Original Investigation

Psychopharmacology

, Volume 193, Issue 2, pp 283-294

First online:

Stress-induced relapse to cocaine seeking: roles for the CRF2 receptor and CRF-binding protein in the ventral tegmental area of the rat

  • Bin WangAffiliated withBehavioral Neuroscience Branch, Intramural Research Program (IRP), National Institute on Drug Abuse (NIDA), National Institutes of Health
  • , Zhi-Bing YouAffiliated withBehavioral Neuroscience Branch, Intramural Research Program (IRP), National Institute on Drug Abuse (NIDA), National Institutes of Health Email author 
  • , Kenner C. RiceAffiliated withLaboratory of Medicinal Chemistry, NIDDK, National Institutes of Health
  • , Roy A. WiseAffiliated withBehavioral Neuroscience Branch, Intramural Research Program (IRP), National Institute on Drug Abuse (NIDA), National Institutes of Health

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Abstract

Rationale

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.

Objective

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

Methods

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.

Results

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. CRF6–33, 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.

Conclusions

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.

Keywords

Stress Addiction Cocaine Corticotropin-releasing factor Binding protein Reinstatement