GABA-related drugs modulate the behavioral effects of lorazepam.
The behavioral effects of the GABA-related drugs SL 75102 (4-[[(4-chlorophenyl)-(5-fluoro-2-hydroxyphenyl)-methylene]amino]butyric acid) and THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyrindin-3-ol) were studied alone and in combination with lorazepam. Two groups of squirrel monkeys responded under a fixed-interval schedule of food presentation. In one group, responding was suppressed by superimposing a fixed-ratio schedule of response-produced electric shock; responding was not suppressed in the second group. Dose-response curves were determined by administering cumulative doses IV during timeout periods that preceded sequential components of the fixed-interval schedule. Neither SL 75102 (1.0-30.0 mg/kg) nor THIP (0.1-3.0 mg/kg) significantly altered rates of either suppressed or nonsuppressed responding, whereas lorazepam (0.01-0.3 mg/kg) produced dose-related increases in response rate under both schedules. Pretreatment with 1.0 mg/kg SL 75102 significantly enhanced the rate-increasing effects of lorazepam on suppressed responding. Pretreatment with 10.0 mg/kg SL 75102 also enhanced the rate-increasing effects of lorazepam on nonsuppressed responding. In contrast, the rate-increasing effects of lorazepam were not enhanced by pretreatment with 0.3 or 1.0 mg/kg THIP under either schedule. Moreover, pretreatment with 1.0 mg/kg THIP attenuated the rate-increasing effects of lorazepam on nonsuppressed responding. Enhancement of the behavioral effects of lorazepam by SL 75102 may reflect positive allosteric interactions between the two drugs at the benzodiazepine-GABA receptor complex.
Wettstein
J G
JG
Department of Psychiatry, Harvard Medical School, Boston, MA 02115.
Spealman
R D
RD
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D004357:Drug Synergism; D007555:Isoxazoles / Q000008:administration & dosage / Q000494:pharmacology*; D008140:Lorazepam / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D010080:Oxazoles / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000187:drug effects; D012453:Saimiri; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
D007555:Isoxazoles; D010080:Oxazoles; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; C017984:progabide acid; C015542:gaboxadol; D008140:Lorazepam