Gamma-hydroxybutyric acid tolerance and withdrawal in a rat model.
Long-term daily use of gamma-hydroxybutyrate (GHB) and related compounds has recently been associated with a withdrawal syndrome. To the best of the authors' knowledge, there are currently no animal models of GHB withdrawal.


OBJECTIVE
The authors studied and described the effect of chronic dosing of GHB (3-6 days) on tolerance and withdrawal in a rat model.


METHODS
Rats were administered GHB every three hours via intraperitoneal catheter. Groups of rats (2 per group) were dosed with GHB for either 3 (24 doses), 4 (32 doses), 5 (40 doses), or 6 (48 doses) days. The GHB dose was 0.25 g/kg for doses 1-8, 0.75 g/kg for doses 9-12, 1 g/kg for doses 13-16, 1.25 g/kg for doses 17-24, 1.5 g/kg for doses 25-32, 1.75 g/kg for doses 33-40, and 2 g/kg for doses 41-48. Following the last dose of GHB, the rats were scored using a 16-point ethanol intoxication-withdrawal scale rating spontaneous behaviors, response to handling, grooming, and neurological signs. Lower scores indicate intoxication, while higher scores indicate withdrawal. Scores were recorded at hours 0, 1, 2, 3, 4, 5, 6, 9, 12, and 24.


RESULTS
Tolerance: Rats dosed with GHB for more days were less intoxicated one hour after their last GHB dose despite receiving higher doses. WITHDRAWAL: The scores for all rats dosed with GHB increased at hours 4 (p = 0.028), 5 (p = 0.037), 6 (p = 0.007), and 9 (p = 0.024) after the last dose, indicating withdrawal. The scores demonstrated a linear increase dependent upon the number of days of GHB dosing at hours 3 (p < 0.000), 4 (p = 0.004), 5 (p = 0.002), and 12 (p = 0.039) as well as prior to the last dose at hour 0 (p = 0.000). No rats developed seizures.


CONCLUSIONS
Tolerance and mild withdrawal in rats can be induced by administering intraperitoneal GHB every three hours for 3-6 days. More prolonged dosing and higher doses of GHB may be necessary to induce severe withdrawal.
Bania
Theodore C
TC
Department of Emergency Medicine, St. Luke's-Roosevelt Hospital Center, Columbia University, College of Physicians and Surgeons, New York, NY, USA. toxtod@aol.com
Ashar
Tom
T
Press
Gregory
G
Carey
Patricia M
PM
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D008297:Male; D020714:Maximum Tolerated Dose; D023421:Models, Animal; D011336:Probability; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment; D012720:Severity of Illness Index; D012978:Sodium Oxybate / Q000009:adverse effects / Q000494:pharmacology*; D013375:Substance Withdrawal Syndrome / Q000209:etiology / Q000503:physiopathology*
D012978:Sodium Oxybate