Footshock reinstates cocaine seeking in cocaine-experienced rats by inducing corticotropin-releasing factor (CRF) and glutamate release in the ventral tegmental area (VTA) and thus activating VTA dopaminergic neurons. Footshock-induced VTA glutamate release, dopamine activation and reinstatements are blocked by VTA administration of a α-helical CRF, a nonselective CRF receptor antagonist. The effects of selective CRF antagonists have not yet been reported.

The present studies were designed to explore the roles of VTA CRF receptor subtypes and CRF-BP in these effects induced by footshock.

Rats were first trained to lever-press for intravenous cocaine (1 mg/infusion/0.13 ml, FR-1 schedule), and then tested under extinction conditions until response rates returned to the pretraining baseline. Reinstatements, VTA glutamate and dopamine levels [microdialysis with high performance liquid chromatography (HPLC)] were then assessed, under various pharmacological conditions, after mild inescapable footshock.

Footshock-induced reinstatement of cocaine seeking and release of VTA glutamate and dopamine were blocked by selective blockade of VTA CRF₂ receptors (CRF₂Rs) but not CRF₁Rs. VTA perfusion of CRF or CRF₂R agonists that have strong affinity for CRF-BP mimicked the effects induced by footshock while CRFR agonists that do not bind CRF-BP were ineffective. CRF_6–33, which competes for the CRF binding site on CRF-BP, attenuated the effects of CRF or urocortin I on VTA glutamate and dopamine release and on reinstatement of cocaine seeking.

The present studies revealed a role of VTA CRF-BP and suggest an involvement of CRF₂R in the effectiveness of stress in triggering glutamate and dopamine release and cocaine seeking in drug-experienced animals.