the same rate as saline controls, and gross observation did not indicate any behavioural abnormalities due to the subchronic raclopride treatment. Possible changes in brain DA receptor sensitivity due to prolonged blockade of DA receptors were evaluated in behavioural and biochemical models. There were no effects on locomotor activity, as observed by means of photobeam‐equipped activity cages, 24 hr or 72 hr after withdrawal of 0.5 or 8.0 mg kg−1subchronic raclopride treatment. Twenty‐four hr after withdrawal of the raclopride treatment there was an increased post‐synaptic DA receptor sensitivity as evidenced by increased behavioural and biochemical responses to apomorphine, and by an attenuated response to acute raclopride treatment, 0.1 mg kg−1. Thus, there was an increase in locomotor activity by the apomorphine treatment in animals pretreated with the 8 mg kg−1dose, as compared to the response obtained in saline controls. Furthermore, the suppression of locomotor activity in saline controls produced by acute raclopride treatment was dose‐dependently antagonized by the raclopride pretreatment and this also applied to the increase in striatal DOPAC levels produced by acute raclopride treatment. Finally, there was an increased DA receptor sensitivity presynaptically as evidenced by an enhanced effect on striatal DOPA levels by apomorphine in rats treated with NSD 1015 and reserpine. Thus, the increase in DOPA accumulation induced by reserpine was partially antagonized by treatment with apomorphine, 0.05 mg kg−1, and this effect was enhanced in animals pretreated with the highest dose of raclopride (8 mg kg−1). This effect persisted for at least 72 hr following withdrawal of raclopride treatment. Taken together, the present results shows that withdrawal of subchronic raclopride treatment with 8.0, but not 0.5, mg kg−1produces an increased response to apomorphine challenge pre‐ and postsynaptically, and this effect was observed for up to 72 hr after withdrawal of raclopride treatment. Both pretreatment doses of raclopride (0.5 and 8.0 mg−1) produce behavioural and biochemical signs of tolerance to the treatment.