Muscimol-Like Discriminative Stimulus Effects of GABA Agonists in Rats

doi:10.1016/S0091-3057(97)00413-9

Pharmacology Biochemistry and Behavior

Volume 59, Issue 2, February 1998, Pages 319-326

https://doi.org/10.1016/S0091-3057(97)00413-9 Get rights and content

Abstract

The discriminative stimulus effects of GABAergic drugs were evaluated in rats trained to discriminate the direct GABA_A agonist, muscimol (1.0 mg/kg IP), from saline under a two-lever fixed ratio (FR) 32 schedule of food reinforcement. Another direct GABA_A agonist, THIP, produced full substitution for muscimol, however, at doses producing response rate decreasing effects. Diazepam, an allosteric modulator of GABA-mediated postsynaptic inhibition, yielded a maximum of 50% muscimol-lever responding at a dose that also decreased rates of responding. Partial substitution for muscimol (maximal levels of 71% muscimol-lever responding) was also produced by the GABA agonist progabide. Propofol, an anesthetic that potentiates GABA_A receptor function, and the GABA uptake inhibitor, tiagabine, produced no greater than 53 and 48% muscimol-lever responding, respectively. Valproic acid, a reversible GABA transaminase inhibitor, failed to substitute for muscimol, and vigabatrin, an irreversible GABA transaminase inhibitor, yielded a maximal 46% muscimol-lever responding. These results demonstrate the pharmacological specificity of muscimol discrimination by showing that only direct agonists for the GABA site on the GABA_A receptor complex produce full substitution. GABA agonists acting by other mechanisms can be distinguished from muscimol and THIP in this procedure.

Section snippets

Subjects

Twelve male Sprague–Dawley rats (COBS CD) were obtained from Charles River Farms (Wilmington, MA). The animals weighed between 250 and 300 g upon arrival and were housed individually in wire mesh cages with water available ad lib. The vivarium was maintained at an ambient temperature of 22°C and a 12 L:12 D cycle. All training and testing sessions were conducted during the light phase (between 0800 and 1000 h). After completion of the training and testing sessions, rats were returned to their

Acquisition and Control Test Results

Acquisition of the muscimol/saline discrimination required an average of 117 training sessions (range 78–196). The stability of stimulus control by muscimol and saline injections during drug testing was examined via repeated control tests with 1 mg/kg muscimol and saline (Fig. 1–Fig. 2, Fig. 3, Fig. 4, Fig. 5, Fig. 6, Fig. 7, upper panels). Saline control tests always resulted in averages of less than 10% muscimol-lever responding and muscimol control tests nearly always resulted in greater

Discussion

The principal finding of this study is that complete substitution for muscimol in a drug discrimination study was produced only by THIP, another direct GABA_A agonist. Other types of GABA agonists that were studied produced, at best, partial substitution, and their profile of discriminative stimulus and response rate effects could be easily distinguished from those of muscimol and THIP. Drugs that failed to produce full substitution for muscimol in this study were valproic acid, vigabatrin,

Acknowledgements

This research was supported by NIDA Grant DA-01442. Hendrée E. Jones is supported by a NIDA predoctoral Fellowship DA-05665. The technical assistance of Hua Li and invaluable advise of Dr. Doreen Grech is greatly appreciated in completing these studies.

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The GABA-A agonists act at extrasynaptic receptors to inactivate neurons locally (i.e., at the soma and the dendrite) and do not affect fibers of passage, unlike other drugs such as TTX and lidocaine (Waszczak et al., 1980). THIP has substantially lower affinity and binding rate to GABA-A receptors compared to muscimol (Jones and Balster, 1998; Waszczak et al., 1980), and is therefore particularly useful when larger areas need to be inactivated and when only modest behavioral deficits are desired (Wilke et al., 2010a,b). Two fMRI studies inactivated the lateral intraparietal region (area LIP) with muscimol to study the neural basis of spatial decision, attention and neglect-like symptoms, and their compensation (Balan et al., 2019; Wilke et al., 2012).
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ArticlesMuscimol-Like Discriminative Stimulus Effects of GABA Agonists in Rats

Abstract

Section snippets

Subjects

Acquisition and Control Test Results

Discussion

Acknowledgements

Prog. Neurobiol.

Eur. J. Pharmacol.

Pharmacol. Biochem. Behav.

Gen. Pharmacol.

Neurosci. Lett.

Pharmacol. Biochem. Behav.

Neuropharmacology

Biochem. Pharmacol.

Eur. J. Pharmacol.

Biochem. Pharmacol.

Biochem. Pharmacol.

Discriminative-stimulus effects of the GABAA agonist THIP and GABAB agonist baclofen

Soc. Neurosci. Abstr.

Lorazepam and pentobarbital drug discrimination in baboonsCross drug generalization tests and interaction with Ro-15-1788

J. Pharmacol. Exp. Ther.

Discriminative stimulus effects of atypical anxiolytics in baboons and rats

J. Pharmacol. Exp. Ther.

Differential generalization to pentobarbital in rats trained to discriminate lorazepam, chlordiazepoxide, diazepam or triazolam

Psychopharmacology (Berlin)

Classification of drugs according to their discriminable effects in rats

Fed. Proc.

ProgabideA new GABA-mimetic agent in clinical use

Clin. Neuropharmacol.

R)-N-[4,4-Bis(3-methyl-2-thienyl)but-3-en-l-yl] nipecotic acid binds with high affinity to the brain gamma-aminobutyric acid uptake carrier

J. Neurochem.

Effects of propofol, pentobarbital and alphaxalone on t-[35S]butylbicyclophosphorothionate binding to rat cerebral cortex

Eur. J. Pharmacol.

Tolerance to the discriminative stimulus effects of ethanol

Behav. Pharmacol.

TiagabineA novel drug with a GABAergic mechanism of action

Epilepsia

Articles
Muscimol-Like Discriminative Stimulus Effects of GABA Agonists in Rats

Discriminative-stimulus effects of the GABA_A agonist THIP and GABA_B agonist baclofen

Effects of propofol, pentobarbital and alphaxalone on t-[³5S]butylbicyclophosphorothionate binding to rat cerebral cortex