PG01037, a novel dopamine D3 receptor antagonist, inhibits the effects of methamphetamine in rats.
Our previous studies have shown that the selective dopamine D(3) receptor antagonists SB-277011A or NGB 2904 significantly attenuate cocaine self-administration under a progressive-ratio reinforcement schedule and cocaine-, methamphetamine- or nicotine-enhanced brain stimulation reward. However, the poor bioavailability of SB-277011A has limited its potential use in humans. In the present study, we investigated the effects of the novel D(3) receptor antagonist PG01037 on methamphetamine self-administration, methamphetamine-associated cue-induced reinstatement of drug seeking and methamphetamine-enhanced brain stimulation reward. Rats were allowed to intravenously self-administer methamphetamine under fixed-ratio 2 and progressive-ratio reinforcement conditions, and then the effects of PG01037 on methamphetamine self-administration and cue-induced reinstatement were assessed. Additional groups of rats were trained for intracranial electrical brain stimulation reward and the effects of PG01037 and methamphetamine on brain stimulation reward were assessed. Acute intraperitoneal administration of PG01037 (3, 10, 30 mg/kg) failed to alter methamphetamine or sucrose self-administration under fixed-ratio 2 reinforcement, but significantly lowered the break-point levels for methamphetamine or sucrose self-administration under progressive-ratio reinforcement. In addition, PG01037 significantly inhibited methamphetamine-associated cue-triggered reinstatement of drug-seeking behavior and methamphetamine-enhanced brain stimulation reward. These data suggest that the novel D(3) antagonist PG01037 significantly attenuates the rewarding effects as assessed by progressive-ratio self-administration and brain stimulation reward, and inhibits methamphetamine-associated cue-induced reinstatement of drug-seeking behavior These findings support the potential use of PG01037 or other selective D(3) antagonists in the treatment of methamphetamine addiction.
Neuropsychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institute of Health, Biomedical Research Center, 251 Bayview Boulevard, Baltimore, MD 21224 USA. ahigley@scripps.edu
Amanda E
AE
Higley
Krista
K
Spiller
Peter
P
Grundt
Amy Hauck
AH
Newman
Stephen W
SW
Kiefer
Zheng-Xiong
ZX
Xi
Eliot L
EL
Gardner
D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects*; D003463:Cues; D018492:Dopamine Antagonists / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D058999:Drug-Seeking Behavior / Q000187:drug effects; D004558:Electric Stimulation / Q000379:methods; D005108:Extinction, Psychological / Q000187:drug effects; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors*; D012055:Reinforcement Schedule; D012201:Reward; D012646:Self Administration; D013395:Sucrose / Q000008:administration & dosage / Q000494:pharmacology
D001549:Benzamides; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; C497150:N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)but-2-enyl)-4-pyridine-2-ylbenzamide; D011725:Pyridines; D050637:Receptors, Dopamine D3; D008694:Methamphetamine; D013395:Sucrose