Ethanol markedly increases "GABAergic" neurosteroids in alcohol-preferring rats

Alcohol administration (1 g/kg, i.p.) increased the levels of the neurosteroids 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone) and 3alpha,21-dihydroxy-5alpha-pregnan-20-one (allotetrahydrodeoxycorticosterone, THDOC) in the cerebral cortex and hippocampus both in alcohol-naive Sardinian alcohol-preferring (sP) and -non-preferring (sNP) rats (two rat lines selectively bred for alcohol preference and non-preference, respectively). However, the increase reached several fold higher levels in sP than in sNP rats (6-24 vs. 2-11 fold the basal levels, respectively). Since the two neurosteroids are the most potent endogenous positive modulators of GABA(A) receptors and elicit anxiolytic and rewarding effects, while voluntary alcohol consumption produces anxiolytic and rewarding effects in sP but not in sNP rats, the results suggest that the neurosteroids may play a role in the anxiolytic and rewarding effects of alcohol in sP rats

Ethanol markedly increases "GABAergic" neurosteroids in alcohol-preferring rats

Alcohol administration (1 g/kg, i.p.) increased the levels of the neurosteroids 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone) and 3alpha,21-dihydroxy-5alpha-pregnan-20-one (allotetrahydrodeoxycorticosterone, THDOC) in the cerebral cortex and hippocampus both in alcohol-naive Sardinian alcohol-preferring (sP) and -non-preferring (sNP) rats (two rat lines selectively bred for alcohol preference and non-preference, respectively). However, the increase reached several fold higher levels in sP than in sNP rats (6-24 vs. 2-11 fold the basal levels, respectively). Since the two neurosteroids are the most potent endogenous positive modulators of GABA(A) receptors and elicit anxiolytic and rewarding effects, while voluntary alcohol consumption produces anxiolytic and rewarding effects in sP but not in sNP rats, the results suggest that the neurosteroids may play a role in the anxiolytic and rewarding effects of alcohol in sP rats

Clozapine, but not haloperidol, increases brain concentrations of neuroactive steroids in the rat

The extrapyramidal side effects of typical antipsychotics, which are induced to a markedly reduced extent by clozapine, have been linked to a dysfunction of central gamma -aminobutyric acid (GABA)-mediated neurotransmission. The effects of clozapine on the brain concentrations of 3 alpha -hydroxy-5 alpha -pregnan-20-one (allopregnanolone, AP) and 3 alpha ,21-dihydroxy-5 alpha -pregnan-20-one (allotetrahydrodeoxycorticosterone, THDOC), two potent and endogenous positive allosteric modulators of GABA-mediated chloride current intensities at GABAA receptors, were compared with those of the typical antipsychotic haloperidol, A single administration of clozapine (1.25-20 mg/kg, IP), but not of haloperidol (0.1 or 0.5 mg/kg, TP), induced dose- and time-dependent increases in the concentrations of progesterone, AP, and THDOC in the cerebral cortex and striatum of rats, Clozapine (at 10 mg/kg, but not at lower doses) also increased the concentrations of these steroids as well as that of corticosterone in plasma in intact rats, but failed to increase the cortical concentrations of AP and THDOC in adrenalectomized-orchidecomized rats. An acute challenge with clozapine (10 mg cg), administered 48 h after the termination of daily treatment with the same dose for 19 days, still increased the cortical concentrations of progesterone, AP, and THDOC. These results suggest that the clozapine-induced increases in neuroactive steroid concentrations in the brain may contribute to the atypical pharmacological profile of this antipsychotic drug

Blood pressure circadian rhythm and variability in subjects with severe heart failure

To explore whether a condition of severe heart failure results in alteration of the 24-h-blood pressure (BP) profile and BP circadian rhythm, 19 patients with severe heart failure (NYHA class III-IV, 17M, 2F, mean age 57 ± 8 years) were considered and compared to a control group of age- and sex-matched normal subjects. All subjects were submitted to non-invasive 24- h ambulatory blood pressure monitoring using a SpaceLabs 90207 unit (recording interval 15 min). Both systolic and diastolic BP profiles were evaluated using the two-step method of analysis reported by Staessen: the existence of a BP circadian rhythm was first tested using Siegel's runs test, then a Fourier multiple harmonic analysis allowed us to obtain the BP profile parameters Acrophases (Acro, hh:mm) and Amplitudes (Ampl, mmHg). The same methods were used for pulse rate. Our results showed the presence of a BP circadian rhythm in severe heart failure subjects, as well as in control subjects. Furthermore, no significant difference was found between the two groups when considering the BP profile parameters Acro and Ampl. In conclusion, in contrast with previous reports, our results show that both BP circadian rhythm and BP profile parameters are preserved in patients with severe heart failure

GABA(B) receptor-mediated increase of neurosteroids by gamma-hydroxybutyric acid

Among the pharmacological actions of gamma-hydroxybutyric acid (GHB), some may involve GABA,, receptor-mediated mechanisms. GHB, however, fails to directly interact with sites for agonists and modulators on the GABA(A) receptor complex. We hypothesized that, in vivo, GHB may interfere with GABA, receptor function by altering the brain concentrations of the neurosteroids 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolonc, AP) and 3alpha,21-dihydroxy-5alpha-pregnan-20-one (allotetrahydrodeoxycorticosterone, THDOC), positive allosteric modulators of GABA-gated chloride currents. In male Wistar rats, GHB dose-dependently (75-1000 mg/kg, i.p.) increased AP, THDOC and their precursors pregnenolone and progesterone in brain cortex and hippocampus. The increases of AP (4-5 fold) and THDOC (3-4 fold) elicited by 300 mg/kg GHB peaked between 30 and 90 min and abated by 180 min. The selective GABA(B) receptor antagonist SCH 50911 (50 mg/kg, i.p.) prevented the action of GHB, while the GABA(B) receptor agonist baclofen (5-10 mg/kg) mimicked it. NCS-382 (50 mg/kg, i.p.), the purported selective antagonist of the GHB receptor, failed to antagonize GHB, but at 300 mg/kg increased brain cortical neurosteroids to the same extent as 300 mg/kg GHB; coadtministration of GHB and NCS-382, however, failed to yield an additive effect. These results strongly suggest that GHB, via a GABA(B) receptor-mediated mechanism, increases the brain concentrations of neurosteroids, whose properties as amplifyers of the GABA-gated chloride conductances may play a role in the GABA, receptor-mediated pharmacological actions of GHB. (C) 2002 Elsevier Science Ltd. All rights reserved