Comparative effects of nonselective and subtype-selective gamma-aminobutyric acidA receptor positive modulators in the rat-conditioned emotional response test.
Benzodiazepine receptor anxiolytics show no selectivity between gamma-aminobutyric acid-A receptors containing alpha1, alpha2, alpha3 or alpha5 subunits. Pharmacological studies and data emerging from transgenic mouse models, however, predict that compounds with selective affinity and/or efficacy for gamma-aminobutyric acid-A receptor subtypes would have novel pharmacological profiles. Thus, the gamma-aminobutyric acid-A-alpha1 'affinity selective' drug zolpidem has a sedative-hypnotic profile, whereas L838,417, which has 'selective efficacy' for gamma-aminobutyric acid-A-alpha2, alpha3 and alpha5 receptors, has an anxiolytic-like profile. Here, we compare the nonselective benzodiazepine-site-positive modulators diazepam, lorazepam, midazolam, alprazolam and zopiclone with (i) gamma-aminobutyric acid-AA-alpha1 affinity selective compounds zolpidem and CL218,872 and (ii) L838,417, in the rat-conditioned emotional response test after systemic administration. Given the role of the basolateral amygdala in anxiety and the expression of alpha1, alpha2 and alpha3 subunits in this region, we also assessed the effects of bilateral infusion of L838,417 and midazolam directly into basolateral amygdala in the conditioned emotional response test. Nonselective modulators at low-moderate doses produced anxiolytic effects and sedation at higher doses. Zolpidem was inactive as an anxiolytic and engendered severe sedation, whereas CL218,872 produced an anxiolytic-like profile with minimal sedation. L838,417 produced an anxiolytic-like profile with no sedation, albeit producing behavioural disturbance at high doses. Infusion of midazolam and L838,417 into basolateral amygdala engendered anxiolytic-like effects, although both compounds were more effective after systemic injections, implicating additional brain sites in their anxiolytic-like actions after systemic administration. In conclusion, the diversity of effects of the compounds studied implicates both intrinsic efficacy and/or subtype selectivity as important determinants of anxiolytic-like effects in the rat-conditioned emotional response test.
Mathiasen
Linda S
LS
Division of In-vivo Pharmacology, NeuroSearch A/S, Ballerup, Denmark.
Rodgers
Robert John
RJ
Mirza
Naheed R
NR
D000679:Amygdala / Q000502:physiology; D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects*; D004644:Emotions / Q000187:drug effects*; D005464:Fluorobenzenes / Q000494:pharmacology; D007839:Functional Laterality / Q000502:physiology; D018682:GABA Agents / Q000008:administration & dosage / Q000494:pharmacology*; D018757:GABA Modulators / Q000494:pharmacology; D008024:Ligands; D008297:Male; D008845:Microinjections; D008874:Midazolam / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000494:pharmacology
D005464:Fluorobenzenes; D018682:GABA Agents; D018757:GABA Modulators; C546241:Gabra1 protein, mouse; C546242:Gabra1 protein, rat; D008024:Ligands; D011963:Receptors, GABA-A; D014230:Triazoles; C409903:L 838,417; D008874:Midazolam