Richard W Foltin1, Suzette M Evans2. 1. Division on Substance Abuse, New York State Psychiatric Institute and Department of Psychiatry, Columbia University Medical Center, 1051 Riverside Drive, Unit 120, New York, NY, 10032, USA. Electronic address: rwf2@cumc.columbia.edu. 2. Division on Substance Abuse, New York State Psychiatric Institute and Department of Psychiatry, Columbia University Medical Center, 1051 Riverside Drive, Unit 120, New York, NY, 10032, USA. Electronic address: se18@cumc.columbia.edu.
Abstract
BACKGROUND: The hypocretin/orexin system is involved in regulating arousal, and much recent work demonstrates that decreasing hypocretin receptor-1 (HCRTr1) activity using antagonists decreases appetitive behavior, including stimulant drug self-administration and reinstatement. METHODS: The present study determined the effects of hypocretin-1 and HCRTr1 antagonists on responding reinforced by intravenous (i.v.) cocaine self-administration (0.0125 - 0.05 mg/kg/infusion) in 5 female rhesus monkeys. Responding was examined using 3 schedules of reinforcement: 1) a Fixed interval 1 min, Fixed ratio 10 Chain schedule [FI 1-min (FR10:S)], 2) a Progressive Ratio (PR) schedule, and 3) a cocaine vs. candy. RESULTS: Choice schedule: the HCRTr1 antagonist SB-334867 (8-24 mg/kg, i.m.) decreased cocaine taking under the Chain schedule and PR schedule in all 5 monkeys and in 4 of the 5 monkeys under the Choice schedule. d- Amphetamine (0.06 - 0.25 mg/kg, i.m.), tested as a control manipulation, decreased cocaine taking in all 5 monkeys under the Chain schedule. The peptide hypocretin-1 (0.072 mg/kg, i.v.) increased cocaine taking in the monkeys with low rates of cocaine taking under the Chain (3/4) and Choice (4/5) schedules. Reinstatement of extinguished cocaine responding following response-independent delivery of a large dose of cocaine (0.3 mg/kg) was attenuated in 3 of the 5 monkeys by the HCRTr1 antagonist SB-334867. CONCLUSIONS: These data expand upon work accomplished in predominantly male rodents suggesting that the hypocretin system modulates the response to appetitive stimuli. A better understanding of this system offers promise as a novel approach in medication development for appetitive disorders.
BACKGROUND: The hypocretin/orexin system is involved in regulating arousal, and much recent work demonstrates that decreasing hypocretin receptor-1 (HCRTr1) activity using antagonists decreases appetitive behavior, including stimulant drug self-administration and reinstatement. METHODS: The present study determined the effects of hypocretin-1 and HCRTr1 antagonists on responding reinforced by intravenous (i.v.) cocaine self-administration (0.0125 - 0.05 mg/kg/infusion) in 5 female rhesus monkeys. Responding was examined using 3 schedules of reinforcement: 1) a Fixed interval 1 min, Fixed ratio 10 Chain schedule [FI 1-min (FR10:S)], 2) a Progressive Ratio (PR) schedule, and 3) a cocaine vs. candy. RESULTS: Choice schedule: the HCRTr1 antagonist SB-334867 (8-24 mg/kg, i.m.) decreased cocaine taking under the Chain schedule and PR schedule in all 5 monkeys and in 4 of the 5 monkeys under the Choice schedule. d- Amphetamine (0.06 - 0.25 mg/kg, i.m.), tested as a control manipulation, decreased cocaine taking in all 5 monkeys under the Chain schedule. The peptide hypocretin-1 (0.072 mg/kg, i.v.) increased cocaine taking in the monkeys with low rates of cocaine taking under the Chain (3/4) and Choice (4/5) schedules. Reinstatement of extinguished cocaine responding following response-independent delivery of a large dose of cocaine (0.3 mg/kg) was attenuated in 3 of the 5 monkeys by the HCRTr1 antagonist SB-334867. CONCLUSIONS: These data expand upon work accomplished in predominantly male rodents suggesting that the hypocretin system modulates the response to appetitive stimuli. A better understanding of this system offers promise as a novel approach in medication development for appetitive disorders.
Authors: Taylor A Gentile; Steven J Simmons; David J Barker; Jessica K Shaw; Rodrigo A España; John W Muschamp Journal: Addict Biol Date: 2017-04-17 Impact factor: 4.280
Authors: Hans G Cruz; Justin L Hay; Petra Hoever; Federica Alessi; Erik T te Beek; Joop M A van Gerven; Jasper Dingemanse Journal: Eur Neuropsychopharmacol Date: 2014-05-13 Impact factor: 4.600