Section on Neurobiology of Compulsive Behaviors

National Institute Of Mental Health

Investigators

Linked publications & trials

Abstract

"Individual variability in the anxiolytic potency of alcohol is linked to high baseline anxiety state and a shift of balance expression of striatal dopamine D1 and D2 receptors" We investigated the neural mechanisms underlying the anxiolytic effects of alcohol and their contribution to long-term changes in alcohol drinking. Based on the clinical observation that post-traumatic stress disorder shows high rates of comorbidity with alcohol use disorder, we explored the hypothesis that a robust anxiolytic response to alcohol enhances its reinforcing properties rendering some individuals more susceptible to developing compulsive behaviors and alcohol abuse. This also leads to the broader hypothesis that the reinforcing values of alcohol are higher in individuals who are more anxious at baseline. Interestingly, inbred C57Bl6/J mice show great individual variability in both the baseline state of anxiety and the potency of alcohol anxiolytic effects, making them an apt model of the human condition. Baseline anxiety-like behavior and alcohol anxiolytic effects were assessed using three different tests commonly utilized in the field. We found significant correlations among the tests, in support of the robustness of the findings. Given that each of these tests has their own bias and possible caveat, the observed congruence across the tests provides validation that the tests are reporting on a common behavioral phenotype. In support of our first hypothesis, we discovered that alcohol has higher anxiolytic potency in mice with an elevated baseline anxiety phenotype. We speculated that predisposing differences in brain circuitry could underly the heightened baseline phenotype and the more robust acute anxiolytic response to alcohol. We then sought to better understand the mechanisms that mediate the anxiolytic effects of alcohol in rodents. In vivo fiber photometry experiments revealed that alcohol increased population calcium events in neurons expressing dopamine type-1 receptor (D1R) in the dorsomedial striatum. When rodents were placed in the elevated zero maze, these D1R-expressing neurons were activated preferentially when the mouse entered the open arm, the anxiogenic zone of the maze. Using pharmacology, we showed that activation of the D1R is required for alcohol anxiolytic effects. We hypothesize that either lower threshold of activation for D1R-expressing neurons or enhanced activity of D1R could drive more potent anxiolytic effects in response to alcohol. Thus, the factors and mechanisms that regulate D1R function in these striatal neurons are important contributors to higher anxiolytic potency of alcohol and possibly the vulnerability to other long-term effects of alcohol. We recently published data in collaboration with Dr. Lex Kravitz that indicated that the levels of D2R expression and the activation of the neurons expressing dopamine type-2 receptors (D2Rs) are important in determining an anxiety phenotype in mice. At first glance, these findings could be interpreted as contradictory to our current observations with alcohol. However, given the important interconnection of neurons expressing D1R and D2R, both within the striatum and throughout the basal ganglia, these results merited further investigation. We manipulated striatal D2R availability using targeted deletion (homozygotes) or knockdown (heterozygotes) of the Drd2 gene selectively on D2R-expressing striatal projection neurons. We found a gene-dose dependent decrease in D2-like agonist bindings: 2050% reduction in binding by removing one allele and 8090% reduction by removing both Drd2 alleles from striatal neurons, dependent on striatal subregion. Surprisingly, single allele deletion was sufficient to induce full expression of an anxiety phenotype in a battery of tests. Mice with low levels of striatal D2Rs were more sensitive to the anxiolytic properties of alcohol. Like in wildtype mice, D1R activation is required for alcohol anxiolytic effects in mice with low D2Rs. We investigated possible mechanisms linking D2R availability with D1R activity in these mice. To our surprise, increased striatal D1-like ligand binding was found in brains with low striatal D2R leading to an overall increase in the D1/D2 binding ratio. We propose that alterations in the balance of D1/D2 receptor activation generates an anxiogenic phenotype that renders mice more sensitive to the anxiolytic properties of alcohol conferring an increased vulnerability for compulsive-like drinking. Finally, to determine if this imbalance of D1/D2 receptor activation in mice with low levels of D2Rs and enhanced acute anxiolytic properties of alcohol could show long-term compulsive-like alcohol consumption relevant to alcohol use disorder, we examined the propensity of these mice to continue drinking despite pairing consumption with adverse outcomes. To do this, we used the Intellicages which allowed us to assess operant alcohol consumption, alcohol preference, and the effect of quinine adulteration of alcohol solution on drinking behavior in a group-housed setting. While there was no difference in overall alcohol preference and consumption, mice with low striatal D2Rs displayed punishment-resistant alcohol drinking, a selective phenotype associated with alcohol use disorder in humans. Overall, this set of studies demonstrated that D1R activity is necessary for the anxiolytic properties of alcohol and alcohol increases the activity of neurons expressing D1R in the dorsomedial striatum, potentiating the anxiolytic effects of alcohol. However, rather than being independent of D1R activation, the anxiolytic response to alcohol seems to be dependent on the balance of striatal D1R and D2R activity. Furthermore, the skewed ratio of D1R and D2R activation leads to a vulnerability to compulsive-like alcohol consumption, as seen in the punishment resistant drinking. Taken together, this data has profound clinical implications, suggesting a neuronal mechanism by which an enhanced acute response to alcohol can be linked to long-term maladaptive drinking.