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GABA receptor-linked chloride channels and the behavioral effects of naltrexone in rats
M V Gewiss1, R J Marley, E B Thorndike
1Behavioral Pharmacology and Genetics Section, NIDA Addiction Research Center, Baltimore, MD 21224.
Abstract:
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.
Insights
Naltrexone
Area of Science:
- Neuroscience
- Pharmacology
- Behavioral Science
Background:
- Naltrexone's effects on behavior are well-documented.
- The role of the GABAergic system in naltrexone's action requires further elucidation.
- Naltrexone treatment can induce hypersensitivity, potentially altering drug effects.
Purpose of the Study:
- To investigate if naltrexone's effects on schedule-controlled behavior in rats involve the GABAergic system.
- To examine how naltrexone-induced sensitization influences the interaction between naltrexone and GABAergic compounds.
Main Methods:
- Rats were administered naltrexone to induce sensitization.
- Various GABAergic system modulators (agonists, antagonists, chloride-channel agents) were tested in sensitized and non-sensitized rats.
- Naltrexone dose-effect functions were determined with and without GABAergic pretreatments in sensitized animals.
Main Results:
- Naltrexone-induced sensitization altered the effects of the GABA agonist muscimol.
- GABA agonists and antagonists did not consistently modify the naltrexone dose-effect function.
- The chloride-channel antagonist picrotoxin shifted the naltrexone dose-effect function leftward in sensitized rats.
- The chloride-channel facilitator pentobarbital shifted the naltrexone dose-effect function rightward in sensitized rats.
Conclusions:
- Naltrexone's behavioral effects are at least partially mediated by the GABA-linked chloride channel.
- The mechanism appears to involve the chloride channel rather than direct interaction with the GABA receptor itself.