Novel γ-Hydroxybutyric Acid (GHB) Analogs Share Some, but Not All, of the Behavioral Effects of GHB and GABA_BReceptor Agonists

Abstract

␥-Hydroxybutyrate (GHB), a therapeutic for narcolepsy and a drug of abuse, has several mechanisms of action that involve GHB and GABA B receptors, metabolism to GABA, and modulation of dopaminergic signaling. The aim of these studies was to examine the role of GHB and GABA B receptors in the behavioral effects of GHB. Three approaches were used to synthesize GHB analogs that bind selectively to GHB receptors and are not metabolized to GABA-active compounds. Radioligand binding assays identified UMB86 (4-hydroxy-4-napthylbutanoic acid, sodium salt), UMB72 [4-(3-phenylpropyloxy)butyric acid, sodium salt], UMB73 (4-benzyloxybutyric acid, sodium salt), 2-hydroxyphenylacetic acid, 3-hydroxyphenylacetic acid (3-HPA), and 4-hydroxy-4-phenylbutyric acid as compounds that displace In rats and pigeons, GHB discriminative stimulus effects were not mimicked or attenuated by UMB86, UMB72, or 3-HPA up to doses that decreased responding. In mice, GHB, GHB precursors (␥-butyrolactone and 1,4-butanediol) and GABA B receptor agonists [SKF97541 [3-aminopropyl(methyl)phosphinic acid hydrochloride] and baclofen] dose-dependently produced hypolocomotion, catalepsy, ataxia, and loss of righting. The GABA B receptor antagonist CGP35348 (3-aminopropyl(diethoxymethyl)phosphinic acid) attenuated catalepsy and ataxia that was observed after GHB and GABA B receptor agonists SKF97541 and baclofen. UMB86, UMB72, UMB73, and 3-HPA, like GHB, produced hypolocomotion, ataxia, and loss of righting; however, catalepsy was never observed with these compounds, which is consistent with the cataleptic effects of GHB being

Cataleptic effects of γ-hydroxybutyrate (GHB) and baclofen in mice: mediation by GABAB receptors, but differential enhancement by N-methyl-d-aspartate (NMDA) receptor antagonists

“…in Swiss-Webster mice (Itzhak and Ali 2002), and 320 mg/kg GHB i.p. in C57BL/6J mice (Carter et al 2005;Koek et al 2007b), the same strain as used in the present study. The lowest dose of GHB and baclofen that produced near-maximal catalepsy in the cumulative dosing procedure used here (i.e., 320 and 10 mg/kg i.p., respectively) was the same as in the single dosing procedure used previously (Carter et al 2005;Koek et al 2007b), suggesting that, under the conditions of these experiments, the potency of GHB and baclofen to produce catalepsy in C57BL/6J mice is not markedly affected by the use of single or cumulative dosing.…”

“…in C57BL/6J mice (Carter et al 2005;Koek et al 2007b), the same strain as used in the present study. The lowest dose of GHB and baclofen that produced near-maximal catalepsy in the cumulative dosing procedure used here (i.e., 320 and 10 mg/kg i.p., respectively) was the same as in the single dosing procedure used previously (Carter et al 2005;Koek et al 2007b), suggesting that, under the conditions of these experiments, the potency of GHB and baclofen to produce catalepsy in C57BL/6J mice is not markedly affected by the use of single or cumulative dosing. The observation that GHB, which has agonist activity at GABA B receptors (Lingenhoehl et al 1999), has cataleptic effects in common with a wellcharacterized GABA B receptor agonist and the finding that these effects can be blocked by the GABA B receptor antagonist CGP35348 (e.g., Koek et al 2007b) are further evidence that GABA B receptors are involved in GHB-induced catalepsy.…”

“…As described elsewhere (Carter et al 2005;Koek et al 2007b), catalepsy was examined using a horizontal cylindrical metal bar (diameter, 1 cm) supported 4 cm above the floor by two 8×8-cm square pieces of Plexiglas (Instrumentation Services, University of Texas Health Science Center). Mice were tested for catalepsy by placing their forepaws on the bar while the hind paws remain on the floor and then recording the time that both forepaws remained on the bar up to a maximum of 30 s. Each animal received an i.p.…”

“…At present, there appears to be little evidence for a role for GHB receptors in the in vivo effects of GHB (Wong et al 2004). Instead, many studies suggest that GABA B receptors are particularly important for various behavioral effects of GHB, including discriminative stimulus effects (e.g., Winter 1981, Colombo et al 1998, Carter et al 2003, decreased operant responding (Goodwin et al 2005), and directly observable effects such as hypolocomotion (Kaupmann et al 2003), catalepsy (Carter et al 2005), ataxia (Goodwin et al 2005), and loss of righting (Carai et al 2001). Consistent with the involvement of GABA B receptors, all of these effects of GHB are produced also by the prototypical GABA B receptor agonist baclofen (Carter et al 2003(Carter et al , 2005.…”

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

“…Numerous effects induced by GHB, including sedation, catalepsy (10), increased striatal dopamine release, changes in EEG pattern (11), discriminative stimulus properties (12), and reinforcing effects (13), are dose-dependently decreased by pretreatment with the GHB receptor-specific ligand NCS-382. Additionally, ataxia seems to be mediated through the high-affinity GHB sites (14). The reported euphoric effect of GHB and its therapeutic effect in narcolepsy cannot be mimicked by baclofen (3) and thus, might involve other targets.…”