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Abstract

Loss of control over drinking has long been recognized as a defining feature of alcohol use disorder (AUD), yet its mechanistic bases remain unclear. One influential account, the habit theory of addiction, proposes that chronic alcohol exposure shifts behavioral regulation from goal-directed to habitual control. However, this view is grounded largely in animal studies that rely on oversimplified dichotomous classifications of behavior and on overinterpreted null findings from classical outcome-devaluation paradigms. Human studies rarely replicate these results, instead pointing to impaired goal-directed regulation rather than strengthened habits. Across three aims, this thesis critically re-examines the habit framework using both quantitative synthesis and experimental investigation. A meta-analysis of rodent studies (Aim 1) reveals that alcohol-dependent animals do not reliably exhibit a qualitative transition to habitual control, aligning with human evidence demonstrating preserved sensitivity to outcome value but weakened goal-directed processing. Building on this foundation, I assessed behavioral control across instrumental learning, spatial navigation, and motor-skill paradigms (Aim 2). These experiments show that classically defined stimulus-response (S-R) habits are short-lived and readily overridden by goal-directed adjustments. Alcohol-dependent rats instead display a domain-general deficit in flexible adaptation to novel contingencies, accompanied by heightened automaticity. These findings support modern graded accounts of behavioral control rather than a categorical dominance of habit mechanisms. Bidirectional chemogenetic manipulations further identify the posterior dorsomedial striatum (pDMS) as a domain-general hub for behavioral flexibility and a critical locus whose disengagement may underlie alcohol-induced impairments. In alcohol-naïve rats, pDMS inhibition reproduced the broad deficits in adaptive control observed in alcohol-dependent animals. Conversely, chemogenetic activation of the pDMS in alcohol-dependent rats restored flexible, goal-directed behavior across all domains tested, demonstrating that re-engaging this region is sufficient to rescue alcohol-induced deficits. Thus, pDMS activity is necessary for the expression of flexible, goal-directed control irrespective of behavioral domain. Complementary cell-type–specific manipulations show that D1-expressing medium spiny neurons (D1-MSNs) within the pDMS critically support flexible action selection without affecting the expression of instrumental habits. Finally, experiments using a novel combination of CB1 receptor gain- and loss-of-function rat lines (Aim 3) reveal that sex moderates CB1 receptor signaling. Females showed greater habitual tendencies than males, with loss-of-function females displaying impaired operant acquisition and gain-of-function females exhibiting hyperlocomotion; behavioral effects that corresponded to elevated CB1R activity across the dorsal striatum and increased CB1R availability in the pDMS. These findings point to a sex-specific neurobiological contribution to differences in habit propensity and may help explain sex-dependent vulnerability to addiction. Together, these findings challenge the classical habit theory of addiction and demonstrate that chronic alcohol exposure impairs goal-directed control in a broad, domain-general manner rather than generating a categorical shift toward S-R habits. This work reframes loss of control in alcohol dependence as an impairment in the flexible updating of action selection rooted in dorsomedial striatal dysfunction, offering experimental evidence for a more nuanced and mechanistically grounded account of addictive behavior.