Enhanced sucrose pellet consumption induced by benzodiazepine-type drugs in squirrel monkeys: role of GABAA receptor subtypes.
BACKGROUND
Benzodiazepine agonists characteristically increase food intake in humans and non-human subjects, and the underlying mechanisms of this effect are not understood completely.


OBJECTIVE
Compounds with selectivity for GABAA receptor subtypes were used to evaluate the role of GABAA receptors containing alpha1 and alpha5 subunits (alpha1GABAA and alpha5GABAA receptors, respectively) in benzodiazepine-induced increases in sucrose pellet consumption.


METHODS
Adult male squirrel monkeys (N=4-6), maintained under free-feeding conditions, were administered with intramuscular injections of the nonselective benzodiazepines diazepam and alprazolam, the alpha1GABAA-preferring compounds zolpidem and zaleplon, or the alpha5GABAA-preferring agonist QH-ii-066 before daily 10-min periods when sucrose pellets were available. In a separate experiment, observable behavioral effects (e.g., ataxia and procumbent posture) were quantified after administration of alprazolam, zaleplon, and QH-ii-066. To further assess the roles of GABAA receptor subtypes, zolpidem-induced increases in pellet consumption were re-evaluated after pretreatment with nonselective antagonist flumazenil, the alpha1GABAA-preferring antagonist beta-carboline-3-carboxylate-t-butyl ester (BCCT), or QH-ii-066.


RESULTS
Alprazolam, diazepam, zolpidem, and zaleplon but not QH-ii-066 significantly increased sucrose pellet consumption. In addition, all agonists decreased locomotion and environment-directed behavior as well as engendered ataxia and procumbent posture. For all compounds except QH-ii-066, these behaviors occurred at doses similar to those that increased pellet consumption. Flumazenil and BCCT, but not QH-ii-066, antagonized zolpidem-induced increases in pellet consumption in a surmountable fashion.


CONCLUSIONS
These results suggest that the alpha1GABAA receptor subtype plays a key role in benzodiazepine-induced increases in consumption of palatable food, whereas the alpha5GABAA receptor subtype may not be involved in this effect.
Duke
Angela N
AN
New England Primate Research Center, Harvard Medical School, One Pine Hill Drive, P.O. Box 9102, Southborough, MA 01772-9102, USA. angela_duke@hms.harvard.edu
Platt
Donna M
DM
Cook
James M
JM
Huang
Shengming
S
Yin
Wenyuan
W
Mattingly
Bruce A
BA
Rowlett
James K
JK
D000525:Alprazolam / Q000494:pharmacology; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D003975:Diazepam / Q000494:pharmacology; D005442:Flumazenil / Q000494:pharmacology; D008297:Male; D011725:Pyridines / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000145:classification / Q000502:physiology*; D012453:Saimiri; D013395:Sucrose / Q000008:administration & dosage*; D000077334:Zolpidem
D011725:Pyridines; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005442:Flumazenil; D013395:Sucrose; D000077334:Zolpidem; D003975:Diazepam; D000525:Alprazolam