Substance use disorders are among the leading causes of premature death and disability. Most prominent among these, opioid misuse and dependence have become a devastating crisis. Despite this, a complete understanding of the neural circuit adaptations driving substance use disorders remains unknown.Animal models have revealed a key role of the mesolimbic dopamine (DA) pathway in mediating the reinforcing effects of many commonly abused drugs. The ventral tegmental area (VTA), a central hub of this circuitry, is well known for its robust dopaminergic projections to forebrain regions and their crucial roles in modulating reward, aversion, motivation and cognition. However, VTA GABA cells, while long understudied, are increasingly recognized as powerful mediators of reward and potential therapeutic targets for addiction, depression and other stress-linked neuropsychiatric disorders characterized by disruptions in reward processing. Multiple commonly abused drugs act directly on VTA GABA neurons, including, morphine, diazepam, and alcohol. Moreover, their effects are exacerbated by prior drug exposure. The central hypothesis of this dissertation is that changes in drug-induced inhibitory signaling in the VTA contribute to increased addiction-like behaviors in rodents and that correction of this aberrant midbrain GABA signaling reverses the heightened rewarding behavior. In vivo circuit manipulation tools, pharmacological interventions, and rodent models of reward were utilized. The second chapter identifies a novel electrophysiological mechanism in VTA GABA neurons in response to morphine, following two weeks of nicotine exposure in adolescence, that is causally implicated in enhanced morphine reward in adulthood. Importantly, reducing VTA GABA neuron firing during adult morphine exposure prevents the heightened morphine preference observed after adolescent nicotine. Moreover, Chapters 3 and 4 provide evidence that an acute drug exposure (single injection of nicotine or alcohol) or chronic, volitional alcohol consumption diminishes chloride transport in VTA GABA neurons. Normalization of this dysregulated chloride homeostasis by pharmacological upregulation of the potassium chloride cotransporter, KCC2, via the agonist CL290, or through serotonin 2A receptor activation is shown ex vivo and is correlated with KCC2 or 5-HT2AR agonist-mediated reduction in diazepam or alcohol consumption, respectively. In all three chapters, correction of the aberrant inhibitory signaling reversed the corresponding behavior back to its control level. Collectively, this work suggests that through distinct mechanisms, disruption of inhibitory signaling in the VTA leads to increased addiction-like behaviors in rodents across several drugs of abuse. These findings strongly position VTA GABA neurons as a therapeutic target for substance use disorders. Future work is needed both to further probe the mechanistic changes driving altered VTA GABA signaling and to unveil effective clinical treatments to reverse dysregulated inhibitory signaling in individuals suffering from substance use disorders.