RT Journal Article SR Electronic T1 Locomotor- and Reward-Enhancing Effects of Cocaine Are Differentially Regulated by Chemogenetic Stimulation of Gi-Signaling in Dopaminergic Neurons JF eneuro JO eNeuro FD Society for Neuroscience SP ENEURO.0345-17.2018 DO 10.1523/ENEURO.0345-17.2018 VO 5 IS 3 A1 Annika H. Runegaard A1 Andreas T. Sørensen A1 Ciarán M. Fitzpatrick A1 Søren H. Jørgensen A1 Anders V. Petersen A1 Nikolaj W. Hansen A1 Pia Weikop A1 Jesper T. Andreasen A1 Jens D. Mikkelsen A1 Jean-Francois Perrier A1 David Woldbye A1 Mattias Rickhag A1 Gitta Wortwein A1 Ulrik Gether YR 2018 UL http://www.eneuro.org/content/5/3/ENEURO.0345-17.2018.abstract AB Dopamine plays a key role in the cellular and behavioral responses to drugs of abuse, but the implication of metabotropic regulatory input to dopaminergic neurons on acute drug effects and subsequent drug-related behavior remains unclear. Here, we used chemogenetics [Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)] to modulate dopamine signaling and activity before cocaine administration in mice. We show that chemogenetic inhibition of dopaminergic ventral tegmental area (VTA) neurons differentially affects locomotor and reward-related behavioral responses to cocaine. Stimulation of Gi-coupled DREADD (hM4Di) expressed in dopaminergic VTA neurons persistently reduced the locomotor response to repeated cocaine injections. An attenuated locomotor response was seen even when a dual-viral vector approach was used to restrict hM4Di expression to dopaminergic VTA neurons projecting to the nucleus accumbens. Surprisingly, despite the attenuated locomotor response, hM4Di-mediated inhibition of dopaminergic VTA neurons did not prevent cocaine sensitization, and the inhibitory effect of hM4Di-mediated inhibition was eliminated after withdrawal. In the conditioned place-preference paradigm, hM4Di-mediated inhibition did not affect cocaine-induced place preference; however, the extinction period was extended. Also, hM4Di-mediated inhibition had no effect on preference for a sugar-based reward over water but impaired motivation to work for the same reward in a touchscreen-based motivational assay. In addition, to support that VTA dopaminergic neurons operate as regulators of reward motivation toward both sugar and cocaine, our data suggest that repeated cocaine exposure leads to adaptations in the VTA that surmount the ability of Gi-signaling to suppress and regulate VTA dopaminergic neuronal activity.