Genetic loss of the dopamine transporter significantly impacts behavioral and molecular responses to sub-chronic stress in mice.

Dopaminergic neurotransmission has emerged as a critical determinant of stress susceptibility and resilience. Although the dopamine transporter (DAT) is known to play a key role in maintaining dopamine (DA) homeostasis, its importance for the regulation of stress susceptibility remains largely unknown. Indeed, while numerous studies have examined the neurochemical and behavioral consequences of genetic loss of DAT, very few have compared responses to stress in wild-type and DAT-knockout (KO) animals. The current study compared the responses of male and female WT and DAT-KO mice to a model of sub-chronic stress. Our results reveal that DAT-KO mice are resistant to stress-induced increases in the latency to enter the light chamber of the light-dark emergence test and demonstrate that DAT-KO mice exhibit baseline reductions in forced swim test immobility and grooming time in the splash test of grooming behavior. In addition to these behavioral changes, our results highlight the importance of sex and dopaminergic neurotransmission on stress-induced changes in the expression and phosphorylation of several signal transduction molecules in the nucleus accumbens that have previously been implicated in the regulation of stress susceptibility, including ERK, GSK3ß, and ΔFosB. Overall, these results provide further evidence of the importance of dopaminergic neurotransmission in regulating stress susceptibility and suggest that genetic loss of DAT prevents stress-induced increases in anxiety-like behavior.

Chronic, but not sub-chronic, stress increases binge-like alcohol consumption in male and female c57BL6 mice.

Stress is known to contribute to mental illness and alcohol use disorders, which are highly prevalent and lead to considerable disability. These stress-related disorders are characterized by significant sex differences, which remain poorly understood. Preclinical research comparing the effects of stress in males and females has the potential to provide new insights into the neurobiology of these conditions. The current study compared the effects of chronic and sub-chronic exposure to variable environmental stressors on binge-like alcohol consumption using the drinking-in-the-dark model in male and female c57BL6 mice. The results reveal that chronic, but not sub-chronic, exposure to variable stress increases alcohol intake in both sexes. Stress-induced alterations in gene expression were also compared in the nucleus accumbens, a brain region widely known to play a key role in stress susceptibility and reward processing. Real-time PCR data indicate that chronic, but not sub-chronic, environmental stress leads to downregulation of adenosine 2A (A2A) receptor mRNA. By contrast, sub-chronic stress increased CREB expression, while chronic stress did not. Several sex differences in the effects of stress on gene expression were also noted. Our results demonstrate that reductions in A2A receptor mRNA in the nucleus accumbens are associated with the increased binge drinking of chronically stressed animals, but future work will be required to determine the functional importance of this gene expression change. Continuing to define the molecular alterations associated with stress-induced increases in alcohol intake has the potential to provide insights into the development and progression of stress-related disorders.