The novel MAGL inhibitor MJN110 enhances responding to reward-predictive incentive cues by activation of CB1 receptors
| Autor: | Justin J. McGraw, Benjamin F. Cravatt, Martin P.K. Leigh, Ajay N. Baindur, Ken T. Wakabayashi, Malte Feja, Caroline E. Bass |
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| Rok vydání: | 2020 |
| Předmět: |
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0301 basic medicine Sucrose Cannabinoid receptor Succinimides Arachidonic Acids Article Glycerides 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Receptor Cannabinoid CB1 Reward Rimonabant medicine Animals Rats Long-Evans GABAergic Neurons Latency (engineering) Receptor Pharmacology Motivation Behavior Animal business.industry Dopaminergic Neurons Ventral Tegmental Area Antagonist Neural Inhibition Endocannabinoid system Monoacylglycerol Lipases Rats Monoacylglycerol lipase 030104 developmental biology Facilitation Conditioning Operant Carbamates Cues business Neuroscience psychological phenomena and processes 030217 neurology & neurosurgery Endocannabinoids medicine.drug |
| Zdroj: | Neuropharmacology |
| ISSN: | 0028-3908 |
| DOI: | 10.1016/j.neuropharm.2019.107814 |
| Popis: | CB1 receptor antagonists disrupt operant responding for food and drug reinforcers, and cue-induced reinstatement of cocaine and heroin seeking. Conversely, enhancing endocannabinoid signaling, particularly 2-arachidonyl glycerol (2-AG), by inhibition of monoacyl glycerol lipase (MAGL), may facilitate some aspects of reward seeking. To determine how endocannabinoid signaling affects responding to reward-predictive cues, we employed an operant task that allows us to parse the incentive motivational properties of cues. Rats were required to nosepoke during an intermittent audiovisual incentive cue (IC) to obtain a 10% sucrose reward. The CB1 receptor antagonist, rimonabant, dose-dependently decreased the response ratio (rewarded ICs/total presented) and active nosepokes per IC, while it increased the latency to respond to the cue and obtain the reward, indicating an overall decrease in both the choice and vigor of responding. Yet rats persisted in entering the reward cup. Using a modified version of the task, the novel MAGL inhibitor MJN110 increased the response ratio, decreased the latencies to respond to the IC and enhanced active nosepokes per IC, indicating a facilitation of cue-induced reward seeking. These effects were blocked by a subthreshold dose of rimonabant. Finally, MJN110 did not alter consumption of freely available sucrose within volumes obtained in the operant task. Together these data demonstrate blocking endocannabinoid tone at the CB1 receptor attenuates the ability of cues to induce reward seeking, while some aspects of motivation for the reward are retained. Conversely, enhancing 2-AG signaling at CB1 receptors facilitates IC responding and increases the motivational properties of the IC. |
| Databáze: | OpenAIRE |
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