EFFECTS OF ANTIPSYCHOTIC DRUGS ON NORMAL AND ABNORMAL ANIMAL BEHAVIOUR

Abstract

The antipsychotic drugs of the phenothiazine and the butyrophenone groups are known to increase the synthesis and release of catecholamines as a consequence of their ability to block central catecholamine receptors (Carlsson and Lindqvist, 1973). This feedback-mediated activation of catecholamine turnover should serve to partially neutralize the receptor blocking action of these drugs. If so, inhibition of the compensatory increase in the catecholamine synthesis should potentiate the behavioural effects induced by drugs that primarily act by blocking central catecholamine receptors. In fact we have found such a potentiation by α-methyltyrosine on the behavioural suppression induced by the antipsychotic drugs haloperidol, pimozide, chlorpromazine or thioridazine on feed-reinforced lever-pressing performance in rats. However, the behaviour effects of the noradrenaline (NA) receptor blocking agent phenoxybenzamine could not be potentiated by pre-treatment with α-methyltyrosine, nor could the dopamine (DA) β-hydroxylase inhibitor FLA-63 potentiate the behavioural effects of haloperidol, chlorpromazine or thioridazine, indicating that a blockade of central DA receptors appears to be more essential for the behavioural effects observed. Also in schizophrenic patients α-methyltyrosine has been found to markedly potentiate the antipsychotic effects of chlorpromazine or thioridazine (Carlsson et al., 1972, 1973). The potentiation observed was of similar magnitude to that found in the animal experiments. Taken together, the observations from the clinical and laboratory studies support the hypothesis that the antipsychotic action of neuroleptic drugs like phenothiazine and butyrophenones is due to blockade of central catecholamine, especially DA, receptors. This may point to that at least part of the symptoms displayed in schizophrenia, may be mediated via increased neurotransmission in central DA neurons. By the use of the discriminative avoidance situation it is possible to study a behavioural disturbance induced by an increased DA receptor activation. This disturbance induced by L–Dopa, amphetamine or ampomorphine manifests itself as a loss of discriminative, but not of avoidance performance, i.e. the animals perform a conditioned avoidance response but perform incorrectly. This biochemically induced abnormality could be completely normalized by antipsychotic drugs that block central DA receptors. The NA receptor blocking agent phenoxybenzamine had no effect on the Dopa-induced abnormal behaviour, further indicating an involvement of central DA mechanisms. These data show that antipsychotic drugs, that act by blocking central DA receptors, not only specifically inhibit normal behaviour but can also improve the abnormal behaviour in animals with an increased activation of central DA receptors, which further point to the possibility that a disturbance of central DA neurons may be involved in the symptomatology in schizophrenia.