MODE OF ACTION OF ATYPICAL NEUROLEPTICS IN RELATION TO THE PHENCYCLIDINE MODEL OF SCHIZOPHRENIA - ROLE OF 5-HT2 RECEPTOR AND ALPHA(1)-ADRENOCEPTOR ANTAGONISM

In experiments in rats, by the use of single-cell recordings from midbrain dopamine (DA) neurons of the ventral tegmental area (VTA), the systemic administration of the schizophrenomimetic N-methyl-D-aspartate receptor antagonists phencyclidine (PCP) or dizocilpine (MK-801) caused an increased firing rate but reduced the variability of firing in VTA DA neurons. Burst firing was increased in cells predominantly located in the paranigral nucleus, a subdivision of the VTA largely projecting to the nucleus accumbens and other Limbic regions, but reduced in DA cells predominantly located in the parabrachial pigmented nucleus, another subdivision of the VTA that projects largely to the prefrontal cortex (PFC). Thus, a severely impaired signal-to-noise ratio within the PFC DA projection was obtained, concomitant with an overactive mesolimbic DA system. The administration of high doses of ritanserin or atypical neuroleptics with prominent serotonin (5-hydroxytrypyamine) 5-HT2 receptor antagonist action, such as clozapine or amperozide, produced preferential activation of the PFC DA projection. In contrast, the selective D-2 receptor antagonist raclopride caused a greater activation of the subcortical than cortical DA projections, as assessed by microdialysis experiments in vivo from our laboratory. Adding ritanserin treatment to raclopride markedly enhanced the raclopride-induced increase in DA levels in the medial PFC, an effect probably mediated by augmentation of the raclopride-induced increase in the burst firing of mesocortical DA neurons, but failed to affect the action of raclopride on striatal DA levels. In addition, ritanserin alone preferentially increased extracellular concentrations of DA in the shell subdivision of the nucleus accumbens that is closely linked to the limbic system, as assessed by in vivo voltammetry. However, the PCP- or MK-801-induced increased burst firing within the mesolimbic DA projection, which is probably causally related to the hyperlocomotion induced by these drugs in low doses, was significantly inhibited by the administration of the alpha(1)-adrenoceptor antagonist prazosin. Like high but not low doses of raclopride, prazosin also antagonized the behavioral stimulation induced by the systemic administration of MK-801 in rats. Thus, atypical antipsychotic drugs such as clozapine and amperozide with high affinity for 5-HT2 receptors and relatively high affinity for al-adrenoceptors can, by 5-HT2 blockade, preferentially activate and improve DA signaling in the mesocortical DA projection after distortion by drugs such as PCP. At the same time, these drugs may antagonize a hyperactive mesolimbic DA system not only postsynaptically through D-2 antagonism, but also presynaptically through their alpha(1)-adrenoceptor-blocking properties.