title: Discriminative stimulus properties of GABAA receptor positive allosteric modulators TPA023, ocinaplon and NG2-73 in rats trained to discriminate chlordiazepoxide or zolpidem.
abstract: There is increased understanding that distinct GABA(A) receptor subtypes mediate different effects of classical benzodiazepines. Here, we aimed to define the contributions of α(1)-containing subtypes of the subtype-selective GABA(A) receptor positive allosteric modulators TPA023, ocinaplon, and NG2-73 using drug discrimination. We characterized these compounds with defined subunit preferences in rats that were trained to discriminate either the non-selective benzodiazepine chlordiazepoxide (CDP, 5.0 mg/kg) or the α(1)-selective drug zolpidem (1.5 mg/kg). In short, CDP but not zolpidem generalized to the CDP cue. In contrast, zolpidem-trained rats showed opposite effects and generalized to zolpidem but not to CDP, while the response rate reducing effects of both ligands were comparable. Moreover, TPA023, lacking efficacy at the GABA(A) receptor α(1) subunit, occasioned dose-dependent CDP-appropriate responding but generalized only to around 10% to zolpidem. Both ocinaplon and NG2-73 completely generalized to both the CDP and zolpidem cue. Overall, our data confirm and extend the previous findings in rats that compounds that lack efficacy at α(1)-containing GABA(A) receptors generalize to CDP, whereas the opposite holds true for α(1)-preferential compounds, which generalize to the α(1)-selective positive allosteric modulator zolpidem. Also, our data support the hypothesis that subtle in vitro differences in α subunit efficacy and/or affinity may eventually have large consequences in vivo. Together, our data demonstrate a reliable in vivo method to determine the contribution of the subtype-selective mechanism(s) of action for novel and subtype-selective GABA(A) receptor positive allosteric modulators, suggesting that a complex activation of multiple α subunits accounts for drug discrimination between non-selective and selective GABA(A) receptor ligands.
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences and Rudolf Magnus Institute of Neuroscience, Utrecht University, Utrecht, The Netherlands. c.h.vinkers@uu.nl
authors.forename: Christiaan H
authors.initials: CH
authors.lastname: Vinkers
authors.forename: Berend
authors.initials: B
authors.lastname: Olivier
authors.forename: Taleen
authors.initials: T
authors.lastname: Hanania
authors.forename: Wenzhong
authors.initials: W
authors.lastname: Min
authors.forename: Rudy
authors.initials: R
authors.lastname: Schreiber
authors.forename: Seth C
authors.initials: SC
authors.lastname: Hopkins
authors.forename: Una
authors.initials: U
authors.lastname: Campbell
authors.forename: Neil
authors.initials: N
authors.lastname: Paterson
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D002707:Chlordiazepoxide / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects*; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D008024:Ligands; D008297:Male; D011724:Pyridazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D013379:Substrate Specificity; D014230:Triazoles / Q000494:pharmacology*; D000077334:Zolpidem
chemical_list: C507018:7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo(4,3-b)pyridazine; D014151:Anti-Anxiety Agents; D006993:Hypnotics and Sedatives; D008024:Ligands; D011724:Pyridazines; D011725:Pyridines; D011743:Pyrimidines; D011963:Receptors, GABA-A; D014230:Triazoles; C501948:ocinaplon; D002707:Chlordiazepoxide; D000077334:Zolpidem; C568848:adipiplon