Imidazenil, a positive allosteric GABAA receptor modulator, inhibits the effects of cocaine on locomotor activity and extracellular dopamine in the nucleus accumbens shell without tolerance liability.
Imidazenil, a benzodiazepine recognition site ligand that acts as partial positive allosteric modulator of gamma-aminobutyric acid (GABA) action at GABAA receptors, inhibits in a dose-dependent manner (0.56-2.5 micromol/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 micromol/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 micromol/kg i.p.) fails to reduce spontaneous locomotor activity, whereas diazepam (4.4 micromol/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.
Giorgetti
M
M
The Psychiatric Institute, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.
Javaid
J I
JI
Davis
J M
JM
Costa
E
E
Guidotti
A
A
Appel
S B
SB
Brodie
M S
MS
D000494:Allosteric Regulation; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D003042:Cocaine / Q000037:antagonists & inhibitors*; D003342:Corpus Striatum / Q000737:chemistry / Q000187:drug effects; D003975:Diazepam / Q000494:pharmacology; D004298:Dopamine / Q000032:analysis*; D004361:Drug Tolerance; D018757:GABA Modulators / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D009714:Nucleus Accumbens / Q000737:chemistry / Q000187:drug effects*; D051381:Rats; D011916:Rats, Inbred F344; D011963:Receptors, GABA-A / Q000187:drug effects*; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D018757:GABA Modulators; D007093:Imidazoles; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005680:gamma-Aminobutyric Acid; C082661:imidazenil; D003042:Cocaine; D003975:Diazepam; D004298:Dopamine