Effect of typical and atypical neuroleptics on the behavioural consequences of activation by muscimol of mesolimbic and nigro-striatal dopaminergic pathways in the rat

Direct injections of muscimol into the ventral tegmental area (VTA) or substantia nigra zona reticulata (SNR) have been used to selectively stimulate the mesolimbic and nigro-striatal dopamine pathways respectively. Such injections induced locomotor activity, rearing, sniffing and in some animals an intermittent grooming response. These responses were rapid in onset, dose-related and relatively short lasting (<40 min). Selective increases in dopamine turnover were seen in the nucleus accumbens and in the striatum following VTA and SNR injections of muscimol (100 ng) respectively. Haloperidol inhibited the behavioural consequences of VTA and SNR injections of muscimol with similar potency (ED₅₀s 0.01–0.03 mg/kg IP), and fluphenazine did likewise (ED₅₀s 0.05–0.16 mg/kg IP). However, thioridazine (ED₅₀s VTA: 1.45–2.04 mg/kg IP, SNR 8.50–9.20 mg/kg IP) and in particular clozapine (ED₅₀s VTA: 0.24–0.58 mg/kg IP, SNR: 6.10–9.70 mg/kg IP) were more potent at inhibiting the locomotor activity and sniffing responses due to VTA rather than SNR administered muscimol. Since dopamine D₂ antagonists are believed to exert their anti-psychotic effects via an action on mesolimbic dopaminergic systems, and their ability to induce extrapyramidal side effects (EPS) is thought to be due to an action on nigro-striatal dopamine systems, these results suggest that the behavioural models described can be used to predict efficacy and side-effect liability of potential neuroleptic drugs.Preliminary accounts of these experiments were communicated to the Animal Models in Psychopharmacology and British Association for Psychopharmacology conferences held in Amsterdam and Cambridge, July 1990.