Role of Astrocyte Voltage-gated Potassium Channels in Cocaine Seeking ( RPA Pilot/ Seed Project)

Accumulating evidence supports active role of astrocytes in control over cocaine seeking. Cocaine use impacts astrocytes at the structural level with implications for their ability to interact with neuronal cells. Human and pre-clinical literature indicates that cocaine use alters expression of multiple K+ channel subtypes. Of particular relevance to astrocytes are the “passive leak” channels, among which the inward-rectifying, Kir, channels are the main driver of astrocyte permeability to K+. We present electrophysiological evidence that Kir activity in astrocytes of the nucleus accumbens shell (NAc) is not altered by cocaine self-administration (SA). Our preliminary data indicate, however, that upon challenge with dopamine, astrocytes rapidly up-regulate voltage-gated KCNQ-type channels. We find that blockade of KCNQ channels with the antagonist, XE 991, increases amplitude and frequency of astrocyte Ca2+ transients with a potential to influence subsequent Ca2+-dependent events. We also find that microinjection of XE 991 into the NAc attenuates cocaine SA and that this effect is occluded by pre-treatment with the astrocyte metabolic toxin, fluorocitrate (FC). We propose that astrocyte KCNQ channels regulate astrocyte Ca2+ signaling to impact expression of cocaine seeking. Data in support of this hypothesis are expected to facilitate subsequent evaluation of voltage-gated K+ channels in astrocytes as mediators of neuroglial coupling after cocaine.