1Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC, USA
There is now compelling epidemiological evidence that anxiety disorders and alcohol dependence frequently co-occur and individuals that suffer from both of these disorders have a poor prognosis in recovery. Unfortunately, the neural substrates underlying the relationship between anxiety disorders and alcohol addiction are poorly understood. To that end, we have established a rodent model of early life stress that engenders robust and enduring increases in numerous behaviors that have been linked with increased vulnerability to alcoholism and anxiety disorders and have begun to characterize the neurobiological adaptations that contribute to this “vulnerable” phenotype. In this model, male Long Evans rats are raised in cohorts of four in large cages (adolescent Group Housed, aGH) or are housed individually in smaller cages (Adolescent socially isolated, aSI) throughout adolescence (postnatal day 28-70). Following the adolescent housing manipulation, all subjects are then housed individually in adulthood. This early life stressor results in numerous behavioral changes including hyperactivity in a novel environment, impaired extinction of fear learning and long-lasting increases in anxiety-like behaviors and measures of ethanol self-administration. Initial neurochemical studies have found that aSI results in significant alterations in mesolimbic catecholamine signaling, including increased stimulated dopamine release and uptake in the ventral and dorsal striatum and increased ethanol-induced dopamine and norepinephrine release in the nucleus accumbens and basolateral amygdala. aSI is also associated with increased measures of neuronal excitability in the basolateral amygdala and the ventral hippocampus. Moreover, pharmacological treatments that reverse some of these neural adaptations can also decrease the elevated anxiety-like behavior and ethanol drinking associated with aSI. Together, these data provide strong initial evidence for the face, construct and predictive validity of aSI as a model of heightened vulnerability to anxiety disorders and alcoholism. These findings also suggest that this model may prove useful in helping to identify novel pharmacotherapies that may particularly effective in treating individuals diagnosed with both disorders. Supported by AA 17531, AA 21099 and AA 10422.