The anxiolytic-like effect of 5-HT1B receptor ligands in rats: a possible mechanism of action.
We have examined the effect of lesions of 5-hydroxytryptamine (5-HT) neurons, produced by p-chloroamphetamine (p-CA; 2 x 10 mg kg(-1)), and the influence of flumazenil (Ro 15-1788, 10 mg kg(-1)), a benzodiazepine receptor antagonist, on the anxiolytic-like activity of CP 94253 (5-propoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-pyrrolo[3,2-b]pyridine), a 5-HT1B receptor agonist, SB 216641 (N-[3-[3-(dimethylamino)ethoxy]-4-methoxyphenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide), a 5-HT1B receptor antagonist, and GR 127935 (N-[4-methoxy-3-(4-methyl-l-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-l, l'-biphenyl-4-carboxamide), a 5-HT1B/1D receptor antagonist, in the Vogel conflict drinking test in rats. Diazepam was used as a reference compound. CP 94253 (2.5 mg kg(-1)), SB 216641 (2.5 mg kg(-1)), GR 127935 (10 mg kg(-1)) and diazepam (5 mg kg(-1)) significantly increased the number of shocks accepted during experimental sessions in the conflict drinking test in vehicle- and p-CA-pretreated rats. Flumazenil did not change the anxiolytic-like effect of CP 94253 (2.5 mg kg(-1)), but wholly blocked the anxiolytic-like effects of SB 216641 (2.5 mg kg(-1)), GR 127935 (10 mg kg(-1)) and diazepam (5 mg kg(-1)). p-CA and flumazenil alone were inactive in the conflict drinking test. The results suggested that the anxiolytic-like effect of the 5-HT1B receptor ligands CP 94253, SB 216641 and GR 127935 was possibly linked to the postsynaptic 5-HT1B receptors or/and 5-HT1B heteroreceptors. The results suggested also that benzodiazepine receptors were indirectly involved in the effects of SB 216641 and GR 127935 (but not of CP 94253), which might have been due to a possible interaction between the 5-HT and the GABA/benzodiazepine systems.
Chojnacka-Wójcik
Ewa
E
Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland. wojcik@if-pan.krakow.pl
Kłodzińska
Aleksandra
A
Tatarczyńska
Ewa
E
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D001549:Benzamides / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D003220:Conflict, Psychological; D003975:Diazepam / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D004327:Drinking Behavior / Q000187:drug effects; D004334:Drug Administration Schedule; D004597:Electroshock / Q000009:adverse effects / Q000379:methods; D005442:Flumazenil / Q000494:pharmacology; D008571:Men; D009474:Neurons / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D010069:Oxadiazoles / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D010879:Piperazines / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011044:Poland; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D044302:Receptor, Serotonin, 5-HT1B / Q000008:administration & dosage; D012701:Serotonin / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D014867:Water / Q000008:administration & dosage; D010133:p-Chloroamphetamine / Q000008:administration & dosage / Q000009:adverse effects
D014151:Anti-Anxiety Agents; D001549:Benzamides; C097067:CP 94253; C108531:N-(3-(2-dimethylamino)ethoxy-4-methoxyphenyl)-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1'-biphenyl)-4-carboxamide; D010069:Oxadiazoles; D010879:Piperazines; D011725:Pyridines; D044302:Receptor, Serotonin, 5-HT1B; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D014867:Water; C090701:GR 127935; D012701:Serotonin; D005442:Flumazenil; D010133:p-Chloroamphetamine; D003975:Diazepam