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CB1 receptor antagonism blocks stress-potentiated reinstatement of cocaine seeking in rats.
Psychopharmacology (Berl). 2016 Jan; 233(1):99-109.P

Abstract

RATIONALE

Under some conditions, stress, rather than directly triggering cocaine seeking, potentiates reinstatement to other stimuli, including a subthreshold cocaine dose. The mechanisms responsible for stress-potentiated reinstatement are not well defined. Endocannabinoid signaling is increased by stress and regulates synaptic transmission in brain regions implicated in motivated behavior.

OBJECTIVES

The objective of this study was to test the hypothesis that cannabinoid type 1 receptor (CB1R) signaling is required for stress-potentiated reinstatement of cocaine seeking in rats.

METHODS

Following i.v. cocaine self-administration (2 h access/day) and extinction in male rats, footshock stress alone does not reinstate cocaine seeking but reinstatement is observed when footshock is followed by an injection of an otherwise subthreshold dose of cocaine (2.5 mg/kg, i.p.). CB1R involvement was tested by systemic administration of the CB1R antagonist AM251 (0, 1, or 3 mg/kg, i.p.) prior to testing for stress-potentiated reinstatement.

RESULTS

Stress-potentiated reinstatement was blocked by both 1 and 3 mg/kg AM251. By contrast, AM251 only attenuated food-reinforced lever pressing at the higher dose (i.e., 3 mg/kg) and did not affect locomotor activity at either dose tested. Neither high-dose cocaine-primed reinstatement (10 mg/kg, i.p.) nor footshock stress-triggered reinstatement following long-access cocaine self-administration (6 h access/day) was affected by AM251 pretreatment. Footshock stress increased concentrations of both endocannabinoids, N-arachidonylethanolamine and 2-arachidonoylglycerol, in regions of the prefrontal cortex.

CONCLUSIONS

These findings demonstrate that footshock stress increases prefrontal cortical endocannabinoids and stress-potentiated reinstatement is CB1R-dependent, suggesting that CB1R is a potential therapeutic target for relapse prevention, particularly in individuals whose cocaine use is stress-related.

Authors+Show Affiliations

Department of Biomedical Sciences, Marquette University, Milwaukee, WI, 53233, USA.Department of Biomedical Sciences, Marquette University, Milwaukee, WI, 53233, USA.Department of Biomedical Sciences, Marquette University, Milwaukee, WI, 53233, USA.Department of Biomedical Sciences, Marquette University, Milwaukee, WI, 53233, USA.Department of Biomedical Sciences, Marquette University, Milwaukee, WI, 53233, USA.Department of Pharmacology and Toxicology and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.Department of Biomedical Sciences, Marquette University, Milwaukee, WI, 53233, USA. john.mantsch@marquette.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26455361

Citation

McReynolds, Jayme R., et al. "CB1 Receptor Antagonism Blocks Stress-potentiated Reinstatement of Cocaine Seeking in Rats." Psychopharmacology, vol. 233, no. 1, 2016, pp. 99-109.
McReynolds JR, Doncheck EM, Vranjkovic O, et al. CB1 receptor antagonism blocks stress-potentiated reinstatement of cocaine seeking in rats. Psychopharmacology (Berl). 2016;233(1):99-109.
McReynolds, J. R., Doncheck, E. M., Vranjkovic, O., Ganzman, G. S., Baker, D. A., Hillard, C. J., & Mantsch, J. R. (2016). CB1 receptor antagonism blocks stress-potentiated reinstatement of cocaine seeking in rats. Psychopharmacology, 233(1), 99-109. https://doi.org/10.1007/s00213-015-4092-x
McReynolds JR, et al. CB1 Receptor Antagonism Blocks Stress-potentiated Reinstatement of Cocaine Seeking in Rats. Psychopharmacology (Berl). 2016;233(1):99-109. PubMed PMID: 26455361.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - CB1 receptor antagonism blocks stress-potentiated reinstatement of cocaine seeking in rats. AU - McReynolds,Jayme R, AU - Doncheck,Elizabeth M, AU - Vranjkovic,Oliver, AU - Ganzman,Geoffrey S, AU - Baker,David A, AU - Hillard,Cecilia J, AU - Mantsch,John R, Y1 - 2015/10/12/ PY - 2015/03/09/received PY - 2015/09/18/accepted PY - 2015/10/13/entrez PY - 2015/10/13/pubmed PY - 2016/8/19/medline KW - Addiction KW - Cocaine KW - Endocannabinoid KW - Reinstatement KW - Relapse KW - Self-administration KW - Stress SP - 99 EP - 109 JF - Psychopharmacology JO - Psychopharmacology (Berl.) VL - 233 IS - 1 N2 - RATIONALE: Under some conditions, stress, rather than directly triggering cocaine seeking, potentiates reinstatement to other stimuli, including a subthreshold cocaine dose. The mechanisms responsible for stress-potentiated reinstatement are not well defined. Endocannabinoid signaling is increased by stress and regulates synaptic transmission in brain regions implicated in motivated behavior. OBJECTIVES: The objective of this study was to test the hypothesis that cannabinoid type 1 receptor (CB1R) signaling is required for stress-potentiated reinstatement of cocaine seeking in rats. METHODS: Following i.v. cocaine self-administration (2 h access/day) and extinction in male rats, footshock stress alone does not reinstate cocaine seeking but reinstatement is observed when footshock is followed by an injection of an otherwise subthreshold dose of cocaine (2.5 mg/kg, i.p.). CB1R involvement was tested by systemic administration of the CB1R antagonist AM251 (0, 1, or 3 mg/kg, i.p.) prior to testing for stress-potentiated reinstatement. RESULTS: Stress-potentiated reinstatement was blocked by both 1 and 3 mg/kg AM251. By contrast, AM251 only attenuated food-reinforced lever pressing at the higher dose (i.e., 3 mg/kg) and did not affect locomotor activity at either dose tested. Neither high-dose cocaine-primed reinstatement (10 mg/kg, i.p.) nor footshock stress-triggered reinstatement following long-access cocaine self-administration (6 h access/day) was affected by AM251 pretreatment. Footshock stress increased concentrations of both endocannabinoids, N-arachidonylethanolamine and 2-arachidonoylglycerol, in regions of the prefrontal cortex. CONCLUSIONS: These findings demonstrate that footshock stress increases prefrontal cortical endocannabinoids and stress-potentiated reinstatement is CB1R-dependent, suggesting that CB1R is a potential therapeutic target for relapse prevention, particularly in individuals whose cocaine use is stress-related. SN - 1432-2072 UR - https://www.unboundmedicine.com/medline/citation/26455361/CB1_receptor_antagonism_blocks_stress_potentiated_reinstatement_of_cocaine_seeking_in_rats_ L2 - https://dx.doi.org/10.1007/s00213-015-4092-x DB - PRIME DP - Unbound Medicine ER -