Neuroscience Institute, Section of Cagliari, National Research Council of Italy, 09042, Monserrato (CA), Italy.
Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, 09042, Monserrato (CA), Italy.
Psychopharmacology (Berl). 2017 Sep;234(17):2525-2543. doi: 10.1007/s00213-017-4644-3. Epub 2017 May 24.
COR659 [methyl2-(4-chlorophenylcarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate] is a new, positive allosteric modulator (PAM) of the GABA receptor. This study evaluated whether COR659 shared with previously tested GABA PAMs the capacity to reduce alcohol self-administration in rats.
Treatment with non-sedative doses of COR659 (2.5, 5, and 10 mg/kg; i.p.) suppressed lever-responding for alcohol (15% v/v) in Sardinian alcohol-preferring (sP) rats under the fixed ratio (FR) 4 (FR4) and progressive ratio (PR) schedules of reinforcement; COR659 was more potent and effective than the reference GABA PAM, GS39783. Treatment with COR659, but not GS39783, suppressed (a) lever-responding for a sucrose solution (1-3% w/v) in sP rats under the FR4 and PR schedules, (b) lever-responding for a chocolate solution [5% (w/v) Nesquik®] in Wistar rats under the FR10 and PR schedules, and (c) cue-induced reinstatement of chocolate seeking in Wistar rats. Treatment with COR659 was completely ineffective on lever-responding (FR10) for regular food pellets in food-deprived Wistar rats. Pretreatment with the GABA receptor antagonist, SCH50911, partially blocked COR659-induced reduction of alcohol self-administration, being ineffective on reduction of chocolate self-administration. Pretreatment with the cannabinoid CB receptor antagonist, AM4113, fully blocked COR659-induced reduction of chocolate self-administration, being ineffective on reduction of alcohol self-administration.
COR659 might exert its behavioral effects via a composite mechanism: (i) positive allosteric modulation of the GABA receptor, responsible for a large proportion of reduction of alcohol self-administration; (ii) an action at other receptor system(s), including the cannabinoid CB receptor, through which COR659 affects seeking and consumption of highly palatable foods.
COR659[甲基 2-(4-氯苯甲酰胺基)-4-乙基-5-甲基噻吩-3-羧酸酯]是一种新的、GABA 受体的正变构调节剂（PAM）。本研究评估了 COR659 是否与之前测试的 GABA PAMs 具有相同的能力，以减少大鼠的酒精自我给药。
用非镇静剂量的 COR659（2.5、5 和 10mg/kg；ip）治疗，在 Sardinian 酒精偏好（sP）大鼠中，根据固定比率（FR）4（FR4）和递增比率（PR）强化程序，抑制酒精（15%v/v）的杆反应；COR659比参考 GABA PAM GS39783 更有效。COR659 治疗而非 GS39783 治疗，可抑制（a）sP 大鼠在 FR4 和 PR 程序下对 1-3%w/v 蔗糖溶液的杆反应，（b）Wistar 大鼠在 FR10 和 PR 程序下对 5%（w/v）Nesquik®巧克力溶液的杆反应，以及（c）Wistar 大鼠巧克力寻求线索诱导的复吸。COR659 对禁食 Wistar 大鼠的常规食物颗粒（FR10）的杆反应完全无效。GABA 受体拮抗剂 SCH50911 的预处理部分阻断了 COR659 引起的酒精自我给药减少，对巧克力自我给药减少无效。大麻素 CB 受体拮抗剂 AM4113 的预处理完全阻断了 COR659 引起的巧克力自我给药减少，对酒精自我给药减少无效。
COR659 可能通过一种复合机制发挥其行为作用：（i）GABA 受体的正变构调制，负责大部分酒精自我给药的减少；（ii）对其他受体系统（包括大麻素 CB 受体）的作用，COR659 通过该系统影响对高可口食物的寻求和消耗。
