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Chemogenetic activation of ventral tegmental area GABA neurons, but not mesoaccumbal GABA terminals, disrupts responding to reward-predictive cues

Neuropsychopharmacologyvolume 44pages372380 (2019) | Download Citation


Cues predicting rewards can gain motivational properties and initiate reward-seeking behaviors. Dopamine projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) are critical in regulating cue-motivated responding. Although, approximately one third of mesoaccumbal projection neurons are GABAergic, it is unclear how this population influences motivational processes and cue processing. This is largely due to our inability to pharmacologically probe circuit level contributions of VTA-GABA, which arises from diverse sources, including multiple GABA afferents, interneurons, and projection neurons. Here we used a combinatorial viral vector approach to restrict activating Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to GABA neurons in the VTA of wild-type rats trained to respond during a distinct audiovisual cue for sucrose. We measured different aspects of motivation for the cue or primary reinforcer, while chemogenetically activating either the VTA-GABA neurons or their projections to the NAc. Activation of VTA-GABA neurons decreased cue-induced responding and accuracy, while increasing latencies to respond to the cue and obtain the reward. Perseverative and spontaneous responses decreased, yet the rats persisted in entering the reward cup when the cue and reward were absent. However, activation of the VTA-GABA terminals in the accumbens had no effect on any of these behaviors. Together, we demonstrate that VTA-GABA neuron activity preferentially attenuates the ability of cues to trigger reward-seeking, while some aspects of the motivation for the reward itself are preserved. Additionally, the dense VTA-GABA projections to the NAc do not influence the motivational salience of the cue.

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We thank Dr. David C. Lyon for providing the GAD1 promoter used in these experiments. We thank Raquel Lima, Karie Chen, and Martin Leigh for technical assistance and Dr. Paul Meyer for very helpful comments on the manuscript. We also thank Dr. Wade Sigurdson and the University at Buffalo Confocal Microscopy Core for invaluable assistance. This research was supported by the State University of New York BRAIN Network of Excellence Postdoctoral Fellow program and T32 AA007583 (K.T.W.), the Whitehall Foundation 2017-08-43 (J.P.); 2017-12-98 (C.E.B.), as well as R01 AA024112 and R21 DA043190, (C.E.B.).

Author information


  1. Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, 14203, USA

    • Ken T. Wakabayashi
    • , Malte Feja
    • , Ajay N. Baindur
    • , Michael J. Bruno
    •  & Caroline E. Bass
  2. Research Institute on Addictions, University at Buffalo, State University of New York, Buffalo, NY, 14203, USA

    • Ken T. Wakabayashi
    • , Kathryn Hausknecht
    • , Roh-Yu Shen
    • , Samir Haj-Dahmane
    •  & Caroline E. Bass
  3. Department of Biotechnical and Clinical Laboratory Sciences, University at Buffalo, State University of New York, Buffalo, NY, 14214, USA

    • Rohan V. Bhimani
    •  & Jinwoo Park


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The authors declare no competing interests.

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Correspondence to Caroline E. Bass.

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