Differential Impact of Inhibitory G-Protein Signaling Pathways in Ventral Tegmental Area Dopamine Neurons on Behavioral Sensitivity to Cocaine and Morphine

Drugs of abuse engage overlapping but distinct molecular and cellular mechanisms to enhance dopamine (DA) signaling in the mesocorticolimbic circuitry. DA neurons of the ventral tegmental area (VTA) are key substrates of drugs of abuse and have been implicated in addiction-related behaviors. Enhanced VTA DA neurotransmission evoked by drugs of abuse can engage inhibitory G-protein-dependent feedback pathways, mediated by GABA(B) receptors (GABA(B)Rs) and D(2) DA receptors (D(2)Rs). Chemogenetic inhibition of VTA DA neurons potently suppressed baseline motor activity, as well as the motor-stimulatory effect of cocaine and morphine, confirming the critical influence of VTA DA neurons and inhibitory G-protein signaling in these neurons on this addiction-related behavior. To resolve the relative influence of GABA(B)R-dependent and D(2)R-dependent signaling pathways in VTA DA neurons on behavioral sensitivity to drugs of abuse, we developed a neuron-specific viral CRISPR/Cas9 approach to ablate D(2)R and GABA(B)R in VTA DA neurons. Ablation of GABA(B)R or D(2)R did not impact baseline physiological properties or excitability of VTA DA neurons, but it did preclude the direct somatodendritic inhibitory influence of GABA(B)R or D(2)R activation. D(2)R ablation potentiated the motor-stimulatory effect of cocaine in male and female mice, whereas GABA(B)R ablation selectively potentiated cocaine-induced activity in male subjects only. Neither D(2)R nor GABA(B)R ablation impacted morphine-induced motor activity. Collectively, our data show that cocaine and morphine differ in the extent to which they engage inhibitory G-protein-dependent feedback pathways in VTA DA neurons and highlight key sex differences that may impact susceptibility to various facets of addiction.