Faculty Collaboration Database

Augmented cocaine seeking in response to stress or CRF delivered into the ventral tegmental area following long-access self-administration is mediated by CRF receptor type 1 but not CRF receptor type 2. J Neurosci 2011 Aug 03;31(31):11396-403

Date

08/05/2011

Pubmed ID

21813699

Pubmed Central ID

PMC3449095

DOI

10.1523/JNEUROSCI.1393-11.2011

Scopus ID

2-s2.0-79961236775 (requires institutional sign-in at Scopus site)   89 Citations

Abstract

Stressful events are determinants of relapse in recovering cocaine addicts. Excessive cocaine use may increase susceptibility to stressor-induced relapse through alterations in brain corticotropin-releasing factor (CRF) regulation of neurocircuitry involved in drug seeking. We previously reported that the reinstatement of cocaine seeking by a stressor (footshock) is CRF dependent and is augmented in rats that self-administered cocaine under long-access (LgA; 6 h daily) conditions for 14 d when compared with rats provided shorter daily cocaine access [short access (ShA) rats; 2 h daily]. Further, we have demonstrated that reinstatement in response to intracerebroventricular CRF administration is heightened in LgA rats. This study examined the role of altered ventral tegmental area (VTA) responsiveness to CRF in intake-dependent increases in CRF- and stress-induced cocaine seeking. Bilateral intra-VTA administration of CRF (250 or 500 ng/side) produced reinstatement in LgA but not ShA rats. In LgA rats, intra-VTA CRF-induced reinstatement was blocked by administration of the CRF-receptor type 1 (CRF-R1) antagonist antalarmin (500 ng/side) or CP-376395 (500 ng/side), but not the CRF-R2 antagonist astressin-2B (500 ng or 1 μg/side) or antisauvagine-30 (ASV-30; 500 ng/side) into the VTA. Likewise, intra-VTA antalarmin, but not astressin-2B, blocked footshock-induced reinstatement in LgA rats. By contrast, neither intra-VTA antalarmin nor CP-376395 altered food-reinforced lever pressing. Intra-VTA injection of the CRF-R1-selective agonist cortagine (100 ng/side) but not the CRF-R2-selective agonist rat urocortin II (rUCN II; 250 ng/side) produced reinstatement. These findings reveal that excessive cocaine use increases susceptibility to stressor-induced relapse in part by augmenting CRF-R1-dependent regulation of addiction-related neurocircuitry in the VTA.

Author List

Blacktop JM, Seubert C, Baker DA, Ferda N, Lee G, Graf EN, Mantsch JR

Author

John Mantsch PhD Chair, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Aminopyridines
Analysis of Variance
Animals
Behavior, Addictive
Behavior, Animal
Cocaine
Conditioning, Operant
Corticotropin-Releasing Hormone
Dopamine Uptake Inhibitors
Dose-Response Relationship, Drug
Drug Synergism
Extinction, Psychological
Flavonoids
Food Preferences
Glucosides
Male
Peptide Fragments
Peptides, Cyclic
Pyrimidines
Pyrroles
Rats
Rats, Sprague-Dawley
Receptors, Corticotropin-Releasing Hormone
Self Administration
Stress, Psychological
Ventral Tegmental Area