Drug-induced neuroadaptations in the prefrontal cortex (PFC) have been implicated in drug-associated memories that motivate continued drug use. Chronic cocaine exposure increases pyramidal neuron excitability in the prelimbic subregion of the PFC (PL), an adaptation that has been attributed in part to a suppression of inhibitory signalling mediated by the GABAB receptor (GABABR) and G protein-gated inwardly rectifying K+ (GIRK/Kir3) channels. Although reduced GIRK channel activity in PL pyramidal neurons enhances the motor-stimulatory effect of cocaine in mice, the impact on cocaine reward and associated memories remains unclear. Here, we employed Cre- and CRISPR/Cas9-based viral manipulation strategies to evaluate the impact of GIRK channel or GABABR ablation in PL pyramidal neurons on cocaine-induced conditioned place preference (CPP) and extinction. Neither ablation of GIRK channels nor GABABR impacted the acquisition of cocaine CPP. GIRK channel ablation in PL pyramidal neurons, however, impaired extinction of cocaine CPP in male but not female mice. Since ablation of GIRK channels but not GABABR increased PL pyramidal neuron excitability, we used a chemogenetic approach to determine if acute excitation of PL pyramidal neurons impaired the expression of extinction in male mice. While acute chemogenetic excitation of PL pyramidal neurons induced locomotor hyperactivity, it did not impair the extinction of cocaine CPP. Lastly, we found that persistent enhancement of GIRK channel activity in PL pyramidal neurons accelerated the extinction of cocaine CPP. Collectively, our findings show that the strength of GIRK channel activity in PL pyramidal neurons bi-directionally regulates cocaine CPP extinction in male mice.
|Original language||English (US)|
|State||Published - Jan 2023|
Bibliographical noteFunding Information:
This work was supported by National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism grants T. R. R. and E. H. M. (DA007234), K. W. (DA034696 and AA027544) and the University of Minnesota Viral Vector and Cloning Core (DA048742), as well as a University of Minnesota Doctoral Dissertation Fellowship to T. R. R. We thank Hannah Oberle, Mehrsa Zahiremami and Courtney Wright for exceptional care of the mouse colony.
© 2022 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.
- conditioned place preference
- GABA receptor
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't