Combination of buspirone and other drugs with beta-CCE in monkeys: effects on respiration and behavior.
The respiratory and behavioral effects of the benzodiazepine receptor (BZR) inverse agonist ethyl-beta-carboline-3-carboxylate (beta-CCE) were determined alone and in combination with buspirone, lorazepam, flumazenil, and SR 95195 in rhesus monkeys. For the respiratory studies, one group of monkeys inhaled either air or 5% CO2 mixed in air according to a fixed alternating schedule; respiratory frequency and minute volume were monitored. For the behavioral studies, another group of monkeys responded under a fixed-ratio (FR 30) schedule of food presentation. The respiratory stimulant effects of beta-CCE in both air and 5% CO2 were enhanced by prior treatment with the 5-hydroxytryptamine1A (5-HT1A) partial agonist buspirone (0.03 and 0.3 mg/kg) and a weak BZR inverse agonist, SR 95195 (10.0 mg/kg). Coadministration of buspirone (0.1 and 0.3 mg/kg) also potentiated the rate-decreasing effects of beta-CCE under the FR schedule. The BZR agonist lorazepam (3.0 mg/kg) and BZR antagonist flumazenil (1.0 mg/kg) attenuated the effects of beta-CCE on respiratory frequency and minute volume particularly under the 5% CO2 condition, and lorazepam (0.1 and 0.3 mg/kg) and flumazenil (0.1 and 0.3 mg/kg) attenuated the effects of beta-CCE on FR responding. These latter results show that the respiratory and behavioral effects of beta-CCE in rhesus monkeys are at least in part due to effects at BZRs. Moreover, the findings suggest either that coactivation of benzodiazepine and 5-HT1A sites lead to a greater than additive effect or that beta-CCE and buspirone share a common mechanism of action that is unrelated to the receptor at which BZR inverse agonists act.
Wettstein
J G
JG
Harvard Medical School, Boston, MA 02115.
Teeple
E S
ES
Morse
W H
WH
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D002065:Buspirone / Q000494:pharmacology*; D002243:Carbolines / Q000494:pharmacology*; D002245:Carbon Dioxide / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D004347:Drug Interactions; D005260:Female; D005442:Flumazenil / Q000494:pharmacology; D008140:Lorazepam / Q000494:pharmacology; D008253:Macaca mulatta; D008297:Male; D011724:Pyridazines / Q000494:pharmacology; D012119:Respiration / Q000187:drug effects*; D015656:Respiratory Mechanics / Q000187:drug effects; D013990:Tidal Volume / Q000187:drug effects
D014151:Anti-Anxiety Agents; D002243:Carbolines; D011724:Pyridazines; C051712:7-phenyl-3-methyl-1,2,4-triazolo-(4,3b)pyridazine; D002245:Carbon Dioxide; D005442:Flumazenil; C024915:beta-carboline-3-carboxylic acid ethyl ester; D008140:Lorazepam; D002065:Buspirone