Evidence that systemically administered dopamine antagonists activate dopamine neuron firing primarily by blockade of somatodendritic autoreceptors

ML Pucak and AA Grace

Department of Neuroscience, University of Pittsburgh, Pennsylvania.

Systemic administration of dopamine antagonists increases the activity of some dopamine neurons in the substantia nigra, and this effect is thought to occur through two potential mechanisms: 1) local blockade of dopamine acting at somatodendritic autoreceptors or 2) blockade of receptors on postsynaptic targets in the striatum, resulting in long- loop feedback modulation. Several studies have provided evidence that the major influence is via striatonigral feedback. In this study, we tested the latter model by comparing the actions of systemically administered dopamine antagonists on dopamine neuron activation after removing striatonigral feedback. Systemic administration of either haloperidol or of the dopamine D2-specific antagonist sulpiride caused significant increases in the firing rate of many dopamine neurons recorded both in intact rats and in rats with hemisection of the striatonigral projection. Dopamine cells recorded in hemisected rats did not show consistent differences in either the proportion of cells excited or in the magnitude of the excitation produced by antagonist administration. The magnitude of dopamine cell excitation occurring with antagonist administration was dependent on the spontaneous firing rate of the recorded cell, with slow-firing neurons generally exhibiting the largest excitatory responses. These results provide evidence that blockade of dopamine neurons in the striatum is not the primary mechanism by which systemically administered dopamine antagonists excite dopamine neurons. Thus, dopamine antagonists most likely increase dopamine cell firing rate by blockade of somatodendritic autoreceptors, suggesting that the basal activity of the cells is dependent in part on dendritically released dopamine within the substantia nigra.

Volume 271, Issue 3, pp. 1181-1192, 12/01/1994
Copyright © 1994 by American Society for Pharmacology and Experimental Therapeutics

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