Differential effects of acute clozapine and haloperidol on the activity of ventral tegmental (A10) and nigrostriatal (A9) dopamine neurons.

Extracellular single-unit recording techniques were used to evaluate the effects of acute intravenous (i.v.) clozapine (CLOZ) and haloperidol (HAL) on the activity of dopamine (DA) neurons of the ventral tegmental area (VTA or A10) and the substantia nigra pars compacta (SNC or A9). CLOZ increased the firing rate of A10 but not A9 cells, and drove 9/23 (39%) of A10 cells into an apparent depolarization blockade. HAL, on the other hand, produced a rate elevation and, at higher doses, depolarization inactivation in both subpopulations of DA neurons. Cell firing was restored in inactivated cells with i.v. apomorphine (APO) or iontophoretic GABA. CLOZ always fully reversed APO-induced suppression of A10 DA activity, but in many cases only partially reversed suppression of A9 DA neurons. Scopolamine did not mimic the effects of CLOZ on A10 neurons, and it also failed to block the activating effect of HAL on A9 units, indicating that the selective action of CLOZ cannot be interpreted simply by its anticholinergic properties. After hemi-transections of the diencephalon, which severed the medial forebrain bundle and other feedback pathways to the DA somata, CLOZ was still ineffective in altering A9 DA activity. This suggests that the lack of effect on CLOZ on A9 cells is not due to the inhibitory influence of forebrain feedback pathways. This hemi-transection also left intact the activation of A10 neurons produced by HAL and CLOZ, but it did prevent the excitatory action of HAL on most A9 neurons sampled. This indicates that forebrain feedback pathways are less critical in mediating the action of APDs on A10 DA neurons. Finally, iontophoretic application of CLOZ and HAL into the vicinity of DA cell bodies blocked the rate-reducing effects of locally applied DA, but not those of GABA. This suggests that both APDs block somatodendritic DA autoreceptors. However, HAL was considerably more potent than CLOZ in producing this blockade. It is suggested that the different pharmacological and clinical properties of HAL and CLOZ may be partially explained by a differential mode of action on the A10 and A9 subpopulations of DA cells. The data also provide pharmacological evidence that these 2 groups of DA cells are regulated by different mechanisms.