RATIONALE: It has been suggested that different BZ (omega) receptor subtypes may mediate distinct behavioural effects of BZ receptor ligands. OBJECTIVE: The present study examined this hypothesis further. METHODS: The antagonism exerted by the selective BZ(1) (omega(1)) receptor antagonist beta-CCT on the pharmacological effects of the selective BZ(1) (omega(1)) receptor agonist zolpidem and the non-selective BZ (omega) receptor agonist diazepam in behavioural, biochemical and electrophysiological experiments was assessed. RESULTS: beta-CCT which was devoid of activity per se, antagonized the effects of the non-selective BZ (omega) receptor full agonist diazepam and the selective BZ(1) (omega(1)) receptor full agonist zolpidem against seizures produced by isoniazid, but beta-CCT failed to affect their action on seizures produced by pentylenetetrazole (PTZ), suggesting that BZ(2) (omega(2)) receptors may be primarily involved in the convulsant action of PTZ. In the light/dark test, beta-CCT abolished the anxiolytic-like action of diazepam. In tests designed to investigate the central depressant activity of drugs, beta-CCT antagonized the sedative effects of diazepam and zolpidem, but failed to modify clearly the myorelaxant effects of diazepam. These differences may be related to the selectivity of beta-CCT for BZ(1) (omega(1)) sites as indicated by the preferential displacement of [(3)H]flumazenil in BZ(1) (omega(1))-enriched structures as compared to BZ(2) (omega(2))-enriched structures in the mouse. In in vitro experiments, beta-CCT antagonized the potentiation of the GABA-induced Cl(-) current produced by zolpidem in HEK cells expressing the alpha(1)beta(2)gamma(2) receptor or in cerebellar Purkinje neurones, while it failed to modify the diazepam potentiation at either alpha(3)beta(2)gamma(2) or alpha(5)beta(3)gamma(2) receptor subtypes. CONCLUSION: These results are consistent with the hypothesis that BZ(1) (omega(1)) receptors play an important role in the anxiolytic and sedative/hypnotic effects of BZ (omega) receptor ligands, whereas activity at BZ(2) (omega(2)) sites might be associated primarily with muscle relaxation.
RATIONALE: It has been suggested that different BZ (omega) receptor subtypes may mediate distinct behavioural effects of BZ receptor ligands. OBJECTIVE: The present study examined this hypothesis further. METHODS: The antagonism exerted by the selective BZ(1) (omega(1)) receptor antagonist beta-CCT on the pharmacological effects of the selective BZ(1) (omega(1)) receptor agonist zolpidem and the non-selective BZ (omega) receptor agonist diazepam in behavioural, biochemical and electrophysiological experiments was assessed. RESULTS:beta-CCT which was devoid of activity per se, antagonized the effects of the non-selective BZ (omega) receptor full agonist diazepam and the selective BZ(1) (omega(1)) receptor full agonist zolpidem against seizures produced by isoniazid, but beta-CCT failed to affect their action on seizures produced by pentylenetetrazole (PTZ), suggesting that BZ(2) (omega(2)) receptors may be primarily involved in the convulsant action of PTZ. In the light/dark test, beta-CCT abolished the anxiolytic-like action of diazepam. In tests designed to investigate the central depressant activity of drugs, beta-CCT antagonized the sedative effects of diazepam and zolpidem, but failed to modify clearly the myorelaxant effects of diazepam. These differences may be related to the selectivity of beta-CCT for BZ(1) (omega(1)) sites as indicated by the preferential displacement of [(3)H]flumazenil in BZ(1) (omega(1))-enriched structures as compared to BZ(2) (omega(2))-enriched structures in the mouse. In in vitro experiments, beta-CCT antagonized the potentiation of the GABA-induced Cl(-) current produced by zolpidem in HEK cells expressing the alpha(1)beta(2)gamma(2) receptor or in cerebellar Purkinje neurones, while it failed to modify the diazepam potentiation at either alpha(3)beta(2)gamma(2) or alpha(5)beta(3)gamma(2) receptor subtypes. CONCLUSION: These results are consistent with the hypothesis that BZ(1) (omega(1)) receptors play an important role in the anxiolytic and sedative/hypnotic effects of BZ (omega) receptor ligands, whereas activity at BZ(2) (omega(2)) sites might be associated primarily with muscle relaxation.
Authors: Miroslav M Savić; Dragan I Obradović; Nenad D Ugresić; James M Cook; P V V S Sarma; Dubravko R Bokonjić Journal: Psychopharmacology (Berl) Date: 2005-02-18 Impact factor: 4.530
Authors: Jovana Divljaković; Marija Milić; Ojas A Namjoshi; Veera V Tiruveedhula; Tamara Timić; James M Cook; Miroslav M Savić Journal: Brain Res Bull Date: 2012-11-10 Impact factor: 4.077
Authors: Shannon L Gourley; Joseph F Debold; Wenyuan Yin; James Cook; Klaus A Miczek Journal: Psychopharmacology (Berl) Date: 2004-08-17 Impact factor: 4.530
Authors: Ojas A Namjoshi; Zhi-jian Wang; Sundari K Rallapalli; Edward Merle Johnson; Yun-Teng Johnson; Hanna Ng; Joachim Ramerstorfer; Zdravko Varagic; Werner Sieghart; Samarpan Majumder; Bryan L Roth; James K Rowlett; James M Cook Journal: Bioorg Med Chem Date: 2012-11-15 Impact factor: 3.641
Authors: Srđan Joksimović; Zdravko Varagic; Jovana Kovačević; Michael Van Linn; Marija Milić; Sundari Rallapalli; Tamara Timić; Werner Sieghart; James M Cook; Miroslav M Savić Journal: Psychopharmacology (Berl) Date: 2013-05-18 Impact factor: 4.530