γ-Aminobutyric AcidB (GABAB)-Receptor Mediation of Different In Vivo Effects of γ-Butyrolactone

Abstract

Abstract. The endogenous brain constituent, γ-hydroxybutyric acid (GHB), as well as its prodrug, γ-butyrolactone (GBL), have recently gained interest in the drug addiction field due to their abuse potential and fatalities caused by overdose. It is known that GHB has two sites of actions: the γ-aminobutyric acid B (GABA B ) receptor and a specific-GHB binding site. The present study was designed to extend to GBL the investigations on the contribution of the GABA B receptor and the specific-GHB binding site to its in vivo effects. To this aim, DBA mice were pretreated either with GABA B -receptor antagonists, (3-aminopropyl)(diethoxymethyl)phosphinic acid (CGP 35348) and (2S)(+)-5,5-dimethyl-2-morpholineacetic acid (SCH 50911), or a putative antagonist of the specific-GHB binding site, 6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylideneacetic acid (NCS-382), prior to the administration of doses of GBL that induced hypothermia, motor-incoordination (measured as motor-impairment at the Rota-Rod task), and sedation / hypnosis. The capability of SCH 50911 and NCS-382 to protect against GBL-induced lethality was also investigated. Pretreatment with either GABA B -receptor antagonist completely prevented GBL-induced hypothermia, motor-incoordination, and sedation / hypnosis. SCH 50911 also provided complete protection against GBL-associated lethality. Vice versa, NCS-382 failed to exert any antagonistic or protective effect. These results suggest that the in vivo GBL effects tested in the present study are mediated by activation of the GABA B receptor.

Differential Effects of GABABReceptor Subtypes, γ-Hydroxybutyric Acid, and Baclofen on EEG Activity and Sleep Regulation

“…Although the mechanism of action is still unclear, GHB decreases excessive daytime sleepiness and attacks of cataplexy in narcolepsy patients (Xyrem International Study Group, 2005;Black and Houghton, 2006). Despite conflicting results suggesting that GHB acts via specific GHB receptors (Doherty et al, 1978;Castelli et al, 2004), compelling evidence suggests that most of the physiological and pharmacological effects of exogenous GHB are mediated through GABA B receptors (Waldmeier, 1991;Jensen and Mody, 2001;Kaupmann et al, 2003;Quéva et al, 2003;Carai et al, 2008).…”

α4βδ GABA A receptors are high-affinity targets for γ-hydroxybutyric acid (GHB)

“…When GHB is ingested in high doses and reaches millimolar concentrations in the brain, it induces behavioral effects such as sedation, motor incoordination and hypothermia (3). These actions are largely mediated by metabotropic GABA B receptors, because effects are prevented by GABA B receptor antagonist pretreatment (5) and completely abolished in GABA B(1) KO mice (6). In addition to the validated GABA B receptor effects and other suggested receptors (7), GHB binds with nanomolar to micromolar affinity to a remarkably abundant protein of distinct spatial distribution and ontogenesis (4), representing an additional functional target.…”

Novel Radioiodinated γ-Hydroxybutyric Acid Analogues for Radiolabeling and Photolinking of High-Affinity γ-Hydroxybutyric Acid Binding Sites

“…Although many of the reported pharmacological and clinical effects of exogenously administered GHB seem to be mediated through GABA B receptors (Carai et al, 2008), the presence of [ 3 H]GHB high-affinity binding sites with distinct ontogenesis (Snead, 1994) and distribution (Castelli et al, 2000;Gould et al, 2003) argues in favor of a specific GHB molecular site of action (sometimes referred to as the GHB receptor). There is notable interest in elucidating the functional correlates of this GHB-interacting protein.…”

“…The unequivocal role for GABA B receptors in mediating important pharmacological GHB effects has since been underlined by the lack of effects of GHB on behavior, temperature regulation, locomotion, and dopamine synthesis in mice lacking functional GABA B receptors and otherwise produced in wild-type mice Quéva et al, 2003;Carter et al, 2004) and by the notion that GABA B receptor antagonists can block many GHB-induced behavioral effects in normal rats (Carai et al, 2008). However, clear differences also exist between the effects of GHB and the prototypical GABA B receptor agonist baclofen [4-amino-3-(4-chlorophenyl)-butanoic acid], e.g., in relation to the abuse potential and in terms of efficacy of GHB in patients with narcolepsy versus baclofen.…”