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PubMed2005

Low tolerance and dependence liabilities of etizolam: molecular, functional, and pharmacological correlates.

The effects of prolonged exposure to and subsequent withdrawal of the thienotriazolobenzodiazepine etizolam on gamma-aminobutyric acid (GABA) type A receptor gene expression and function were compared with those of the benzodiazepine lorazepam. Exposure of rat hippocampal neurons in culture to 10 microM etizolam for 5 days reduced the amounts of alpha5 and gamma2S receptor subunit mRNAs, whereas etizolam withdrawal was associated with a persistent reduction in gamma2S mRNA and an increase in alpha2 and alpha3 mRNAs. Neither chronic exposure to nor withdrawal of etizolam affected the acute modulatory effects of etizolam or lorazepam on GABA-evoked Cl- current. Treatment with 10 microM lorazepam for 5 days reduced the amounts of alpha1 and gamma2S subunit mRNAs and increased that of alpha3 mRNA, whereas lorazepam withdrawal was associated with persistence of the changes in alpha3 and gamma2S mRNAs and an increase in alpha2 and alpha4 mRNAs. Parallel changes in the abundance of alpha1 and alpha4 subunit proteins induced by chronic exposure to and withdrawal of lorazepam, but not etizolam, were detected by immunocytofluorescence analysis. Chronic lorazepam treatment resulted in a reversible reduction in the modulatory efficacy of this drug and conferred on flumazenil the ability to potentiate GABA-evoked Cl- current. The anticonvulsant action of etizolam was not altered in mice chronically treated with this drug, whereas lorazepam-treated animals became tolerant to the acute anticonvulsant effect of this benzodiazepine. These data suggest that etizolam is endowed with a reduced liability to induce tolerance and dependence compared with classical benzodiazepines.

Animals↗
PubMed2003

Extrasynaptic GABA(A) channels activated by THIP are modulated by diazepam in CA1 pyramidal neurons in the rat brain hippocampal slice.

Single-channel currents were activated by THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) in cell-attached patches on CA1 pyramidal neurons in the rat hippocampal slice preparation. THIP activated GABA(A) channels after a delay that was concentration-dependent and decreased by 1 microM diazepam. The currents showed outward rectification. Channels activated at depolarized 40 mV relative to the chloride reversal potential had low conductance (<40 pS) but the conductance increased with time, resulting in high-conductance channels (>40 pS). The average maximal-channel conductances for 2 and 100 microM THIP were 59 and 62 pS (-Vp = 40 mV), respectively, whereas in 2 microM THIP plus 1 microM diazepam, it was 71 pS. The results show that in hippocampal neurons THIP activates channels with characteristics similar to those of channels activated by low concentrations (0.5-5 microM ) of GABA. The increase in the inhibitory conductance with membrane depolarization permits gradation of the shunt pathway relative to the level of the excitatory input.

Animals↗
PubMed2005

[Neonatal consequences of benzodiazepines used during the last month of pregnancy].

INTRODUCTION: Since benzodiazepines (BZD) are largely prescribed during pregnancy, the Regional Pharmacovigilance Center (RPVC) of Tours regularly deals with questions about the risk of their administration to pregnant women and the monitoring of the newborns exposed in utero to these drugs. During the third trimester, we recommend a switch in the BZD maternal treatment to oxazepam, which has an intermediary half-life and no active metabolite, and a hospitalisation of the newborn in order to monitor his respiratory rate. The purpose of our study was to evaluate the neonatal consequences of BZD used at the end of pregnancy and to analysed if our recommendations were taken into account and if they were appropriate. METHODS: From 1989 to the end of 2002, we studied the files in which women had received a BZD during the 30 days prior to delivery. We analysed maternal treatments, the outcome of pregnancy and the development of the newborn, the therapeutically attitude recommended and whether or not it was respected. RESULTS: A total of 73 files were selected. Seventy neonates were born to 73 women. The newborns were hospitalised (73%) and they developed adverse reactions possibly related to the use of BZD (51,5%) : an impregnation syndrome (42%) characterized by hypotonia and hypoventilation, and a withdrawal syndrome (20%) with tremulations as the main symptom. CONCLUSION: Considering the most frequent neonatal manifestations, hospitalization and the respiratory monitoring recommended by the RPVC seemed adequate. However, the switch to oxazepam was seldom done and its advantages should be pointed out.

Adult↗
PubMed2002

Evaluation of immunomodulatory potential of Ocimum sanctum seed oil and its possible mechanism of action.

The present study investigates the effect of Ocimum sanctum seed oil (OSSO) on some immunological parameters in both non-stressed and stressed animals. An attempt has also been made to explore the possible mechanism of immunomodulatory activity. OSSO (3 ml/kg, ip) produced a significant increase in anti-sheep red blood cells (SRBC) antibody titre and a decrease in percentage histamine release from peritoneal mast cells of sensitized rats (humoral immune responses), and decrease in footpad thickness and percentage leucocyte migration inhibition (LMI) (cell-mediated immune responses). Restraint stress (RS) produced a significant reduction in the anti-SRBC antibody titre, foot pad thickness and percentage LMI (% LMI). The effects of RS on humoral as well as cell-mediated immune responses were effectively attenuated by pretreating the animals with OSSO. Co-administration of diazepam (1 mg/kg, sc), a benzodiazepine (BZD), with OSSO (1 ml/kg, ip) enhanced the effect of OSSO on RS-induced changes in both humoral and cell-mediated immune responses. Further, flumazenil (5 mg/kg, ip), a central BZD receptor antagonist inhibited the immunomodulatory action of OSSO on RS-induced immune responsiveness. Thus, OSSO appears to modulate both humoral and cell-mediated immune responsiveness and these immunomodulatory effects may be mediated by GABAergic pathways.

