Dysfunctional brain dopamine systems induced by psychotomimetic NMDA-receptor antagonists and the effects of antipsychotic drugs.

Abstract

Clinical studies utilizing imaging techniques demonstrate that classical antipsychotic drugs, such as haloperidol, in clinically effective doses display around 75% dopamine (DA)-D(2) receptor occupancy in the brain. In contrast, the atypical antipsychotic drug clozapine is even more effective at only about 45% D(2)-receptor occupancy. Yet at this D(2)-receptor occupancy classical antipsychotics are not effective, raising the question of which other receptors may be involved in mediating the atypical antipsychotic profile of clozapine and other atypical antipsychotics. The present paper describes experimental work aimed at elucidating this critical question, utilizing the phencyclidine (PCP) model of schizophrenia in combination with studies of typical and atypical antipsychotics as well as various specific receptor blocking agents. Both electrophysiological methods, i.e. single cell recording from DA neurons in the ventral tegmental area (VTA), and biochemical analysis of biogenic amines such as DA following microdialysis in difference DA terminal areas in the brain, were used. In addition, behavioural measurements using the conditioned avoidance response (CAR) paradigm and assessments of locomotor activity were utilized. Experiments with functional inactivation of the medial frontal cortex (mPFC) in the rat as well as with MK-801 and other antagonists at central NMDA-receptors revealed that following systemic administration of schizophrenomimetic NMDA-receptor antagonists a profound dysregulation of the mesocorticolimbic DA system occurs, severely impairing the dynamic physiological response range of the neurons. Specifically, DA neurons which largely project to the mPFC showed a profound loss of burst firing, whereas VTA-DA neurons, which mainly project subcortically, showed an increased monotonous high-frequency firing with increased DA output from nerve terminals and concomitant behavioural activation. Significantly, drugs with a prominent 5-HT(2A)-receptor blocking action could effectively restore the burst firing mode, i.e. phasic responsivity, in mesocortically projecting DA neurons, and also potentiate the CAR suppressant effect of the selective D(2)/D(3)-receptor antagonist raclopride without increasing catalepsy scores. The selective alpha(1)-adrenoreceptor antagonist prazosin effectively suppressed both the stereotyped, high-frequency firing of subcortically projecting DA neurons following systemic MK-801 and the concomitant behavioural, i.e. locomotor, activation. In addition, the MK-801 evoked DA release in the nucleus accumbens was suppressed. A similar effect was seen also with AMPA-receptor antagonists when applied locally into the VTA and, in addition, systemic administration of chemically different AMPA-receptor antagonists caused a CAR-suppressant effect similar to both classical and atypical antipsychotic drugs. These results and other data showing a clearcut difference between typical and atypical antipsychotic drugs on DA output in the shell and core, respectively, of the nucleus accumbens, suggest that both the 5-HT(2A)- and the alpha(1)-adrenoreceptor blocking effects of a number of atypical antipsychotic drugs in all probability contribute to their antipsychotic effect. Moreover, our results indicate that AMPA-receptor antagonists may possess an atypical antipsychotic profile.