Jayme R McReynolds1, Elizabeth M Doncheck1, Oliver Vranjkovic1, Geoffrey S Ganzman1, David A Baker1, Cecilia J Hillard2, John R Mantsch3. 1. Department of Biomedical Sciences, Marquette University, Milwaukee, WI, 53233, USA. 2. Department of Pharmacology and Toxicology and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA. 3. Department of Biomedical Sciences, Marquette University, Milwaukee, WI, 53233, USA. john.mantsch@marquette.edu.
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.
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: Taco J De Vries; Judith R Homberg; Rob Binnekade; Halfdan Raasø; Anton N M Schoffelmeer Journal: Psychopharmacology (Berl) Date: 2003-04-01 Impact factor: 4.530
Authors: John R Mantsch; David A Baker; Joseph P Serge; Michael A Hoks; David M Francis; Eric S Katz Journal: Neuropsychopharmacology Date: 2007-05-30 Impact factor: 7.853
Authors: Lingjun Zuo; Henry R Kranzler; Xingguang Luo; Jonathan Covault; Joel Gelernter Journal: Biol Psychiatry Date: 2007-05-23 Impact factor: 13.382
Authors: Jayme R McReynolds; Analisa Taylor; Oliver Vranjkovic; Terra Ambrosius; Olivia Derricks; Brittany Nino; Beliz Kurtoglu; Robert A Wheeler; David A Baker; Paul J Gasser; John R Mantsch Journal: Neuropsychopharmacology Date: 2016-09-08 Impact factor: 7.853
Authors: Elizabeth M Doncheck; Luke A Urbanik; Margot C DeBaker; Laura M Barron; Gage T Liddiard; Jennifer J Tuscher; Karyn M Frick; Cecilia J Hillard; John R Mantsch Journal: Neuropsychopharmacology Date: 2017-08-21 Impact factor: 7.853
Authors: Jayme R McReynolds; Elizabeth M Doncheck; Yan Li; Oliver Vranjkovic; Evan N Graf; Daisuke Ogasawara; Benjamin F Cravatt; David A Baker; Qing-Song Liu; Cecilia J Hillard; John R Mantsch Journal: Biol Psychiatry Date: 2017-10-06 Impact factor: 13.382
Authors: Elizabeth M Doncheck; Gage T Liddiard; Chaz D Konrath; Xiaojie Liu; Laikang Yu; Luke A Urbanik; Matthew R Herbst; Margot C DeBaker; Nicholas Raddatz; Erik C Van Newenhizen; Jacob Mathy; Marieke R Gilmartin; Qing-Song Liu; Cecilia J Hillard; John R Mantsch Journal: Neuropsychopharmacology Date: 2020-04-17 Impact factor: 7.853
Authors: Andrea S Guzman; Maria P Avalos; Laura N De Giovanni; Pia V Euliarte; Marianela A Sanchez; Bethania Mongi-Bragato; Daiana Rigoni; Flavia A Bollati; Miriam B Virgolini; Liliana M Cancela Journal: Sci Rep Date: 2021-06-21 Impact factor: 4.379