Matthew J Horchar1, Joy L Kappesser2, Maria R Broderick2, Makayla R Wright2, Justin R Yates3. 1. Department of Psychological Science, Northern Kentucky University, 1 Nunn Drive, Highland Heights, KY 41099, USA. 2. Department of Biological Sciences, Northern Kentucky University, 1 Nunn Drive, Highland Heights, KY 41099, USA. 3. Department of Psychological Science, Northern Kentucky University, 1 Nunn Drive, Highland Heights, KY 41099, USA. Electronic address: yatesj1@nku.edu.
Abstract
BACKGROUND: Currently, there are no FDA-approved medications for the treatment of psychostimulant (e.g., cocaine) use disorders. Because the GluN2B subunit of the glutamate N-methyl-D-aspartate (NMDA) receptor is an important mediator of addiction-like behaviors, the goal of the current study was to determine if the GluN2B-selective antagonist Ro 63-1908 is efficacious in attenuating cocaine self-administration. METHODS: Adult Sprague Dawley rats (24 males and 11 females) were implanted with indwelling catheters and were trained to self-administer cocaine (0.75 mg/kg/inf). Rats were then trained in a threshold procedure, in which the dose of cocaine decreased across six 6-min blocks (0.75, 0.27, 0.08, 0.03, 0.01, 0.003 mg/kg/inf). This procedure allowed for the quantification of behavioral economic indices of drug self-administration. Following training in the threshold procedure, rats were treated with the GluN2B-selective antagonist Ro 63-1908 (0, 0.1, 0.3, 1.0 mg/kg; s.c.). Rats also received treatments of the NMDA receptor channel blocker MK-801 (0, 0.01, 0.03, 0.06 mg/kg; s.c.). RESULTS: Blocking NMDA receptors decreased initial intake (i.e., consumption during the first block), although Ro 63-1908 and MK-801 increased area under the curve (global measure of demand) and decreased demand elasticity, an effect observed primarily in males. Neither drug affected demand intensity (i.e., consumption of cocaine at a minimally constrained price). CONCLUSIONS: While blocking the NMDA receptor decreases initial intake of cocaine, NMDA receptor antagonists make cocaine more inelastic with increasing price. These results suggest that NMDA receptor antagonists can exacerbate addiction-like behaviors during self-administration during extinction-like conditions that are observed in later blocks of the threshold procedure.
BACKGROUND: Currently, there are no FDA-approved medications for the treatment of psychostimulant (e.g., cocaine) use disorders. Because the GluN2B subunit of the glutamate N-methyl-D-aspartate (NMDA) receptor is an important mediator of addiction-like behaviors, the goal of the current study was to determine if the GluN2B-selective antagonist Ro 63-1908 is efficacious in attenuating cocaine self-administration. METHODS: Adult Sprague Dawley rats (24 males and 11 females) were implanted with indwelling catheters and were trained to self-administer cocaine (0.75 mg/kg/inf). Rats were then trained in a threshold procedure, in which the dose of cocaine decreased across six 6-min blocks (0.75, 0.27, 0.08, 0.03, 0.01, 0.003 mg/kg/inf). This procedure allowed for the quantification of behavioral economic indices of drug self-administration. Following training in the threshold procedure, rats were treated with the GluN2B-selective antagonist Ro 63-1908 (0, 0.1, 0.3, 1.0 mg/kg; s.c.). Rats also received treatments of the NMDA receptor channel blocker MK-801 (0, 0.01, 0.03, 0.06 mg/kg; s.c.). RESULTS: Blocking NMDA receptors decreased initial intake (i.e., consumption during the first block), although Ro 63-1908 and MK-801 increased area under the curve (global measure of demand) and decreased demand elasticity, an effect observed primarily in males. Neither drug affected demand intensity (i.e., consumption of cocaine at a minimally constrained price). CONCLUSIONS: While blocking the NMDA receptor decreases initial intake of cocaine, NMDA receptor antagonists make cocaine more inelastic with increasing price. These results suggest that NMDA receptor antagonists can exacerbate addiction-like behaviors during self-administration during extinction-like conditions that are observed in later blocks of the threshold procedure.
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Authors: Justin R Yates; Nicholas A Prior; Marissa R Chitwood; Haley A Day; Jonah R Heidel; Sarah E Hopkins; Brittany T Muncie; Tatiana A Paradella-Bradley; Alexandra P Sestito; Ashley N Vecchiola; Emily E Wells Journal: Exp Clin Psychopharmacol Date: 2018-07-23 Impact factor: 3.157
Authors: Justin R Yates; Matthew J Horchar; Alexis L Ellis; Joy L Kappesser; Prodiges Mbambu; Tanner G Sutphin; Destiny S Dehner; Hephzibah O Igwe; Makayla R Wright Journal: Psychopharmacology (Berl) Date: 2020-09-16 Impact factor: 4.530