Effects of the putative antagonist NCS382 on the behavioral pharmacological actions of gammahydroxybutyrate in mice.
BACKGROUND
Gammahydroxybutyrate (GHB) is an endogenous chemical found in the human brain that when administered systemically readily crosses the blood-brain barrier and produces behavioral effects. Some previously reported observations, including reports of specific antagonism by NCS382 (6,7,8,9-tetrahydro-5-[H]-benzocycloheptene-5- ol-4-ylidene acetic acid), support the hypothesis that GHB is a neurotransmitter with its own receptor system. In addition to its uncertain physiological role, the recent interest in GHB has been engendered by its illicit use and abuse.


OBJECTIVE
To further characterize the behavioral effects of GHB and to evaluate NCS382 for its potential antagonistic effects.


METHODS
Following the administration of GHB alone and in combination with NCS382, mice were tested in a Functional Observational Battery (FOB) and for their effects on locomotor activity and on schedule-maintained behavior. Additionally, spontaneous and NCS382-precipitated withdrawal in rats chronically treated with GHB was examined.


RESULTS
In the FOB, GHB generally produced depressant-like effects that were generally not reversed by NCS382. GHB also dose dependently reduced locomotor activity and rates of operant behavior, which were generally not reversed by co-administrations with NCS382. Neither spontaneous nor NCS382-precipitated signs of physical dependence were observed following chronic GHB administration.


CONCLUSIONS
GHB dose dependently produced depressant-like effects on learned and unlearned behavior. The putative GHB antagonist NCS382 failed to convincingly antagonize these effects. Physical dependence was not evident following spontaneous withdrawal or NCS382 challenge. Taken together, these results suggest that NCS382's ability to antagonize GHB's effects may be very limited.
Cook
Charles D
CD
Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, P.O. BOX 980613, Richmond, VA 23298-0613, USA. ccook@hsc.vcu.edu
Aceto
Mario D
MD
Coop
Andrew
A
Beardsley
Patrick M
PM
D018686:Anesthetics, Intravenous / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001567:Benzocycloheptenes / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D012055:Reinforcement Schedule; D012978:Sodium Oxybate / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D013375:Substance Withdrawal Syndrome / Q000523:psychology; D019966:Substance-Related Disorders / Q000523:psychology
D018686:Anesthetics, Intravenous; D001567:Benzocycloheptenes; C066471:NCS 382; D012978:Sodium Oxybate