The neural correlates and role of D1 dopamine receptors in renewal of extinguished alcohol-seeking.

We used an ABA renewal design to study the neural correlates, and role of D1 dopamine receptors, in contextual control over extinguished alcohol-seeking. Rats were trained to respond for 4% beer in one context (A), extinguished in a different (B) context, and then tested for responding in the original training context (A) or the extinction context (B). ABA renewal was mediated by D1 dopamine receptors because it was prevented by SCH23390. ABA renewal of alcohol-seeking was associated with selective increases in c-Fos protein induction in basolateral amygdala, ventral accumbens shell, and lateral hypothalamus (renewal-associated Fos). By contrast, being tested was associated with increased c-Fos induction in anterior cingulate, prelimbic and infralimbic cortex, rostral agranular insula, dorsomedial accumbens shell, and accumbens core (test-associated Fos). Renewal-associated Fos in ventral accumbens shell and lateral hypothalamus, but not basolateral amygdala, was D1 dopamine receptor dependent. Double immunofluorescence showed that renewal-associated Fos was expressed in orexin-negative lateral hypothalamic neurons. However, c-Fos induction in either lateral hypothalamic orexin-negative or orexin-positive neurons was positively and significantly correlated with alcohol-seeking. Test-associated c-Fos induction was observed in orexin-positive perifornical neurons. In both regions, c-Fos expression was dependent on D1 dopamine receptors. These results suggest that renewal of extinguished alcohol-seeking depends on a distributed neural circuit involving basolateral amygdala, ventral accumbens shell, and lateral hypothalamus that involves D1 dopamine receptors. Comparison with our previous results [Hamlin AS, Blatchford KE, McNally GP (2006) Renewal of an extinguished instrumental response: Neural correlates and the role of D1 dopamine receptors. Neuroscience 143:25-38] permits identification of similarities and differences in the correlates of renewal of extinguished drug- and natural-reward seeking.