Hypodopaminergic state of the nigrostriatal pathway drives compulsive alcohol use

Abstract

The neurobiological mechanisms underlying compulsive alcohol use, a cardinal feature of alcohol use disorder, remain elusive. The key modulator of motivational processes, dopamine (DA), is suspected to play an important role in this pathology, but its exact role remains to be determined. Here, we found that rats expressing compulsive-like alcohol use, operationalized as punishment-resistant self-administration, showed a decrease in DA levels restricted to the dorsolateral territories of the striatum, the main output structure of the nigrostriatal DA pathway. We then causally demonstrated that chemogenetic-induced selective hypodopaminergia of this pathway resulted in compulsive-like alcohol self-administration in otherwise resilient rats, accompanied by the emergence of alcohol withdrawal-like motivational impairments (i.e., impaired motivation for a natural reinforcer). Finally, the use of the monoamine stabilizer OSU6162, previously reported to correct hypodopaminergic states, transiently decreased compulsive-like alcohol self-administration in vulnerable rats. These results suggest a potential critical role of tonic nigrostriatal hypodopaminergic states in alcohol addiction and provide new insights into our understanding of the neurobiological mechanisms underlying compulsive alcohol use.

Repeated Cocaine Intake Differentially Impacts Striatal D2/3 Receptor Availability, Psychostimulant-Induced Dopamine Release, and Trait Behavioral Markers of Drug Abuse

“…A tolerance to the DA-elevating effect of cocaine in the nucleus accumbens has previously been observed via microdialysis using both short- [58,59,73] and long-access [74,75] schedules of cocaine SA, and it is viewed as a critical determinant in the development of drug dependence and addiction [76]. Our results extend this effect to the dorsal striatum, where hypodopaminergic functioning has been linked to compulsive drug use [77]. Moreover, we showed that this tolerance was baseline-dependent, and it correlated negatively with baseline levels of AMPH-induced DA overflow, suggesting a floor effect of cocaine exposure in reducing evoked DA release.…”

Sex differences in oxycodone-taking behaviors are linked to disruptions in reward-guided, decision-making functions

“…Individuals with greater midbrain D3 receptors may have lower phasic dopamine release particularly in response to rewards which leads to poorer value updating and, therefore, a lower Δ + parameter. Indeed, a hypodopaminergic state has been proposed to be a risk factor for addiction (Goutaudier et al, 2022; Kótyuk et al, 2022) and associated with poor decision making (Rutledge et al, 2009, 2015; Clarke et al, 2011; Costa et al, 2015). Midbrain D3 receptors may, therefore, be at the nexus between addiction susceptibility and decision-making.…”

Invited Expert Opinion- Bio-informatic and Limitation Di-rectives to Help Adopt Ge-netic Addiction Risk Screening and Identify Preaddictive Reward Dysregulation: Re-quired Analytic Evidence to Induce Dopamine Homeo-statsis

“…In summary, unlike one gene-one disease (OGOD), RDS is polygenetic and complex. Even though the genes selected for GARS are not the only ones associated with all addictive behaviors, we decided to focus on specific reward genes, and associated polymorphisms were chosen based on hypodopaminergia [ 79 ]. Other genes, such as alcohol metabolism genes (e.g., alcohol dehydrogenase) combined with GARS, may provide an even stronger association in terms of addiction vulnerability.…”