Anti-conflict effects of benzodiazepines in rhesus monkeys: relationship with therapeutic doses in humans and role of GABAA receptors.
OBJECTIVE
Conflict procedures are used to study mechanisms underlying the anxiolytic effects of benzodiazepines (BZs). We established a conflict procedure with rhesus monkeys in order to examine the role of GABAA receptors in the anxiolytic-like effects of BZs.


METHODS
Four rhesus monkeys responded under a two-component multiple schedule in which responding was maintained under a fixed-ratio schedule of food delivery in the absence (non-suppressed responding) and presence (suppressed responding) of response-contingent electric shock.


RESULTS
Conventional BZs (alprazolam, flunitrazepam, clonazepam, nitrazepam, lorazepam, bromazepam, diazepam, flurazepam, clorazepate, chlordiazepoxide) engendered increases in the average rates of suppressed responding at low to intermediate doses and decreased the average rates of non-suppressed responding at higher doses. Positive correlations were observed when the therapeutic potencies of BZs in humans were compared with potencies to increase the rates of suppressed responding (R2=0.83) or decrease the rates of non-suppressed responding (R2=0.60). The 5-HT1A agonist buspirone increased the rates of suppressed responding, although the effects were modest, whereas the opioid morphine lacked anti-conflict effects. The BZ antagonist flumazenil also modestly increased the rates of suppressed responding. A relatively low dose of flumazenil enhanced, while a high dose blocked, alprazolam's anti-conflict effects. Compounds selective for alpha1 subunit-containing GABAA receptors (zolpidem, zaleplon, CL218,872) engendered relatively weak increases in the rates of suppressed responding.


CONCLUSIONS
A rhesus monkey conflict procedure was established with predictive validity for therapeutic doses in people and provided evidence that anxiolytic-like effects of BZs can occur with relatively low intrinsic efficacy at GABAA receptors and are reduced by alpha1GABAA receptor selectivity.
Rowlett
James K
JK
Harvard Medical School, New England Primate Research Center, Box 9102, One Pine Hill Drive Southborough, MA, 01772-9102, USA. james_rowlett@hms.harvard.edu
Lelas
Snjezana
S
Tornatzky
Walter
W
Licata
Stephanie C
SC
D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001569:Benzodiazepines / Q000008:administration & dosage / Q000494:pharmacology*; D002065:Buspirone / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D003220:Conflict, Psychological; D004597:Electroshock; D005260:Female; D005442:Flumazenil / Q000494:pharmacology; D005502:Food; D018757:GABA Modulators / Q000494:pharmacology; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects*; D012055:Reinforcement Schedule; D012054:Reinforcement, Psychology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
D014151:Anti-Anxiety Agents; D018757:GABA Modulators; C546240:GABRA1 protein, human; D009294:Narcotics; D011963:Receptors, GABA-A; D017366:Serotonin Receptor Agonists; D001569:Benzodiazepines; D005442:Flumazenil; D009020:Morphine; D002065:Buspirone