Potentiation of the anticonflict effects of diazepam, but not pentobarbital and phenobarbital, by aminooxyacetic acid (AOAA).
The Conditioned Suppression of Drinking (CSD) paradigm is an "animal model" for anxiety which has been used to study the anticonflict effects of the benzodiazepines. It has been postulated that benzodiazepines produce their effects through interactions with GABA. The present study examined this potential GABA-BZ interaction on CSD behavior. In daily 10-minute sessions, water-deprived rats were trained to drink from a tube which was occasionally electrified (0.5 mA), electrification being signalled by a tone. Within 2-3 weeks control CSD responding had stabilized (16-24 shocks session and 10-14 ml water/session); drug tests were conducted at weekly intervals. As expected, diazepam (0.3-20.0 mg/kg), pentobarbital (0.6-10.0 mg/kg) and phenobarbital (10.0-40.0 mg/kg) alone markedly increased the number of shocks received at doses which did not depress background responding (i.e., water intake). Treatment with the GABA-transaminase inhibitor aminooxyacetic acid (AOAA: 2.5-10.0 mg/kg, 10- or 60-minute pretreatment) alone had no anticonflict effect on CSD behavior. However, pretreatment (60-minute) with 10.0 mg/kg AOAA significantly potentiated the effects of diazepam, as indicated by a significant shift to the left in the diazepam dose-response curve relative to diazepam alone. By contrast, the anticonflict effects of pentobarbital and phenobarbital were unaffected by this AOAA pretreatment. Thus, while increases in GABA transmission alone do not appear to affect CSD behavior, the anticonflict effect of benzodiazepines, but not barbiturates, appear to be potentiated by increases in GABA transmission.
McCloskey
T C
TC
Department of Pharmaceutical Sciences, College of Pharmacy, Wayne State University, Detroit, MI 48202.
Beshears
J F
JF
Halas
N A
NA
Commissaris
R L
RL
D000085:Acetates / Q000494:pharmacology*; D000625:Aminooxyacetic Acid / Q000494:pharmacology*; D000818:Animals; D001007:Anxiety; D001522:Behavior, Animal / Q000187:drug effects*; D003220:Conflict, Psychological; D003975:Diazepam / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D010424:Pentobarbital / Q000494:pharmacology*; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D000085:Acetates; D000625:Aminooxyacetic Acid; D005680:gamma-Aminobutyric Acid; D010424:Pentobarbital; D003975:Diazepam; D010634:Phenobarbital