Self-administration of gamma-hydroxybutyric acid (GHB) precursors gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) in baboons

Abstract

Rationale Gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) are gamma-hydroxybutyrate (GHB) pro-drugs and drugs of abuse. Objective Given the reports of abuse, and the ease at which GBL and 1,4-BD may be obtained, we investigated the reinforcing of GBL (n=5) and 1,4-BD (n=4) in baboons using IV self-administration procedures. Methods Sessions ran 24 h/day. Each injection was contingent upon completion of a fixed number (120 or 160) of lever responses. A 3-h timeout period followed each injection, limiting the total number of injections to 8/day. Self-administration was first established with cocaine (0.32 mg/kg/injection). GBL (10–130.0 mg/kg/injection), 1,4-BD (10–100 mg/kg/injection) or vehicle were substituted for cocaine at least 15 days. Food pellets were available ad libitum 24 h/day and were contingent upon completion of 10 lever responses. Results GBL (32–100 mg/kg/injection) maintained significantly greater numbers of injections when compared to vehicle in 4 of 5 baboons and mean rates of injection were high (>6 per day) in 3 baboons and moderate in the fourth baboon (4–6 per day). 1,4-BD (78–130 mg/kg/injection) maintained significantly greater numbers of injections when compared to vehicle in only 2 out of 4 baboons and rates were moderate to high in both baboons. Self-injection of these doses of GBL and 1,4-BD generally inhibited food-maintained responding. Conclusions GBL and 1,4-BD have abuse liability. Given that GBL and 1,4-BD are self-administered, are easier to obtain than GHB, and are detected in seized samples, additional legal control measures of these GHB pro-drugs may be needed.

Mechanisms for the Specific Properties of γ‐Hydroxybutyrate in Brain

“…The high amount of catabolites produced from GHB raises the question of their potential toxicity after chronic GHB ingestion. However, when given under medical supervision in specific indications like narcolepsy, alcohol dependence and withdrawal, but also in experimental animals for more than 8 months daily, GHB exhibited no chronic toxicity except dependence and withdrawal disturbances in some patients or animals . GHB is also a recreational drug of abuse because of its easy availability, synthesis, and low cost with a reported high acute toxicity and mortality rate in medical and forensic publications .…”

“…However, when given under medical supervision in specific indications like narcolepsy, 33,34 alcohol dependence and withdrawal, 7,35 but also in experimental animals for more than 8 months daily, 36 GHB exhibited no chronic toxicity except dependence and withdrawal disturbances in some patients 37 or animals. 38 GHB is also a recreational drug of abuse because of its easy availability, synthesis, and low cost with a reported high acute toxicity and mortality rate in medical and forensic publications. 39,40 It is also considered as a "date-rape" substance, like many sedative-hypnotics compounds that target GABA receptors (especially GABA-A receptors).…”

GHB, GBL and 1,4-BD Addiction

“…They did a series of experiments in baboons, a nonhuman primate that shows a close genetic proximity to humans. Physical dependence was shown after chronic intragastric administration of GHB, GBL and 1,4-BD [41][42][43][44]. Chronic GHB (350-750 mg/kg), GBL (400-600 mg/kg) or 1,4-BD (600 mg/kg) decreased feeding behavior, disrupted performance and produced sedation and muscle relaxation.…”

“…However, there is convincing evidence now that frequent GHB use can rapidly cause dependence and withdrawal [39,40]. First of all, preclinical evidence of the dependence potential of GHB and its precursors has recently been accumulating based on animal studies [41][42][43][44][45]. Similarily, in humans, physical dependence has been described within weeks of frequent and heavy use [46].…”

Preclinical assessment of abuse liability of biologics: In defense of current regulatory control policies

“…Though several groups of researchers previously have investigated the abuse liability of GHB in monkeys, adjustments in the experimental and pharmacological preparation resulted in a marked increase in the experimentally-demonstrated self-administration of GHB. Goodwin et al (2013) extended their earlier work with baboons by examining the GHB precursors 1,4-BD and GBL. Using similar training and testing methods as Goodwin et al, 2011, GBL (10e130 mg/kg) and 1,4-BD (10e100 mg/kg) were substituted for periods of at least 15 days, with return to cocaine baseline prior to progression to the next test dose.…”