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.