gamma-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 [(3)H]
NCS-382 [5-[(3)H]-(2E)-(5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[
a][7] annulen-6-ylidene) ethanoic
acid] from GHB receptors at concentrations that do not markedly affect [(3)H]
GABA binding to
GABA(B) receptors. 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 (gamma-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 mediated by
GABA(B) receptors.
Ataxia that was observed with UMB86, UMB72, UMB73, and
3-HPA was not antagonized by CGP35348, suggesting that
ataxia induced by these analogs is not mediated by
GABA(B) receptors and might involve GHB receptors.