Pattern of neural activation following yohimbine-induced reinstatement of alcohol seeking in rats.

Alcohol use disorders represent an extensive socioeconomic burden, yet effective treatment options are suboptimal. A major hurdle in treating alcohol use disorders is the high rate of relapse. Stress is a major factor that promotes relapse in abstinent drug users; therefore, understanding neural mechanisms that underpin the effects of stress on alcohol seeking is critical. In rodent models of stress-induced relapse, the α2 -adrenoceptor antagonist, yohimbine, is a widely used chemical stressor to elicit reinstatement of drug/alcohol seeking. However, the exact mechanism how yohimbine precipitates reinstatement of alcohol seeking and the pattern of neural activation associated with yohimbine-induced reinstatement is poorly understood. Therefore, we counted Fos-protein positive nuclei across 42 brain regions in alcohol-experienced alcohol preferring rats that received either yohimbine in the home-cage (1 mg/kg i.p.) or following yohimbine-induced reinstatement of alcohol seeking. The number of Fos-protein positive nuclei was increased in the prefrontal cortex and extended amygdala after home-cage yohimbine compared to naïve- and vehicle-treated rats. Yohimbine-induced reinstatement increased the number of Fos-protein expressing nuclei in multiple other regions including the thalamus, hypothalamus and hippocampus. We then examined inter-regional correlations in Fos-protein expression for all 42 brain regions, which showed Fos expression was more strongly positively correlated following yohimbine-induced reinstatement of alcohol seeking, compared to home-cage yohimbine. These data suggest low-dose yohimbine in a non-drug-associated context activates stress/impulsivity centres within the brain, whereas yohimbine in the drug-associated context recruits additional brain regions to drive alcohol seeking.