Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

Publication

Enhanced CRFR1-Dependent Regulation of a Ventral Tegmental Area to Prelimbic Cortex Projection Establishes Susceptibility to Stress-Induced Cocaine Seeking.

The Journal of neuroscience : the official journal of the Society for Neuroscience | 2018

The ability of stress to trigger cocaine seeking in humans and rodents is variable and is determined by the amount and pattern of prior drug use. This study examined the role of a corticotropin releasing factor (CRF)-regulated dopaminergic projection from the ventral tegmental area (VTA) to the prelimbic cortex in shock-induced cocaine seeking and its recruitment under self-administration conditions that establish relapse vulnerability. Male rats with a history of daily long-access (LgA; 14 × 6 h/d) but not short-access (ShA; 14 × 2 h/d) self-administration showed robust shock-induced cocaine seeking. This was associated with a heightened shock-induced prelimbic cortex Fos response and activation of cholera toxin b retro-labeled VTA neurons that project to the prelimbic cortex. Chemogenetic inhibition of this pathway using a dual virus intersectional hM4Di DREADD (designer receptor exclusively activated by designer drug) based approach prevented shock-induced cocaine seeking. Both shock-induced reinstatement and the prelimbic cortex Fos response were prevented by bilateral intra-VTA injections of the CRF receptor 1 (CRFR1) antagonist, antalarmin. Moreover, pharmacological disconnection of the CRF-regulated dopaminergic projection to the prelimbic cortex by injection of antalarmin into the VTA in one hemisphere and the D1 receptor antagonist, SCH23390, into the prelimbic cortex of the contralateral hemisphere prevented shock-induced cocaine seeking. Finally, LgA, but not ShA, cocaine self-administration resulted in increased VTA CRFR1 mRNA levels as measured using in situ hybridization. Altogether, these findings suggest that excessive cocaine use may establish susceptibility to stress-induced relapse by recruiting CRF regulation of a stressor-responsive mesocortical dopaminergic pathway.SIGNIFICANCE STATEMENT Understanding the neural pathways and mechanisms through which stress triggers relapse to cocaine use is critical for the development of more effective treatment approaches. Prior work has demonstrated a critical role for the neuropeptide corticotropin releasing factor (CRF) in stress-induced cocaine seeking. Here we provide evidence that stress-induced reinstatement in a rat model of relapse is mediated by a CRF-regulated dopaminergic projection from the ventral tegmental area (VTA) that activates dopamine D1 receptors in the prelimbic cortex. Moreover, we report that this pathway may be recruited as a result of daily cocaine self-administration under conditions of extended drug access/heightened drug intake, likely as a result of increased CRFR1 expression in the VTA, thereby promoting susceptibility to stress-induced cocaine seeking.

Pubmed ID: 30355627 RIS Download

Research resources used in this publication

Additional research tools detected in this publication

None found

Antibodies used in this publication

Associated grants

Agency: NIDA NIH HHS, United States
Id: R01 DA015758
Agency: NIDA NIH HHS, United States
Id: R01 DA038663

Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.

This is a list of tools and resources that we have found mentioned in this publication.

Living Colors® DsRed Polyclonal Antibody (antibody)

RRID:AB_10013483

This polyclonal targets DsRed

View all literature mentions

Anti-Cholera Toxin B Subunit (antibody)

RRID:AB_10013220

This polyclonal targets Cholera toxin B Subunit

View all literature mentions

Anti-Tyrosine Hydroxylase Antibody, clone LNC1 (antibody)

RRID:AB_2201528

This monoclonal targets Tyrosine Hydroxylase

View all literature mentions

VECTASTAIN ABC-Peroxidase Kit (Standard) (antibody)

RRID:AB_2336818

This unknown targets

View all literature mentions

ABE457 | Anti-c-Fos Antibody (antibody)

RRID:AB_2631318

This polyclonal targets N-terminus c-Fos

View all literature mentions

Donkey anti-Mouse IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 488 (antibody)

RRID:AB_141607

This polyclonal secondary targets IgG (H+L)

View all literature mentions

c-Fos Antibody (4) (antibody)

RRID:AB_2106783

This polyclonal targets FOS

View all literature mentions

DAB Substrate Kit (3,3'-diaminobenzidine) (antibody)

RRID:AB_2336382

This unknown targets

View all literature mentions

Anti-Rabbit IgG (H+L), made in goat (antibody)

RRID:AB_2336198

This unknown targets IgG

View all literature mentions

Donkey Anti-Rabbit IgG (H+L) Antibody, Alexa Fluor ?? 594 Conjugated (antibody)

RRID:AB_141637

This unknown targets Rabbit IgG (H+L)

View all literature mentions

Anti-Goat IgG (H+L), made in horse (antibody)

RRID:AB_2336123

This monoclonal targets IgG

View all literature mentions

AxioVision Imaging System (software resource)

RRID:SCR_002677

Digital image processing system where microscope settings and processing steps may be adjusted in single user interface. Can acquire images from variety of cameras. Includes software package for capturing, archiving and preparing images for publication. Allows users to visualize and present images in several dimensions. Functionality of imaging toolbox expands constantly with wide range of different modules that are tailored to specific applications or microscope accessories. This resource is duplicated by SCR_018376

View all literature mentions

ImageJ (software resource)

RRID:SCR_003070

Open source Java based image processing software program designed for scientific multidimensional images. ImageJ has been transformed to ImageJ2 application to improve data engine to be sufficient to analyze modern datasets.

View all literature mentions