a4-Containing GABA A Receptors on DRD2 Neurons of the Nucleus Accumbens Mediate Instrumental Responding for Conditioned Reinforcers and Its Potentiation by Cocaine

Tom Macpherson (Lead / Corresponding author), Claire I. Dixon, Jonathan Robertson, Marsha M. Sindarto, Patricia H. Janak, Delia Belelli, Jeremy J. Lambert, David N. Stephens, Sarah L. King (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)
33 Downloads (Pure)

Abstract

Extrasynaptic GABA A receptors (GABA ARs) composed of a4, b, and d subunits mediate GABAergic tonic inhibition and are potential molecular targets in the modulation of behavioral responses to natural and drug rewards. These GABA ARs are highly expressed within the nucleus accumbens (NAc), where they influence the excitability of the medium spiny neurons. Here, we explore their role in modulating behavioral responses to food-conditioned cues and the behavior-potentiating effects of cocaine. a4-Subunit constitutive knock-out mice (a4 /) showed higher rates of instrumental responding for reward-paired stimuli in a test of conditioned reinforcement (CRf). A similar effect was seen fol-lowing viral knockdown of GABA AR a4 subunits within the NAc. Local infusion of the a4b d-GABA AR-preferring agonist THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol; Gaboxadol) into the NAc had no effect on responding when given alone but reduced cocaine potentiation of responding for conditioned reinforcers in wild-type, but not a4 / mice. Finally, specific deletion of a4-subunits from dopamine D2, but not D1, receptor-expressing neurons (DRD2 and DRD1 neurons), mimicked the phenotype of the constitutive knockout, potentiating CRf responding, and blocking intra-accumbal THIP attenuation of cocaine-potentiated CRf responding. These data demonstrate that a4-GABA AR-mediated inhibition of DRD2 neurons reduces instrumental responding for a conditioned reinforcer and its po-tentiation by cocaine and emphasize the importance of GABAergic signaling within the NAc in mediating the effects of cocaine.

Original languageEnglish
Article numberENEURO.0236-23.2023
Number of pages14
JournaleNeuro
Volume10
Issue number8
Early online date8 Aug 2023
DOIs
Publication statusPublished - Aug 2023

Keywords

  • GABA(A) receptors
  • nucleus accumbens
  • reward
  • cocaine
  • THIP
  • GABA receptors

ASJC Scopus subject areas

  • General Neuroscience

Fingerprint

Dive into the research topics of 'a4-Containing GABA A Receptors on DRD2 Neurons of the Nucleus Accumbens Mediate Instrumental Responding for Conditioned Reinforcers and Its Potentiation by Cocaine'. Together they form a unique fingerprint.

Cite this