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Extracellular single-cell recording techniques were employed to study the mechanism of action of repeated oral clozapine administration on the in vivo spontaneous activity of substantia nigra (A9) and ventral tegmental area (A10) dopamine (DA)-containing neurons in the rat. Clozapine was observed to affect DA neurons differentially within these two regions when compared to haloperidol. Acute treatment (1 hr) with both drugs increased the number of spontaneously firing neurons in both A9 and A10. Chronic (21 day) treatment with haloperidol decreased the number of cells encountered in both regions, whereas repeated treatment with clozapine reduced the number of DA cells per track only in A10. In all cases, the silent DA neurons were inferred to be in a state of depolarization inactivation since they could be induced to discharge normally by the microiontophoretic application of the inhibitory neurotransmitter gamma-aminobutyric acid. These effects were not due to an effect of chloral hydrate anesthesia since they were also observed in gallamine-paralyzed, artificially respired animals. Chronic co- administration with haloperidol of either an anticholinergic (trihexyphenidyl) or the alpha 1-norepinephrine (NE) receptor antagonist, prazosin, but not an alpha 2-NE antagonist, RX781094, resulted in a differential effect on A9 and A10 DA neurons identical to that observed with repeated clozapine administration alone. Thus, chronic treatment with these combinations of drugs resulted in the depolarization inactivation of only A10 cells. These data suggest that anticholinergic and/or alpha 1-NE-blocking properties of clozapine may, in part, mediate its differential effects on A9 and A10 midbrain DA neurons.

Possible mechanisms by which repeated clozapine administration differentially affects the activity of two subpopulations of midbrain dopamine neurons