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The Journal of Neuroscience, July 21, 2004, 24(29):6563-6572; doi:10.1523/JNEUROSCI.0684-04.2004

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Cellular/Molecular
Somatic Localization of a Specific Large-Conductance Calcium-Activated Potassium Channel Subtype Controls Compartmentalized Ethanol Sensitivity in the Nucleus Accumbens

Gilles Martin, Sylvie Puig, Andrzej Pietrzykowski, Paula Zadek, Patrick Emery, and Steven Treistman

Department of Neurobiology, University of Massachusetts Medical School, Worcester, Massachusetts 01605

Alcohol is an addictive drug that targets a variety of ion channels and receptors. To address whether the effects of alcohol are compartment specific (soma vs dendrite), we examined the effects of ethanol (EtOH) on large-conductance calcium-activated potassium channels (BK) in cell bodies and dendrites of freshly isolated neurons from the rat nucleus accumbens (NAcc), a region known to be critical for the development of addiction. Compartment-specific drug action was indeed observed. Clinically relevant concentrations of EtOH increased somatic but not dendritic BK channel open probability. Electrophysiological single-channel recordings and pharmacological analysis of the BK channel in excised patches from each region indicated a number of differences, suggestive of a compartment-specific expression of the 4 subunit of the BK channel, that might explain the differential alcohol sensitivity. These parameters included activation kinetics, calcium dependency, and toxin blockade. Reverse transcription-PCR showed that both BK channel 1 and 4 subunit mRNAs are found in the NAcc, although the signal for 1 is significantly weaker. Immunohistochemistry revealed that 1 subunits were found in both soma and dendrites, whereas 4 appeared restricted to the soma. These findings suggest that the 4 subunit may confer EtOH sensitivity to somatic BK channels, whereas the absence of 4 in the dendrite results in insensitivity to the drug. Consistent with this idea, acute EtOH potentiated 4 BK currents in transfected human embryonic kidney cells, whereas it failed to alter 1 BK channel-mediated currents. Finally, an EtOH concentration (50 mM) that increased BK channel open probability strongly decreased the duration of somatic-generated action potential in NAcc neurons.

Key words: accumbens; alcohol; channel; dendrite; patch clamp; reverse transcription-PCR; RT-PCR

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Received Feb 25, 2004; revised June 9, 2004; accepted June 9, 2004.

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