Sam Z Bacharach1,2, Helen M Nasser1, Natalie E Zlebnik1, Hannah M Dantrassy1, Daniel E Kochli1, Utsav Gyawali1,2, Joseph F Cheer1,2,3, Donna J Calu4,5. 1. Department of Anatomy and Neurobiology, University of Maryland School of Medicine, 20 Penn Street - HSFII Room S263, Baltimore, MD, 21201, USA. 2. Program in Neuroscience, University of Maryland School of Medicine, Baltimore, MD, USA. 3. Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA. 4. Department of Anatomy and Neurobiology, University of Maryland School of Medicine, 20 Penn Street - HSFII Room S263, Baltimore, MD, 21201, USA. dcalu@som.umaryland.edu. 5. Program in Neuroscience, University of Maryland School of Medicine, Baltimore, MD, USA. dcalu@som.umaryland.edu.
Abstract
RATIONALE: Endocannabinoids (eCBs) are critical gatekeepers of dopaminergic signaling, and disrupting cannabinoid receptor-1 (CB1) signaling alters DA dynamics to attenuate cue-motivated behaviors. Prior studies suggest that dopamine (DA) release plays a critical role in driving sign-tracking. OBJECTIVES: Here, we determine whether systemic injections of rimonabant, a CB1 receptor inverse agonist, during Pavlovian lever autoshaping impair the expression of sign-tracking. We next examine whether rimonabant blocks the reinforcing properties of the Pavlovian lever cue in a conditioned reinforcement test. METHODS: In Exp. 1, we trained rats in Pavlovian lever autoshaping prior to systemic rimonabant injections (0, 1, 3 mg/kg) during early and late Pavlovian lever autoshaping sessions. In Exp. 2, we trained rats in Pavlovian lever autoshaping prior to systemic rimonabant injections (0, 1 mg/kg) during a conditioned reinforcement test. RESULTS: Rimonabant dose-dependently decreased lever contact and probability, and increased sign-tracker's latency to approach the lever cue early in Pavlovian training. With extended training, many previously goal-tracking and intermediate rats shifted to lever approach, which remained dose-dependently sensitive to rimonabant. Rimonabant attenuated cue-evoked food cup approach early, but not late, in conditioning, and did not affect pellet retrieval or consumption. The inserted lever cue served as a robust conditioned reinforcer after Pavlovian lever autoshaping, and 1 mg/kg rimonabant blocked conditioned reinforcement. CONCLUSIONS: Together, our results suggest that CB1 signaling mediates two critical properties of incentive stimuli; their ability to attract (Exp. 1) and their ability to reinforce (Exp. 2) behavior.
RATIONALE: Endocannabinoids (eCBs) are critical gatekeepers of dopaminergic signaling, and disrupting cannabinoid receptor-1 (CB1) signaling alters DA dynamics to attenuate cue-motivated behaviors. Prior studies suggest that dopamine (DA) release plays a critical role in driving sign-tracking. OBJECTIVES: Here, we determine whether systemic injections of rimonabant, a CB1 receptor inverse agonist, during Pavlovian lever autoshaping impair the expression of sign-tracking. We next examine whether rimonabant blocks the reinforcing properties of the Pavlovian lever cue in a conditioned reinforcement test. METHODS: In Exp. 1, we trained rats in Pavlovian lever autoshaping prior to systemic rimonabant injections (0, 1, 3 mg/kg) during early and late Pavlovian lever autoshaping sessions. In Exp. 2, we trained rats in Pavlovian lever autoshaping prior to systemic rimonabant injections (0, 1 mg/kg) during a conditioned reinforcement test. RESULTS:Rimonabant dose-dependently decreased lever contact and probability, and increased sign-tracker's latency to approach the lever cue early in Pavlovian training. With extended training, many previously goal-tracking and intermediate rats shifted to lever approach, which remained dose-dependently sensitive to rimonabant. Rimonabant attenuated cue-evoked food cup approach early, but not late, in conditioning, and did not affect pellet retrieval or consumption. The inserted lever cue served as a robust conditioned reinforcer after Pavlovian lever autoshaping, and 1 mg/kg rimonabant blocked conditioned reinforcement. CONCLUSIONS: Together, our results suggest that CB1 signaling mediates two critical properties of incentive stimuli; their ability to attract (Exp. 1) and their ability to reinforce (Exp. 2) behavior.
Authors: Jennifer M Wenzel; Erik B Oleson; Willard N Gove; Anthony B Cole; Utsav Gyawali; Hannah M Dantrassy; Rebecca J Bluett; Dilyan I Dryanovski; Garret D Stuber; Karl Deisseroth; Brian N Mathur; Sachin Patel; Carl R Lupica; Joseph F Cheer Journal: Curr Biol Date: 2018-04-19 Impact factor: 10.834
Authors: Christina M Gremel; Jessica H Chancey; Brady K Atwood; Guoxiang Luo; Rachael Neve; Charu Ramakrishnan; Karl Deisseroth; David M Lovinger; Rui M Costa Journal: Neuron Date: 2016-05-26 Impact factor: 17.173
Authors: Yolanda Mateo; Kari A Johnson; Dan P Covey; Brady K Atwood; Hui-Ling Wang; Shiliang Zhang; Iness Gildish; Roger Cachope; Luigi Bellocchio; Manuel Guzmán; Marisela Morales; Joseph F Cheer; David M Lovinger Journal: Neuron Date: 2017-12-06 Impact factor: 17.173
Authors: Sara E Keefer; Sam Z Bacharach; Daniel E Kochli; Jules M Chabot; Donna J Calu Journal: Front Behav Neurosci Date: 2020-02-04 Impact factor: 3.558