title: Route of administration affects the ability of naltrexone to reduce amphetamine-potentiated brain stimulation reward in rats.
abstract: Opioid receptor antagonism has been shown to attenuate behavioral and neurochemical effects of amphetamine in humans and rodents. The effects of acute (oral or subcutaneous) or extended-release naltrexone (XR-NTX) were tested on the reward-enhancing effects of amphetamine using the intracranial self-stimulation (ICSS) paradigm. Acute exposure to drugs of abuse reduces the locus of rise (LOR) in the ICSS procedure, reflecting enhanced brain stimulation reward (BSR). Rats were treated once a day with naltrexone orally (PO; 5.0 mg/kg) or subcutaneously (SC; 0.5 mg/kg) for four consecutive days and tested with D-amphetamine (0.5 mg/kg, intraperitoneal) in the ICSS paradigm 30 minutes later on days 1 and 4. Separate groups of rats received XR-NTX (50 mg/kg, SC) or placebo microspheres (similar mass to XR-NTX, SC) on day 0 and tested with D-amphetamine in the ICSS paradigm on days 4, 14, 21, 28 and 41 after administration. Naltrexone plasma concentrations were determined for each amphetamine testing session using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). In rats pretreated with naltrexone acutely, amphetamine-potentiated BSR did not differ from vehicle-pretreated rats on either day 1 or day 4 (25-30% decrease in LOR). In XR-NTX-pretreated rats, amphetamine-potentiated BSR was reduced by 64 and 70% on days 4 and 14, respectively, compared to placebo microsphere-treated controls. This effect dissipated by day 21. Naltrexone plasma concentrations were comparable across all treatment groups (14-30 ng/ml) on days 1, 4 and 14. In summary, an extended-release formulation of naltrexone results in significant attenuation of psychostimulant-enhanced BSR that is not observed with acute naltrexone.
authors.affiliation: Department of Life Sciences and Toxicology, Alkermes, Inc., USA. mark.todtenkopf@alkermes.com
authors.forename: Mark S
authors.initials: MS
authors.lastname: Todtenkopf
authors.forename: Krystal S
authors.initials: KS
authors.lastname: O'Neill
authors.forename: Kristina
authors.initials: K
authors.lastname: Kriksciukaite
authors.forename: Ryan Z
authors.initials: RZ
authors.lastname: Turncliff
authors.forename: Reginald L
authors.initials: RL
authors.lastname: Dean
authors.forename: Irina
authors.initials: I
authors.lastname: Ostrovsky-Day
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Deaver
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001921:Brain / Q000187:drug effects*; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D003913:Dextroamphetamine / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D004333:Drug Administration Routes; D004334:Drug Administration Schedule; D008401:Gas Chromatography-Mass Spectrometry; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D008297:Male; D009271:Naltrexone / Q000008:administration & dosage / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012201:Reward
chemical_list: D000697:Central Nervous System Stimulants; D009292:Narcotic Antagonists; D009271:Naltrexone; D003913:Dextroamphetamine