Voltage-gated potassium channels control extended access cocaine seeking: a role for nucleus accumbens astrocytes

Mengfan Xia, Tanner L. Anderson, Emily R. Prantzalos, Tara R. Hawkinson, Harrison A. Clarke, Shannon B. Keohane, Ramon C. Sun, Jill R. Turner, Pavel I. Ortinski

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Dopaminergic signaling in the nucleus accumbens shell (NAc) regulates neuronal activity relevant to reward-related learning, including cocaine-associated behaviors. Although astrocytes respond to dopamine and cocaine with structural changes, the impact of dopamine and cocaine on astrocyte functional plasticity has not been widely studied. Specifically, behavioral implications of voltage-gated channel activity in the canonically non-excitable astrocytes are not known. We characterized potassium channel function in NAc astrocytes following exposure to exogenous dopamine or cocaine self-administration training under short (2 h/day) and extended (6 h/day) access schedules. Electrophysiological, Ca2+ imaging, mRNA, and mass spectrometry tools were used for molecular characterization. Behavioral effects were examined after NAc-targeted microinjections of channel antagonists and astroglial toxins. Exogenous dopamine increased activity of currents mediated by voltage-gated (Kv7) channels in NAc astrocytes. This was associated with a ~5-fold increase in expression of Kcnq2 transcript level in homogenized NAc micropunches. Matrix-assisted laser desorption/ionization mass spectrometry revealed increased NAc dopamine levels in extended access, relative to short access, rats. Kv7 inhibition selectively increased frequency and amplitude of astrocyte intracellular Ca2+ transients in NAc of extended access rats. Inhibition of Kv7 channels in the NAc attenuated cocaine-seeking in extended access rats only, an effect that was occluded by microinjection of the astrocyte metabolic poison, fluorocitrate. These results suggest that voltage-gated K+ channel signaling in NAc astrocytes is behaviorally relevant, support Kv7-mediated regulation of astrocyte Ca2+ signals, and propose novel mechanisms of neuroglial interactions relevant to drug use.

Original languageEnglish
Pages (from-to)551-560
Number of pages10
JournalNeuropsychopharmacology
Volume49
Issue number3
DOIs
StatePublished - Feb 2024

Bibliographical note

Publisher Copyright:
© 2023, The Author(s), under exclusive licence to American College of Neuropsychopharmacology.

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

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