Abstract
Imidazenil, a benzodiazepine recognition site ligand that acts as partial positive allosteric modulator of γ-aminobutyric acid (GABA) action at GABAA receptors, inhibits in a dose-dependent manner (0.56–2.5 μmol/kg i.p. to rats) the cocaine-induced increase in dopamine (DA) content in the dialysates of the nucleus accumbens shell and striatum and also inhibits cocaine-induced locomotor activity. Diazepam, a full allosteric modulator of GABA action at GABAA receptors, in a dose of 4.4 μmol/kg i.p. also attenuates the cocaine-induced increase in DA content in the dialysates of nucleus accumbens shell, and striatum and the cocaine-induced locomotor activity. However, imidazenil (2.5 μmol/kg i.p.) fails to reduce spontaneous locomotor activity, whereas diazepam (4.4 μmol/kg i.p.) elicits sedation and ataxia and clearly impairs spontaneous locomotor activity. When added in vitro, both imidazenil and diazepam potentiate the GABA-mediated reduction of the ventral tegmental area DA neuron firing rate. After protracted treatment (14 days/three times a day with an increasing-dose schedule), the inhibitory actions of imidazenil fail to develop tolerance, whereas the actions of diazepam exhibit high tolerance liability. We conclude that imidazenil is devoid of tolerance liability and that, via a GABAA-mediated reduction in the extracellular DA in nucleus accumbens shell, it might reduce the psychomotor activity and reinforcing properties of cocaine.
Footnotes
-
Send reprint requests to: Erminio Costa, M.D., The Psychiatric Institute, 1601 W. Taylor St., Room 314 W, Chicago, IL 60612.
-
↵1 This study was supported in part by MH 56500, MH 52361 and AA 05846 grants.
-
↵2 Present address: The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612.
-
↵3 Present address: Department of Veteran Affairs, West Side Medical Division, Chicago, IL 60612.
-
↵4 Present address: Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612.
- Abbreviations:
- DA
- dopamine
- DAergic
- dopaminergic
- GABA
- γ-aminobutyric acid
- VTA
- ventral tegmental area
- NAS
- nucleus accumbens shell
- ANOVA
- analysis of variance
- AUC
- area under the curve
- FAM
- full allosteric modulator
- PAM
- partial positive allosteric modulator
- aCSF
- artificial cerebrospinal fluid
- SAM
- selective allosteric modulator
- SNc
- subtantia nigra pars compacta
- BZD
- benzodiazepine
- Received December 22, 1997.
- Accepted June 2, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|