Behavioral analyses of GHB: Receptor mechanisms

Abstract

GHB is used therapeutically and recreationally, although the precise mechanism of action responsible for its different behavioral effects is not entirely clear. The purpose of this review is to summarize how behavioral procedures, especially drug discrimination procedures, have been used to study the mechanism of action of GHB. More specifically, we will review several different drug discrimination procedures and discuss how they have been used to qualitatively and quantitatively study different components of the complex mechanism of action of GHB. A growing number of studies have provided evidence that the behavioral effects of GHB are mediated predominantly by GABA_B receptors. However, there is also evidence that the mechanisms mediating the effects of GHB and the prototypical GABA_B receptor agonist baclofen are not identical, and that other mechanisms such as GHB receptors and subtypes of GABA_A and GABA_B receptors might contribute to the effects of GHB. These findings are consistent with the different behavioral profile, abuse liability, and therapeutic indications of GHB and baclofen. A better understanding of the similarities and differences between GHB and baclofen, as well as the pharmacological mechanisms of action underlying the recreational and therapeutic effects of GHB, could lead to more effective medications with fewer adverse effects.

Introduction

GHB is an interesting and unique compound in that it is an endogenous molecule (gamma-hydroxybutyric acid), a drug of abuse (illicit GHB), and a marketed therapeutic drug (gamma-hydroxybutyrate, sodium salt; or sodium oxybate).¹ The purpose of this review is to summarize how behavioral procedures, especially drug discrimination procedures, have been used to study the mechanism of action of GHB. This review is not intended to serve as a comprehensive summary of the mechanism of action or pharmacological effects of GHB in general, as there are other recent reviews on the biochemistry and neurobiology (e.g., Crunelli et al., 2006, Pardi and Black, 2006), abuse potential (Nicholson and Balster, 2001, Gonzalez and Nutt, 2005, Barker et al., 2007), and therapeutic potential (Mamelak, 2007, Robinson and Keating, 2007) of GHB. Lastly, we will present several conclusions that have been drawn with regard to the pharmacological mechanism of action of GHB, rationale for the continued study of this important endogenous signaling system, and directions for future research.

GHB was first developed as a central nervous system depressant (Laborit et al., 1960) and was used as an anesthetic adjuvant for minor surgical procedures in the laboratory (Laborit et al., 1960, Vickers, 1969) and in the clinic (Aldrete and Barnes, 1968, Kleinschmidt et al., 1997, Kleinschmidt et al., 1998). GHB is still approved in Germany (Somsanit®; Kohler) for intravenous anesthesia, although its use as an anesthetic is thought to be decreasing. In the U.S., Canada, the European Union, and Switzerland GHB is approved to treat cataplexy and excessive daytime sleepiness associated with the sleep disorder narcolepsy (Xyrem®, Jazz Pharmaceuticals Inc., Valeant Pharmaceuticals International, and UCB). It is also approved in Italy and Austria to treat alcohol dependence and withdrawal (Alcover®, C.T. Laboratorio Farmaceutico).

Narcolepsy is a sleep disorder that is characterized by fragmented nighttime sleep (i.e., abrupt transitions between wakefulness and REM sleep) and daytime sleepiness, and can also include cataplexy (loss of muscle tone with consciousness intact), hypnogogic (experienced when falling asleep) or hypnopompic (experienced when waking from sleep) hallucinations, and sleep paralysis (for review, see Scammell, 2003). Studies in narcoleptic patients showed that GHB was effective in treating the daytime cataplexy and fragmented sleep/wake cycles of this clinical population (for review, see Mamelak et al., 1986). Nightly doses of GHB were shown to reduce the number of nocturnal awakenings and daytime attacks of cataplexy, and improve the structure of sleep in narcoleptic patients, increasing the delta power and duration of slow wave sleep and reducing the latency to REM sleep at night, and decreasing the frequency of transitions between wakefulness and REM sleep during the day (Broughton and Mamelak, 1979, Broughton and Mamelak, 1980, Scharf et al., 1985, Mamelak et al., 1986, Scrima et al., 1990, Pardi and Black, 2006). In 2002, GHB was approved as sodium oxybate (U.S. Pharmacopeia) under the trade name Xyrem for the treatment of cataplexy associated with narcolepsy, and in 2005, for the treatment of excessive daytime sleepiness associated with narcolepsy (for review, see Fuller & Hornfeldt, 2003).

