GABA receptor-linked chloride channels and the behavioral effects of naltrexone in rats.
The present study was conducted to determine whether the effects of naltrexone on schedule-controlled behavior in rats were mediated, at least in part, by the GABAergic system. Because the enhanced sensitivity that has been shown to occur following naltrexone treatment might alter the effects of the treatment compounds, a variety of compounds interacting with the GABA system were tested in both sensitized and nonsensitized animals. Of all the compounds tested in this manner, only the dose-effect function for the GABA agonist muscimol was altered by the naltrexone treatment, with the higher doses of muscimol producing response-rate decreasing effects only in naltrexone-sensitized rats. In the naltrexone-treated animals, these same GABA agonists and antagonists were used as pretreatments prior to the determination of the naltrexone dose-effect function. Although shifts in the naltrexone dose-effect function were observed, the effects were not consistent either within or across receptor class. In contrast, the chloride-channel antagonist picrotoxin clearly shifted the naltrexone dose-effect function in sensitized animals to the left, while the chloride-channel facilitator pentobarbital shifted the function to the right. These results indicate that the effects of naltrexone are at least partially mediated by an action at the GABA-linked chloride channel, rather than directly at the GABA receptor.
Gewiss
M V
MV
Behavioral Pharmacology and Genetics Section, NIDA Addiction Research Center, Baltimore, MD 21224.
Marley
R J
RJ
Thorndike
E B
EB
Goldberg
S R
SR
Schindler
C W
CW
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D018118:Chloride Channels / Q000187:drug effects* / Q000378:metabolism; D003216:Conditioning, Operant / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D058786:GABA-B Receptor Agonists; D058788:GABA-B Receptor Antagonists; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D009271:Naltrexone / Q000494:pharmacology*; D010424:Pentobarbital / Q000494:pharmacology; D010852:Picrotoxin / Q000494:pharmacology; D051381:Rats; D018079:Receptors, GABA / Q000187:drug effects*; D012055:Reinforcement Schedule
D018118:Chloride Channels; D018755:GABA Agonists; D018756:GABA Antagonists; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D058786:GABA-B Receptor Agonists; D058788:GABA-B Receptor Antagonists; D009271:Naltrexone; D010424:Pentobarbital; D010852:Picrotoxin; D018079:Receptors, GABA