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Cocaine-induced increases in motivation require 2-arachidonoylglycerol mobilization and CB1 receptor activation in the ventral tegmental area.
Engi, Sheila A; Beebe, Erin J; Ayvazian, Victoria M; Cruz, Fabio C; Cheer, Joseph F; Wenzel, Jennifer M; Zlebnik, Natalie E.
Affiliation
  • Engi SA; Dept. of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA; Dept. of Pharmacology, Universidade Federal de São Paulo - UNIFESP, São Paulo, SP, Brazil.
  • Beebe EJ; Dept. of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA.
  • Ayvazian VM; Dept. of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA.
  • Cruz FC; Dept. of Pharmacology, Universidade Federal de São Paulo - UNIFESP, São Paulo, SP, Brazil.
  • Cheer JF; Dept. of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA; Dept. of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.
  • Wenzel JM; Dept. of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA. Electronic address: jenwenzel@sandiego.edu.
  • Zlebnik NE; Dept. of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA. Electronic address: nzlebnik@som.umaryland.edu.
Neuropharmacology ; 193: 108625, 2021 08 01.
Article in En | MEDLINE | ID: mdl-34058192
ABSTRACT
A wide body of evidence supports an integral role for mesolimbic dopamine (DA) in motivated behavior. In brief, drugs that increase DA in mesolimbic terminal regions, like cocaine, enhance motivation, while drugs that decrease DA concentration reduce motivation. Data from our laboratory and others shows that phasic activation of mesolimbic DA requires signaling at cannabinoid type-1 (CB1) receptors in the ventral tegmental area (VTA), and systemic delivery of CB1 receptor antagonists reduces DA cell activity and attenuates motivated behaviors. Recent findings demonstrate that cocaine mobilizes the endocannabinoid 2-arachidonoylglycerol (2-AG) in the VTA to cause phasic activation of DA neurons and terminal DA release. It remains unclear, however, if cocaine-induced midbrain 2-AG signaling contributes to the motivation-enhancing effects of cocaine. To examine this, we trained male and female rats on a progressive ratio (PR) task for a food reinforcer. Each rat underwent a series of tests in which they were pretreated with cocaine alone or in combination with systemic or intra-VTA administration of the CB1 receptor antagonist rimonabant or the 2-AG synthesis inhibitor tetrahydrolipstatin (THL). Cocaine increased motivation, measured by augmented PR breakpoints, while rimonabant dose-dependently decreased motivation. Importantly, intra-VTA administration of rimonabant or THL, at doses that did not decrease breakpoints on their own, blocked systemic cocaine administration from increasing breakpoints in male and female rats. These data suggest that cocaine-induced increases in motivation require 2-AG signaling at CB1 receptors in the VTA and may provide critical insight into cannabinoid-based pharmacotherapeutic targets for the successful treatment of substance abuse.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Arachidonic Acids / Cocaine / Ventral Tegmental Area / Receptor, Cannabinoid, CB1 / Endocannabinoids / Glycerides / Motivation Limits: Animals Language: En Journal: Neuropharmacology Year: 2021 Document type: Article

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Arachidonic Acids / Cocaine / Ventral Tegmental Area / Receptor, Cannabinoid, CB1 / Endocannabinoids / Glycerides / Motivation Limits: Animals Language: En Journal: Neuropharmacology Year: 2021 Document type: Article