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The Journal of Neuroscience, May 10, 2006, 26(19):5240-5247; doi:10.1523/JNEUROSCI.4976-05.2006

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Cellular/Molecular
D₂ Autoreceptors Chronically Enhance Dopamine Neuron Pacemaker Activity

Junghyun Hahn,¹ Paul H. M. Kullmann,² John P. Horn,² and Edwin S. Levitan¹

¹Departments of Pharmacology and ²Neurobiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261

Correspondence should be addressed to Edwin S. Levitan, Department of Pharmacology, University of Pittsburgh, Pittsburgh, PA 15261. Email: levitan{at}server.pharm.pitt.edu

Activation of D₂ autoreceptors on midbrain dopamine neurons has been shown previously to acutely open K⁺ channels to inhibit intrinsically generated pacemaker activity. Here we report that D₂ autoreceptors act chronically to produce an opposite action: to increase the speed and regularity of repetitive action potential firing. Voltage-, current-, and dynamic-clamp experiments, using conventional whole-cell and perforated patch-clamp recording, with cultured rat midbrain dopamine neurons show that a change in the number of functional A-type K⁺ channels alters firing rate and susceptibility to irregularity produced by other channels. cAMP and protein kinase A mediate the long-term action of D₂ receptors in a manner that counters the short-term effect of this signaling pathway on K⁺ channel gating. We conclude that D₂ autoreceptors, in addition to mediating acute negative feedback, are responsible for long-term enhancement of the rate and fidelity of dopamine neuron pacemaker activity.

Key words: dopamine neuron; K⁺ channel; D₂ receptor; channel noise; pacemaker; antipsychotic drug

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Received July 14, 2005; revised March 30, 2006; accepted March 30, 2006.

Correspondence should be addressed to Edwin S. Levitan, Department of Pharmacology, University of Pittsburgh, Pittsburgh, PA 15261. Email: levitan{at}server.pharm.pitt.edu

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