Efficacy and the Discriminative Stimulus Effects of Negative GABAA Modulators, or Inverse Agonists, in Diazepam-Treated Rhesus Monkeys

Lance R. McMahon, Lisa R. Gerak, and Charles P. France
Departments of Pharmacology (L.R.M., L.R.G., C.P.F.) and Psychiatry (C.P.F.), the University of Texas Health Science Center at San Antonio, San Antonio, Texas

Received February 17, 2006; accepted May 15, 2006.
JPET 318:907-913, 2006

Subjects. One female and five male adult rhesus monkeys were housed individually on a 14-h light/10-h dark schedule, were maintained at 95% free-feeding weight (range 8.0-11 kg) with a diet comprising primate chow (Harlan Teklad, High Protein Monkey Diet; Harlan Teklad, Madison, WI), fresh fruit, and peanuts, and were provided water in the home cage. Monkeys received 5.6 mg/kg/day diazepam, were trained to discriminate flumazenil, and had received GABAA ligands in previous studies (McMahon and France, 2005 ). The animals used in these studies were maintained in accordance with the Institutional Animal Care and Use Committee, The University of Texas Health Science Center at San Antonio, San Antonio, TX, and with the 1996 Guide for the Care and Use of Laboratory Animals (Institute of Laboratory Animal Resources on Life Sciences, National Research Council, National Academy of Sciences).

Apparatus. During experimental sessions, monkeys were seated in chairs (model R001; Primate Products, Miami, FL) that provided restraint at the neck and were placed in ventilated, sound-attenuating chambers equipped with two response levers, stimulus lights, and a food cup to which pellets (Bio-Serv, Frenchtown, NJ) could be delivered from a dispenser. An interface (MedAssociates, St. Albans, VT) connected the chambers to a computer that controlled and recorded experimental events.
 
Discrimination Procedure. Monkeys drank a solution containing diazepam (5.6 mg/kg) 3 h before experimental sessions consisting of multiple 15-min cycles. Each cycle comprised a 10-min timeout period, during which responses had no programmed consequence, followed by a 5-min response period, during which green stimulus lights were illuminated and a fixed ratio (FR) 5 schedule of food presentation was in effect. A maximum of 10 food pellets was available during a cycle; when the maximal number of food pellets was obtained in <5 min, the remainder of the response period was a timeout. The selection of vehicle- and flumazenil-appropriate levers varied among monkeys and remained the same for an individual throughout the study. Responding on the incorrect lever reset the response requirement on the correct lever.