Contribution of dorsostriatal hypodopaminergic states to the development of compulsive alcohol use: new insights into the pathophysiology of alcohol addiction – DOPALCOMP

Because of its prevalence (around 10% in the population) and high levels of morbidity and mortality, alcohol use and related disorders are one of the most detrimental health problems worldwide, associated with a very high social and economical cost. Alcohol use disorder (AUD) is a chronic relapsing disease characterized by recurrent drinking of high amount of alcohol whatever the consequences, due to a compulsive desire to drink (craving) and loss of control, leading to reduced social, occupational or recreational activities, and the emergence of a negative emotional state in the absence of alcohol. Despite the important socio-economical impact of AUD, available therapies are still limited, not least because the psychobiological mechanisms underlying the compulsive nature of alcohol addiction remain to be understood.
Dopamine (DA) has long been thought to be involved in drugs abuse and addictions, but the exact contribution of DA to the pathophysiology of drugs, including alcohol, addiction remains unclear and controversial. An influential hypothesis suggests that the development of a negative emotional state during abstinence is underlined, at least in part, by a decrease in the dopaminergic tone of the reward and motivation system. This may strongly participate to the development of compulsive drug seeking and taking by inducing an aberrant motivation to consume the drug in order to reverse the negative effects of abstinence. However, and despite some supportive empirical data, notably from animal models of alcohol abuse and dependence, it is still unknown whether this hypodopaminergic state related to drug withdrawal is responsible for maladaptative drug taking behaviors and relapse.
Interestingly, with the development of an innovative experimental model in rats, we have recently showed that partial loss of DA within the nigrostriatal system, while sparing the motor function of the animals, induced profound affective and motivational impairments, thereby recapitulating the spectrum of behaviors associated with drug withdrawal. Moreover, this striking behavioral phenotype was fully reversed by the administration of DA agonists, which confirmed the implication of DA in such deficits. Taken together, these data lead us to wonder whether the hypodopaminergic state induced by our experimental approach would render animals vulnerable to the development of abnormal alcohol seeking and drinking behaviors.
In the present project, we will therefore address, through four different and independent tasks, three main questions: 1) Do DA deficiencies within the nigrostriatal system favor the development of compulsive alcohol consumption and relapse? 2) Is compulsive alcohol consumption in specific individuals associated with dorsostriatal DA deficiencies? 3) Does normalization of dorsostriatal DA deficiencies and their behavioral correlates reduce compulsive alcohol consumption and relapse?
This project is likely to provide important breakthroughs in the field of addiction, with a novel and ambitious approach combining behavior, neurochemistry, pharmacology, neuroanatomy and state of the art chemogenetic technics. Understanding the causal role of DA in addictive processes will have a crucial implication for the comprehension of the pathophysiology of AUD and the development of relevant therapeutic strategies.