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) D2 receptor blocking agent raclopride 0.5 or 8.0 mg kg-1 subcutaneously (1.0 and 16.0 mumol 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-1 subchronic 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-1 dose, 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.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of chronic intermittent haloperidol and raclopride effects on striatal dopamine release and synaptic ultrastructure in rats

“…Following subchronic neuroleptic administration, DA autoreceptor supersensitivity has been detected as measured by increased response to apomorphine-induced decreases in DA turnover (Wheeler and Roth, 19801, inhibition of tyrosine hydroxylase activity (Booth et al, 1991), and reduction of in vivo DA release (Ichikawa and Meltzer, 1990). High-dose RAC given for 21 days has also been reported to enhance apomorphine-induced decreases in DOPA accumulation (Ahlenius et al, 1991). The potentiated response to quinpirole seen in this study may involve an increased number of presynaptic DA autoreceptors.…”

Atypical antipsychotics – effects of amisulpride on salivary secretion and on clozapine‐induced sialorrhea

“…In this species, the half‐life of amisulpride is probably about 2 h, as judged by the pharmacokinetics of the closely related drug, sultopride (Kobari et al , 1985). The half‐life of raclopride is about 40 min in rats (Ahlenius et al , 1991). So, in the case of multiple doses of amisulpride, clozapine and raclopride, dose accumulation is likely to have occurred.…”

D2-Receptor Upregulation is Dependent upon Temporal Course of D2-Occupancy: A Longitudinal [11C]-Raclopride PET Study in Cats

“…For instance, several studies have shown that although tolerance develops when antipsychotics are administered continuously, reverse tolerance (sensitization) is observed when antipsychotics are administered intermittently so that the drug is allowed to wear off between repeated administrations (Ezrin-Waters and Seeman, 1977;Carey and DeVeaugh-Geiss, 1984;Barnes et al, 1990;Csernansky et al, 1990;See and Ellison, 1990;Ahlenius et al, 1991). The few studies that have aimed to assess the importance of antipsychotic treatment schedule on alteration of D 2 -receptor density gave conflicting results.…”