Dynamic Changes in Chloride Homeostasis Coordinate Midbrain Inhibitory Network Activity during Reward Learning.

The ability to associate environmental stimuli with positive outcomes is a fundamental form of learning. While extensive research has focused on the response profiles of midbrain dopamine neurons during associative learning, less is known about learning-mediated changes in the afferents that shape their responses. We demonstrate that during critical phases of learning, anion homeostasis in midbrain GABA neurons - a primary source of input to dopamine neurons - is disrupted due to downregulation of the chloride transporter KCC2.

Midbrain KCC2 downregulation: Implications for stress-related and substance use behaviors.

Stress-related and substance use disorders are both characterized by disruptions in reward-related behaviors, and these disorders are often comorbid with one another. Recent investigations have identified a novel mechanism of inhibitory plasticity induced by both stress and substance use within the ventral tegmental area (VTA), a key region in reward processing. This mechanism involves the neuron-specific potassium chloride cotransporter isoform 2 (KCC2), which is essential in modulating inhibitory signaling through the regulation of intracellular chloride (Cl) in VTA GABA neurons.

The serotonin 2A receptor agonist TCB-2 attenuates heavy alcohol drinking and alcohol-induced midbrain inhibitory plasticity.

Disruption of neuronal chloride ion (Cl ) homeostasis has been linked to several pathological conditions, including substance use disorder, yet targeted pharmacotherapies are lacking. In this study, we explored the potential of serotonin 2A receptor (5-HT R) agonism to reduce alcohol consumption in male wild-type C57Bl/6J mice and to ameliorate alcohol-induced inhibitory plasticity in the midbrain. We found that administration of the putative 5-HT R agonist TCB-2 attenuated alcohol consumption and preference but did not alter water or saccharin consumption.

Ethanol produces multiple electrophysiological effects on ventral tegmental area neurons in freely moving rats.

Although alcohol (i.e., ethanol) is a major drug of abuse, the acute functional effects of ethanol on the reward circuitry are not well defined in vivo.

Acute Nicotine Exposure Alters Ventral Tegmental Area Inhibitory Transmission and Promotes Diazepam Consumption.

Nicotine use increases the risk for subsequent abuse of other addictive drugs, but the biological basis underlying this risk remains largely unknown. Interactions between nicotine and other drugs of abuse may arise from nicotine-induced neural adaptations in the mesolimbic dopamine (DA) system, a common pathway for the reinforcing effects of many addictive substances. Previous work identified nicotine-induced neuroadaptations that alter inhibitory transmission in the ventral tegmental area (VTA).