Locomotor- and Reward-Enhancing Effects of Cocaine Are Differentially Regulated by Chemogenetic Stimulation of Gi-Signaling in Dopaminergic Neurons

Abstract 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 (DREADD; Designer Receptors Exclusively Activated by Designer Drugs) to modulate dopamine signaling and activity prior to 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 even seen 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 towards 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. Significance Statement The addictive properties of cocaine and other drugs of abuse are tightly coupled to altered dopamine (DA) neurotransmission mediated by dopaminergic neurons in the ventral tegmental area (VTA). Here, we used DREADD (Designer Receptors Exclusively Activated by Designer Drugs) to investigate how modulation of these neurons via G protein-coupled receptors (GPCRs) affects the behavioral effects of cocaine. The data substantiate dopaminergic VTA neurons as a prime regulator of explorative locomotion and reward motivation as well as they reveal a delicate role of metabotropic Gi-coupled input with differential effects during acute, repeated and sensitized responses to cocaine. The results may provide an important framework for exploring new principles for addiction treatment via modulation of GPCR signaling within the dopaminergic system.