Around the same time that the effects of GHB on sleep were being examined in the United States, a therapeutic indication for GHB in the treatment of alcoholism was emerging in Italy (for review, see Poldrugo & Addolorato, 1999). Early preclinical studies showed that GHB blocked the convulsant effects of ethanol withdrawal and acetaldehyde administration in rodents (Andronova and Barkov, 1981, Fadda et al., 1989). Clinical trials supported a possible role for GHB in the treatment of ethanol withdrawal, as GHB was found to decrease withdrawal signs and symptoms such as tremor, sweating, nausea, depression, and anxiety (Gallimberti et al., 1989, Addolorato et al., 1999). Additional studies showed that the administration of GHB or the GHB prodrug gamma-butyrolactone (GBL) decreased ethanol consumption in rats (Fadda et al., 1983, Biggio et al., 1992), and in humans, who reported decreased craving for ethanol in parallel with reduced ethanol self-administration (Gallimberti et al., 1992, Addolorato et al., 1996). Thus, the increasing number of reports of the effectiveness of GHB in promoting abstinence in alcoholics led to the approval of GHB under the trade name Alcover in Italy and Austria, for the treatment of alcoholism (Beghè & Carpanini, 2000).

In the late 1980s and early 1990s, GHB was sold over the counter in the United States as a “natural” and “organic” supplement to increase muscle mass (increase growth hormone) and to promote sleep (Dyer, 1991, Sanguineti et al., 1997). As the use of GHB as a natural food supplement increased, the number of reports of GHB intoxication and emergency room visits also increased (e.g., Chin et al., 1998, Li et al., 1998), which resulted in the Centers for Disease Control and the Food and Drug Administration issuing warnings about the potential dangers of GHB (Centers for Disease Control, 1990, United States Federal Register, 2000a). Shortly after the highly-publicized involvement of GHB in cases of drug-facilitated sexual assault, GHB was placed in a bifurcated Federal schedule in the U.S.: nonmedical use of illicit GHB or Xyrem can be prosecuted under Schedule I penalties, whereas legitimate medical use of Xyrem is governed by Schedule III restrictions (United States Federal Register, 2000b).

GHB gained a reputation as a “club drug” due to its reported use by individuals while attending nightclubs, raves, and circuit parties (Miotto et al., 2001, Bellis et al., 2003, Rodgers et al., 2004, Halkitis and Palamar, 2006). The “class” of drugs that is generally referred to as “club drugs” typically also includes methamphetamine, 3,4-methylenedioxy-N-methylamphetamine (MDMA; ecstasy), lysergic acid diethylamide (LSD; acid), and ketamine (special K). Common among these drugs is the setting in which they are most frequently used and the pattern of their use, and not a shared pharmacological mechanism of action. Several studies have shown, however, that some “club drugs”, including GHB, MDMA, and ketamine, are frequently used together, as well as with alcohol, marijuana, and other amphetamines (Degenhardt et al., 2002, Halkitis et al., 2007).

GHB gained a reputation as a “date-rape drug” in the 1990s as reports of its involvement in drug-facilitated sexual assault began to appear in the media and the scientific literature (e.g., Stillwell, 2002). It has been suggested that the common illicit formulation of GHB as a colorless odorless liquid facilitates the unsuspected addition of GHB to the drinks of individuals in bars and clubs (Smith, 1999, Schwartz et al., 2000, Varela et al., 2004). In addition, some of the reported effects of GHB such as sedation, euphoria, decreased inhibitions, enhanced sex drive, and anterograde amnesia, might lend GHB to being used for drug-facilitated sexual assault.

Although GHB is almost universally referred to as “the date rape drug” in the media, the prevalence of GHB in cases of drug-facilitated sexual assault, when confirmed by toxicological analyses, is relatively low (1–5%; ElSohly and Salamone, 1999, Varela et al., 2004, Association of Chief Police Officers, 2006). Well-validated assays for the detection of exogenous GHB in biological specimens have only recently become available. Thus, many previous case reports and studies have had to rely upon self-reports or anecdotal reports of GHB use, or upon the results of post-mortem toxicological analyses, the results of which have been shown to vary markedly depending on the storage conditions of the samples and the period of time between death and analysis (Kintz et al., 2004, LeBeau et al., 2007). Together, these challenges have made it difficult to identify with confidence that GHB has been involved in cases of suspected drug-facilitated sexual assault.

Despite the fact that GHB is approved for medical use in North America and Europe, the precise pharmacological mechanism of action of GHB that is responsible for its therapeutic and abuse-related effects is not entirely clear. An increasing number of studies over the last several years have focused on examining the mechanism of action of GHB. A GHB receptor has been cloned (Andriamampandry et al., 2007), new receptor binding and functional assays for the GHB receptor have been characterized (e.g., Mehta et al., 2001, Kemmel et al., 2003), new ligands that bind selectively to GHB receptors have been synthesized (e.g., Carter et al., 2005b, Wellendorph et al., 2005), and new behavioral procedures have been developed (e.g., Carter et al., 2004a, Koek et al., 2005). This review focuses on the behavioral, particularly drug discrimination, procedures that have been used to study the mechanism of action of GHB.