M Manuszak1, W Harding2, S Gadhiya3, R Ranaldi4. 1. Department of Psychology, Queens College, City University of New York, 65-30 Kissena Blvd, Flushing NY, 11367, USA. 2. Department of Chemistry, Hunter College, City University of New York, 695 Park Avenue, NY, 10065, USA; Ph.D. Program in Chemistry, The Graduate Center of the City University of New York, New York, NY, 10016, USA; Ph.D. Program in Biochemistry, The Graduate Center of the City University of New York, New York, NY, 10016, USA. 3. Angion Biomedica Corp., 51 Charles Linndbergh Blvd, Uniondale, NY 11553, USA. 4. Department of Psychology, Queens College, City University of New York, 65-30 Kissena Blvd, Flushing NY, 11367, USA; The Graduate Center of the City University of New York, New York, NY 10016, USA. Electronic address: Robert.Ranaldi@qc.cuny.edu.
Abstract
BACKGROUND: Dopamine receptors are implicated in cocaine reward and seeking. We hypothesize that (-)-stepholidine, a dopamine D1/D2/D3 multi-receptor agent, would be effective in reducing cocaine reward and seeking in an animal model. We investigated the effects of (-)-stepholidine in cue-induced reinstatement of cocaine seeking and cocaine self-administration (reward). METHODS: Cue-induced reinstatement experiment: Rats were trained to press a lever reinforced by cocaine (1 mg/kg/injection) for 15 consecutive daily sessions, after which the response was extinguished by withholding cocaine and cocaine-paired cues (light and pump activation). This was followed by a cue-induced reinstatement test where subjects were exposed to two cocaine cue presentations and presses on the active lever produced cues. Subjects were treated with one of four (-)-stepholidine doses prior to the reinstatement test. Cocaine self-administration (reward) experiment: Rats were trained to self-administer cocaine under a progressive ratio schedule of reinforcement. After stable breakpoints were established, rats were injected with four doses of (-)-stepholidine prior to testing; each dose was injected prior to a separate test session with no-treatment sessions intervening to re-establish break points. RESULTS: (-)-Stepholidine significantly reduced cue-induced reinstatement of cocaine seeking in a dose-related manner. Additionally, (-)-stepholidine significantly reduced break points for cocaine reward. (-)-Stepholidine did not significantly affect locomotor activity. CONCLUSIONS: (-)-Stepholidine reduces cue-induced reinstatement of cocaine seeking and cocaine reward, suggesting that it may be useful in treating relapse in cocaine addiction.
BACKGROUND:Dopamine receptors are implicated in cocaine reward and seeking. We hypothesize that (-)-stepholidine, a dopamine D1/D2/D3 multi-receptor agent, would be effective in reducing cocaine reward and seeking in an animal model. We investigated the effects of (-)-stepholidine in cue-induced reinstatement of cocaine seeking and cocaine self-administration (reward). METHODS: Cue-induced reinstatement experiment: Rats were trained to press a lever reinforced by cocaine (1 mg/kg/injection) for 15 consecutive daily sessions, after which the response was extinguished by withholding cocaine and cocaine-paired cues (light and pump activation). This was followed by a cue-induced reinstatement test where subjects were exposed to two cocaine cue presentations and presses on the active lever produced cues. Subjects were treated with one of four (-)-stepholidine doses prior to the reinstatement test. Cocaine self-administration (reward) experiment: Rats were trained to self-administer cocaine under a progressive ratio schedule of reinforcement. After stable breakpoints were established, rats were injected with four doses of (-)-stepholidine prior to testing; each dose was injected prior to a separate test session with no-treatment sessions intervening to re-establish break points. RESULTS:(-)-Stepholidine significantly reduced cue-induced reinstatement of cocaine seeking in a dose-related manner. Additionally, (-)-stepholidine significantly reduced break points for cocaine reward. (-)-Stepholidine did not significantly affect locomotor activity. CONCLUSIONS:(-)-Stepholidine reduces cue-induced reinstatement of cocaine seeking and cocaine reward, suggesting that it may be useful in treating relapse in cocaine addiction.
Authors: Scott T Ewing; Chris Dorcely; Rivka Maidi; Gulsah Paker; Eva Schelbaum; Robert Ranaldi Journal: Addict Biol Date: 2021-01-25 Impact factor: 4.093
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