g-Hydroxybutyrate (GHB), a naturally occurring compound derived from g-aminobutyric acid (GABA), has been proposed as an effective drug in the treatment of alcohol withdrawal syndrome and in the control of alcohol consumption and craving. It has been recently shown (Neuropharmacology, 42:782, 2002) that GHB shares with ethanol the capability to enhance the brain and plasma concentrations of the neuroactive steroids allopregnanolone (AP) and THDOC, two potent endogenous positive allosteric modulators of the GABAA receptors. To further characterize the mechanism involved in the GHB-induced increase in the concentrations of neuroactive steroids we examined the effects of GHB in adrenalectomized-orchietomized rats (Adx-Orx). The acute administration of GHB (500 mg/kg, i.p.) resulted in a marked increase of progesterone, AP and THDOC levels in the cerebral cortex and plasma of sham-operated rats, while failed to affect the concentrations of these compounds in Adx-Orx rats, suggesting that GHB, like ethanol (World J Biol Psychiatry, 3:87, 2002), increases the brain and plasma neuroactive steroid concentrations through the activation of the hypothalamic-pituitary-adrenal axis. Moreover, we investigated the effect of chronic treatment with GHB (500 mg/kg i.p. twice a day for 10 days) on the cerebrocortical and plasma concentrations of progesterone, AP, and THDOC. The chronic treatment with GHB failed to affect basal levels of these hormones 48 h after the last drug administration, while a challenge administration of GHB (500 mg/kg, i.p.) similarly to ethanol (2 g/kg, i.p.) still increased markedly the cerebrocortical and plasma concentrations of progesterone, AP and THDOC, indicating that chronic treatment with GHB failed to induce tolerance to the effect of this drug and cross-tolerance to the effect of ethanol on the brain and plasma concentrations of these steroids. A new line of mutant mice deficient in succinate semialdehyde dehydrogenase, which display ataxia, develop generalized seizures and have significantly elevated brain GHB levels associated with a down regulation of GHB and GABA receptors in the cerebral cortex and hippocampus, has been recently generated (Nat. Genetics, 29:212, 2001). In these knockout mice we observed a significant lower brain concentration of progesterone and allopregnanolone with respect to wild-type mice. All together, these results provide new insight into the mechanisms for the GHB-induced increase in the brain neurosteroids levels which might help to clarify the anti-alcohol effects in alcohol-dependent subjects of this drug.
Modulation of brain neuroactive steroid by endogenous and exogenous gamma-hydroxybutyrate, a putative therapeutic agent for alcohol dependence
Porcu P;
2003
Abstract
g-Hydroxybutyrate (GHB), a naturally occurring compound derived from g-aminobutyric acid (GABA), has been proposed as an effective drug in the treatment of alcohol withdrawal syndrome and in the control of alcohol consumption and craving. It has been recently shown (Neuropharmacology, 42:782, 2002) that GHB shares with ethanol the capability to enhance the brain and plasma concentrations of the neuroactive steroids allopregnanolone (AP) and THDOC, two potent endogenous positive allosteric modulators of the GABAA receptors. To further characterize the mechanism involved in the GHB-induced increase in the concentrations of neuroactive steroids we examined the effects of GHB in adrenalectomized-orchietomized rats (Adx-Orx). The acute administration of GHB (500 mg/kg, i.p.) resulted in a marked increase of progesterone, AP and THDOC levels in the cerebral cortex and plasma of sham-operated rats, while failed to affect the concentrations of these compounds in Adx-Orx rats, suggesting that GHB, like ethanol (World J Biol Psychiatry, 3:87, 2002), increases the brain and plasma neuroactive steroid concentrations through the activation of the hypothalamic-pituitary-adrenal axis. Moreover, we investigated the effect of chronic treatment with GHB (500 mg/kg i.p. twice a day for 10 days) on the cerebrocortical and plasma concentrations of progesterone, AP, and THDOC. The chronic treatment with GHB failed to affect basal levels of these hormones 48 h after the last drug administration, while a challenge administration of GHB (500 mg/kg, i.p.) similarly to ethanol (2 g/kg, i.p.) still increased markedly the cerebrocortical and plasma concentrations of progesterone, AP and THDOC, indicating that chronic treatment with GHB failed to induce tolerance to the effect of this drug and cross-tolerance to the effect of ethanol on the brain and plasma concentrations of these steroids. A new line of mutant mice deficient in succinate semialdehyde dehydrogenase, which display ataxia, develop generalized seizures and have significantly elevated brain GHB levels associated with a down regulation of GHB and GABA receptors in the cerebral cortex and hippocampus, has been recently generated (Nat. Genetics, 29:212, 2001). In these knockout mice we observed a significant lower brain concentration of progesterone and allopregnanolone with respect to wild-type mice. All together, these results provide new insight into the mechanisms for the GHB-induced increase in the brain neurosteroids levels which might help to clarify the anti-alcohol effects in alcohol-dependent subjects of this drug.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
