Project 1: Reacquisition of cocaine CPP and its inhibition by previous social interaction preferentially affects D1-MSNs
We investigated if counterconditioning with dyadic (i.e., one-to-one) social interaction, a strong inhibitor of the subsequent reacquisition of cocaine conditioned place preference (CPP), differentially modulates the activity of the diverse brain regions oriented along a mediolateral corridor reaching from the interhemispheric border to the anterior commissure, i.e., the nucleus of the vertical limb of the diagonal band, the medial septal nucleus, the major island of Calleja, the intermediate part of the lateral septal nucleus, and the medial accumbens shell and core (together termed ‘accumbens corridor). We also investigated the involvement of the lateral accumbens core and the dorsal caudate putamen. The anterior cingulate 1 (Cg1) region served as a negative control. Contrary to our expectations, we found that all regions of the accumbens corridor showed increased expression of the early growth response protein 1 (EGR1, Zif268) in rats 2 hours after reacquisition of cocaine CPP after a history of cocaine CPP acquisition and extinction. Previous counterconditioning with dyadic social interaction inhibited both the reacquisition of cocaine CPP and the activation of the whole accumbens corridor. EGR1 activation was predominantly found in dynorphin-labeled cells, i.e., presumably D1 receptor-expressing medium spiny neurons (D1-MSNs), with D2-MSNs (immunolabeled with an anti-DRD2 antibody) being less affected. Cholinergic interneurons or GABAergic interneurons positive for parvalbumin, neuropeptide Y or calretinin were not involved in these CPP-related EGR1 changes. Glial cells did not show any EGR1 expression either. The present findings could be of relevance for the therapy of impaired social interaction in substance use disorders, depression, psychosis, and autism spectrum disorders.
Project 2: Increased conditioned place preference for cocaine in high anxiety-related behavior (HAB) mice is associated with an increased activation in the accumbens corridor
Anxiety disorders and substance use disorders are strongly associated in humans. Accordingly, a widely held but controversial concept in the addiction field, the so-called "self-medication hypothesis", posits that anxious individuals are more vulnerable for drug dependence because they use drugs of abuse to alleviate their anxiety. We tested this hypothesis under controlled experimental conditions by quantifying cocaine conditioned place preference (CPP) in CD1 mice selectively bred for high anxiety-related behavior (HAB) vs normal anxiety-related behavior (NAB). HAB mice showed increased cocaine CPP compared to NAB mice. This behavior was associated with an increased expression of the immediate early genes c-Fos and Early Growth Related Protein 1 (EGR1) in the accumbens corridor, i.e., a region stretching from the anterior commissure to the interhemispheric border and comprising the medial nucleus accumbens core and shell, the major island of Calleja and lateral septum, as well as the vertical limb of the diagonal band and medial septum. Within the accumbens corridor the cocaine CPP induced EGR1 expression was only observed in D1- and D2- medium spiny neurons (MSNs), whereas other types of neurons or glial cells were not involved. Overall EGR1 seemed to be a more sensitive marker than c-Fos with respect to the activation by contingent vs noncontingent cocaine. Our findings suggest that cocaine maybe more rewarding in high anxiety individuals, plausibly due to an anxiolytic effect.