Direct CRFR1 antagonism within the VTA prevents the induction and expression of neural cross‐sensitization to cocaine caused by social defeat stress

Abstract

Social defeat stress results in cross‐sensitization to cocaine, both behaviorally, manifested by augmented locomotor activity and neurally, manifested by augmented dopamine (DA) in the nucleus accumbens (NAc) (Holly et al, 2012). We investigated the role of CRF within the ventral tegmental area (VTA) in the induction and expression of neural cross‐sensitization to cocaine. Male Long‐Evans rats were defeated by a larger aggressive resident male in four episodes, separated by 72 hours (induction phase). Ten days later (expression phase) in vivo microdialysis was used to assess DA in the NAc after an acute cocaine challenge (10 mg/kg, ip). In Experiment 1, rats were implanted with bilateral microinjection cannulae aimed at the VTA, as well as a microdialysis cannula aimed at the NAc one week prior to social defeat. The CRFR1 antagonist CP376395 (CP, 500ng/0.25μL/side) was microinjected 20 minutes prior to each defeat. In Experiment 2, rats were implanted with ipsilateral cannulae in the VTA for microinjection and in the NAc for microdialysis after the last defeat. CP was microinjected 20 minutes prior to the cocaine injection during microdialysis. CRFR1 antagonism in the VTA prevented both the induction and expression of neural cross‐sensitization as a result of social defeat stress, indicating a modulatory role of CRF on DAergic function and neuroadaptations in the VTA as a result of intermittent social stress.