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The Journal of Neuroscience, November 5, 2003, 23(31):9981-9986

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Behavioral/Systems/Cognitive
{kappa}-Opioid Agonists Directly Inhibit Midbrain Dopaminergic Neurons

Elyssa B. Margolis,1 Gregory O. Hjelmstad,2 Antonello Bonci,2 and Howard L. Fields1,2

1Joint University of California San Francisco/University of California, Berkeley Bioengineering Graduate Group, San Francisco, California 94143-0775, and 2Department of Neurology, Wheeler Center for the Neurobiology of Addiction, Ernest Gallo Clinic and Research Center, University of California, San Francisco, California 94143-0114

Dopaminergic neurons of the ventral tegmental area (VTA) play a critical role in motivation and reinforcement of goal-directed behaviors. Furthermore, excitation of these neurons has been implicated in the addictive process initiated by drugs such as morphine that act at the µ-opioid receptor (MOR). In contrast, {kappa}-opioid receptor (KOR) activation in the VTA produces behavioral actions opposite to those elicited by MOR activation. The mechanism underlying this functional opposition, however, is poorly understood. VTA neurons have been categorized previously as principal, secondary, or tertiary on the basis of electrophysiological and pharmacological characteristics. In the present study using whole-cell patch-clamp recordings, we demonstrate that a selective KOR agonist (U69593, 1 µM) directly inhibits a subset of principal and tertiary but not secondary neurons in the VTA. This KOR-mediated inhibition occurs via the activation of a G-protein-coupled inwardly rectifying potassium channel and is blocked by the selective KOR antagonist nor-Binaltorphimine (100 nM). Significantly, regardless of cell class, KOR-mediated inhibition was found only in tyrosine hydroxylase-immunoreactive and thus dopaminergic neurons. In addition, we found a subset of principal neurons that exhibited both disinhibition by a selective MOR agonist ([D-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin) (3 µM) and direct inhibition by KOR agonists. These results provide a cellular mechanism for the opposing behavioral effects of KOR and MOR agonists and shed light on how KORs might regulate the motivational effects of both natural rewards and addictive drugs.

Key words: ventral tegmental area; midbrain; dopamine; {kappa}-opioid; µ-opioid; U69593; DAMGO; postsynaptic; in vitro

Received July 7, 2003; revised September 4, 2003; accepted September 10, 2003.




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