The Impact of Decreased Dopamine on Compulsive Alcohol Use
Post by Leanna Kalinowski
The takeaway
Researchers have uncovered a critical role of decreased dopamine in the nigrostriatal pathway in compulsive alcohol use behaviors.
What's the science?
Compulsive alcohol use – defined as the continued seeking and drinking of alcohol despite it having significant negative consequences – is a hallmark symptom of alcohol use disorder (AUD) that impacts millions of people across the globe. Previous research has heavily implicated the mesolimbic dopamine pathway in the etiology of AUD. Specifically, initial alcohol consumption is associated with an increase of dopamine in this pathway, while extended alcohol consumption subsequently leads to a significant decrease of dopamine in this pathway.
More recently, the neighboring nigrostriatal dopamine pathway has also been implicated in AUD. However, due to previous beliefs that this pathway was solely responsible for motor functions, the role of the nigrostriatal pathway in compulsive alcohol use has been significantly understudied. This week in Molecular Psychiatry, Goutaudier and colleagues investigated the role of decreased dopamine in the nigrostriatal pathway on compulsive alcohol use.
How did they do it?
In the first experiment, rats were first trained to press a lever for alcohol in an operant self-administration chamber. Following consistent alcohol self-administration and consumption for 38 sessions, the researchers then identified rats with compulsive-like alcohol use by pairing the alcohol lever with a mild foot shock for 6 sessions, thereby imposing negative consequences for continued alcohol use. Following this procedure, rats were divided into two groups: “foot shock-sensitive” if their lever presses for alcohol decreased following the introduction of foot shocks, or “foot shock resistant” if their lever presses for alcohol increased following the introduction of foot shocks. Ten days after the last alcohol self-administration session, dopamine levels in the brain were analyzed using enzyme-linked immunosorbent assay (ELISA).
In the second experiment, the researchers used chemogenetics to selectively turn off dopamine signaling in the nigrostriatal pathway. To do this, they first started with rats that were bred to conditionally inhibit the th gene; this gene provides instructions for making tyrosine hydroxylase, which is an enzyme that is required for the synthesis of dopamine. Half of these rats then received an injection of a virus, which expresses hM4Di, into the substantia nigra (i.e., the beginning of the nigrostriatal dopamine pathway). hM4Di can then be activated by injecting the rats with C21 (an hM4Di agonist), which then selectively and temporarily inhibits the th gene and blocks dopamine synthesis in the substantia nigra. The other half of the rats received an injection of mCherry into the substantia nigra, which acts as a control that does not inhibit the th gene following C21 exposure.
Both groups of rats then underwent the same alcohol self-administration procedure as described in experiment 1. Following the identification of compulsive-like alcohol use after the initial foot shock sessions, the rats were then injected with C21 to block dopamine signaling in the hM4Di rats, after which their foot shock sensitivity was once again tested for 6 sessions.
What did they find?
First, the researchers found that foot shock-resistant rats (i.e., those with compulsive-like alcohol use) had lower dopamine levels in the anterior dorsolateral striatum – the main output structure of the nigrostriatal pathway – compared to foot shock-sensitive rats. This suggests that this neural pathway is at least somewhat responsible for compulsive-like alcohol use. Second, the researchers found that inhibition of nigrostriatal dopamine signaling causes rats that were previously foot shock-sensitive to persist through the foot shocks and continue to self-administer alcohol. This behavior was not observed in mCherry/control rats, suggesting that blocking dopamine activity in the nigrostriatal pathway is sufficient to induce compulsive alcohol-seeking behaviors in animals that previously did not exhibit these behaviors.
What's the impact?
Taken together, results from this study uncover a critical role of the nigrostriatal pathway – particularly low dopamine levels – in compulsive alcohol use. These results may pave the way for potential new treatment strategies for individuals with an alcohol use disorder. Future studies should determine whether these neural mechanisms are specific to compulsive alcohol use, or if they are also present with compulsive use of other drugs.
