GABAergic projections to the ventral tegmental area govern cocaine-conditioned reward

Moriya Weitz, Alaa Khayat, Rami Yaka*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Elevated dopamine (DA) levels in the reward system underlie various drug-related behaviors, including addiction. As a major DA source in the reward system, the ventral tegmental area (VTA) is highly regulated by GABAergic inputs projected from different brain regions. It was previously shown that cocaine exposure reduces GABAA-mediated inhibitory postsynaptic currents (IPSCs) in VTA DA neurons; however, the specific GABAergic input underlying this inhibitory effect remains unknown. Here, using optogenetics, we separately activate and characterize different GABAergic afferents innervating the VTA, focusing on the rostromedial tegmental nucleus (RMTg) and the nucleus accumbens (NAc). GABAA-mediated IPSCs were recorded from VTA DA neurons, and the effect of DA-induced inhibition was measured in an afferent-specific manner. In addition, to examine the effect of enhanced GABAergic tone on the rewarding properties of cocaine, we exogenously activated the different GABAergic inputs during the acquisition phase of cocaine conditioned place preference (CPP). We found that acute cocaine exposure strongly attenuates GABAA-mediated IPSCs in VTA DA neurons from both inhibitory sources. Furthermore, exogenous light activation of both RMTg and NAc afferents in the VTA during the acquisition of cocaine-CPP significantly reduced the rewarding properties of cocaine. This behavioral observation was correlated with the reduction in the neuronal activity of VTA DA neurons as measured by the expression of c-fos. Together, these results emphasize the critical role of these GABAergic inputs to the VTA in modulating and potentially interrupting cocaine reward.

Original languageAmerican English
Article numbere13026
JournalAddiction Biology
Volume26
Issue number4
DOIs
StatePublished - Jul 2021

Bibliographical note

Funding Information:
We thank Dr. Claire Thornton for valuable feedback on this manuscript. This work was supported by the Israel Science Foundation (ISF; 1283/16 R.Y.), the National Institute for Psychobiology in Israel (NIPI), and the David R. Bloom Center for Pharmacy at the Hebrew University of Jerusalem (R.Y.).

Publisher Copyright:
© 2021 Society for the Study of Addiction

Keywords

  • GABA
  • NAc
  • RMTg
  • VTA
  • cocaine
  • reward

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