Synaptic mechanisms underlying reward seeking and compulsive drug use

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Project A: Pain induces adaptations in ventral tegmental area dopamine neurons to drive anhedonia-like behavior. Pain is a complex phenomenon composed of sensory and emotional affective components. As pain persists, the presence of negative affective states can lead to the development of negative emotional states such as anhedonia, anxiety and depression. While current pharmacological therapies provide high potency in alleviating sensory disturbances, the negative affective states accompanying pain remain undertreated. Emerging evidence from human and preclinical studies show that there are deficits in emotional decision-making, reward evaluation and reward seeking, or motivation in pain states. These deficits can lead to the development of anhedonia and depression. Uncovering the neuronal circuitry mediating these pain-induced negative affective states may provide opportunities to develop safer therapies for pain treatment and limit the development of co-morbid disorders. Using in vivo fiber photometry and ex vivo patch-clamp electrophysiology, we report that in rats, the reduced motivation induced by pain is associated with decreased excitability and reduced activity of VTA DA neurons. This decreased excitability of VTA DA neurons is associated with increased inhibitory drive from GABAergic RMTg afferents. Furthermore, we report that chemogenetic activation of NAc-projecting DA neurons in the VTA is sufficient to overcome the pain-induced reduction in motivated behavior. Finally, a pain-associated decrease in sucrose consumption was reversed by inhibiting RMTg GABAergic input onto the VTA, overcome by increasing the concentration of the sucrose reward, and mimicked in naive animals by chemogenetic stimulation of RMTg GABA neurons. Together, these results indicate that the experience of pain decreases the activity and excitability of VTA DA neurons, which are partially driven by an increased inhibitory drive from the RMTg. This blunted VTA DA activity then contributes to pain-induced negative affective states. Our findings represent a crucial step in understanding the neural mechanisms underlying the emotional component of pain and may provide novel targets for the treatment of pain-induced negative affect. Project B: Ventral tegmental area GABAergic inhibition of cholinergic interneurons in the ventral nucleus accumbens shell promotes reward reinforcement. The long-range GABAergic input from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) is relatively understudied, and therefore its role in reward processing has remained unknown. In the present study, we show, in both male and female mice, that long-range GABAergic projections from the VTA to the ventral NAc shell, but not to the dorsal NAc shell or NAc core, are engaged in reward and reinforcement behavior. We show that this GABAergic projection exclusively synapses on to cholinergic interneurons (CINs) in the ventral NAc shell, thereby serving a specialized function in modulating reinforced/rewarded behavior through the inhibition of ventral NAc shell CINs. These findings highlight the diversity in the structural and functional topography of VTA GABAergic projections, and their neuromodulatory interactions across the dorsoventral gradient of the NAc shell. They also further our understanding of neuronal circuits that are directly implicated in neuropsychiatric conditions such as depression and substance use disorders.