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 GABAB receptors. However, there is also evidence that the mechanisms mediating the effects of GHB and the prototypical GABAB receptor agonist baclofen are not identical, and that other mechanisms such as GHB receptors and subtypes of GABAA and GABAB 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.

Figure 1

Possible pharmacological mechanisms of GHB. Structures of 1,4-butanediol (1,4-BD) and gamma-butyrolactone (GBL), two GHB prodrugs that are metabolized to GHB in vivo. Structures of GABA, GHB (sodium salt), and NCS-382. GABA and GHB are reversibly metabolized in vivo. Three possible pharmacological mechanisms for GHB. GHB is metabolized to GABA, which binds to GABA_A and GABA_B receptors, GHB binds to GABA_B and GHB receptors, and NCS-382 binds to GHB receptors. Selective ligands for GABA_A, GABA_B, and GHB receptors are shown below the respective depiction of each receptor.

Figure 2

Effects of GHB and the GHB receptor ligand UMB 86 in rats discriminating GHB or UMB 86. The percentage of responses on the drug-appropriate lever (top panels) and the rate of responding (responses/sec; bottom panels) are plotted as a function of dose. Data points and error bars represent the mean ± 1 S.E.M. for 9 or 10 animals discriminating GHB from vehicle (left panels; replotted from Carter et al., 2005b) or for 3 or 4 animals discriminating UMB 86 from vehicle (right panels). The number of animals contributing to each data point in the top panels in given in the numerator adjacent to each point. The structures of the compounds studied are shown on the right-hand side of the figure.