Metabolism of [1-14C]γ-hydroxybutyric acid by rat brain after intraventricular injection

The Discriminative Stimulus Effects of γ-Hydroxybutyrate and Related Compounds in Rats Discriminating Baclofen or Diazepam: The Role of GABAB and GABAA Receptors

“…GHB binds to GABA B receptors (Xie and Smart, 1992;Mathivet et al, 1997) and may indirectly activate GABA receptors through conversion to GABA and increased synthesis of neuroactive steroids (Roth, 1970;Doherty et al, 1975;Gold and Roth, 1977;Snead et al, 1989;Barbaccia et al, 2002). Administration of GHB, like baclofen, inhibits the extracellular release of GABA and suppresses K ϩ -stimulated [ 45 Ca 2ϩ ] uptake-effects that are blocked by the GABA B receptor antagonists phaclofen and CGP 35348 (Banerjee and Snead, 1995;Snead, 1996).…”

“…GHB has high affinity for sites labeled with [ 3 H]NCS-382, the purported GHB receptor antagonist (Mehta et al, 2001), and comparatively low affinity for GABA B receptors (Xie and Smart, 1992;Mathivet et al, 1997). GHB can also act indirectly on GABA A or GABA B receptors through its metabolic conversion to GABA in vivo (Roth, 1970;Doherty et al, 1975;Gold and Roth, 1977;Snead et al, 1989) and through GABA B receptormediated increases in neurosteroids that can modulate GABA A receptor function (Barbaccia et al, 2002).…”

“…For instance, the GABA A positive modulators diazepam (Colombo et al, 1998;Carter et al, 2003) and chlordiazepoxide (Winter, 1981), as well as the direct-acting GABA A agonist muscimol (Winter, 1981), occasion some drug-appropriate responding in rats discriminating GHB. Although GHB does not bind to GABA A receptors (Serra et al, 1991), GHB is metabolically converted to GABA (Doherty et al, 1975), and activation of GABA B receptors by GHB can stimulate the synthesis of neurosteroids that positively modulate the actions of GABA at the GABA A receptor complex (Barbaccia et al, 2002). Furthermore, pharmacologically unrelated compounds (i.e., ketamine and morphine) do not share discriminative stimulus effects with GHB (Winter, 1981;Carter et al, 2003).…”

An overview of ?-hydroxybutyrate catabolism: The role of the cytosolic NADP+-dependent oxidoreductase EC 1.1.1.19 and of a mitochondrial hydroxyacid-oxoacid transhydrogenase in the initial, rate-limiting step in this pathway

“…How well these values correspond to measurements of GHB catabolism in vivo can be determined by examination of the half-life of GHB in brain. Doherty et al (16) and M6hler et al (15) have both reported a half-life (tl/:) for labeled GHB in brain of 5 min. If one assumes that the rate of disposal of GHB follows first order kinetics, then from the fol- lowing expression k, the first order rate constant, can be calculated.…”

The Role of GABAB Receptors in the Discriminative Stimulus Effects of γ-Hydroxybutyrate in Rats: Time Course and Antagonism Studies

“…It is likely that multiple mechanisms contribute to the effects of GHB because it binds to multiple sites in brain and because it is metabolized to and from ␥-aminobutyric acid (GABA) in vivo (Roth, 1970;Doherty et al, 1975;Gold and Roth, 1977;Snead et al, 1989). GHB binds to low-and high-affinity sites in cerebral cortex and hippocampus (Snead and Liu, 1984;Mehta et al, 2001), and it has been suggested that the low-affinity sites are GABA B receptors.…”