Adjuvants, Immunologic↗
PubMed2003

Comparison of the effects of allopregnanolone with direct GABAergic agonists on ethanol self-administration with and without concurrently available sucrose.

Behavioral effects of ethanol are mediated by actions at multiple neurotransmitter receptors and signaling systems; prominent among these is the type A gamma-aminobutyric acid (GABA(A)) receptor. Previous work has shown that the GABAergic neuroactive steroid allopregnanolone enhances ethanol-reinforced instrumental responding in rat. In the current study, we compared the effects of allopregnanolone with the direct GABA(A) agonist muscimol and the direct type B GABA (GABA(B)) agonist baclofen in male Long-Evans rats lever pressing for a 10% ethanol solution in a limited-access procedure. The effects of concurrently available sucrose were also tested to determine the selectivity of these drugs for altering ethanol self-administration when an alternate reinforcer was available. In Experiment 1, we found that presession systemic administration of both muscimol (0.3 and 1 mg/kg) and baclofen (1 and 3 mg/kg) reduced responding for ethanol. In contrast, allopregnanolone (3 and 5.6 mg/kg) enhanced responding for ethanol. In Experiment 2, we found that a 1-mg/kg dose of baclofen reduced responding for ethanol, but not for sucrose, whereas both baclofen and muscimol, administered at a higher dose of 3 mg/kg, decreased both ethanol- and sucrose-reinforced responding. Allopregnanolone, at a dose of 5.6 mg/kg, but not of 3 mg/kg, selectively increased ethanol-reinforced responding, indicating a less robust effect of allopregnanolone on responding within the concurrent reinforcement procedure than that observed when ethanol alone was available. The results support the suggestion that direct agonist action at either the GABA(A) or the GABA(B) receptor decreases ethanol self-administration. Muscimol produces a nonselective decrease in instrumental responding, whereas baclofen may selectively reduce ethanol intake at lower doses, but not higher ones, possibly limiting its potential use for treatment of alcohol abuse in human beings. In contrast, allopregnanolone can selectively enhance ethanol self-administration in the presence of a concurrently available alternate reinforcer, indicating that the direct GABA(A) agonist muscimol and the allosteric GABA(A) modulator allopregnanolone do not produce similar behavioral effects on instrumental responding for ethanol reinforcement.

Alcohol Drinking↗
PubMed2004

Maternal behavior regulates benzodiazepine/GABAA receptor subunit expression in brain regions associated with fear in BALB/c and C57BL/6 mice.

Inbred strains of mice, such as BALB/cByJ and C57BL/6ByJ, have been used repeatedly to study genotype-phenotype relations. These strains differ on behavioral measures of fear. In novel environments, for example, BALB/c mice are substantially more neophobic than C57BL/6 animals. The benzodiazepine (BZ)/GABAA receptor system has been proposed as a regulator of behavioral responses to stress, and BALB/c and C57BL/6 mice differ in BZ/GABAA receptor binding. In the present study, we found increased BZ receptor levels in C57BL/6 mice in the central and basolateral nuclei of the amygdala as well as the locus coeruleus using either flunitrazepam (nonselective) or zolpidem (alpha1 subtype selective) as radioligands. Differences in receptor binding were most pronounced in the amygdala and locus coeruleus using [3H]zolpidem. C57BL/6 mice showed increased alpha1 mRNA levels in the locus coeuruleus compared to BALB/c mice. In addition, gamma2 mRNA expression in BALB/c mice was decreased in the central nucleus of the amygdala to levels that were 2-2.5-fold lower than those of C57BL/6 mice. The results of an adoption study revealed that the biological offspring of C57BL/6 mothers fostered after birth to BALB/c dams showed decreased levels of gamma2 mRNA expression in the central nucleus of the amygdala in comparison to peers fostered to other C57BL/6 mothers (the reverse was found for the biological offspring of BALB/c mothers). In a step-down exploration paradigm, BALB/cByJ mice crossfostered onto a C57BL/6ByJ dam expressed reduced anxiety responses. However, among C57BL/6ByJ mice, the relatively low levels of anxiety ordinarily evident were not increased when mice of this strain were reared by a BALB/cByJ dam. These preliminary findings suggest that the strain differences in the BZ/GABAA receptor system occur, at least in part, as a function of parental care. Such findings may reflect a mammalian example of an indirect genetic effect mediated by maternal care.

Adoption↗
PubMed1999

GABAA receptor subunit composition and functional properties of Cl- channels with differential sensitivity to zolpidem in embryonic rat hippocampal cells.

Using flow cytometry in conjunction with a voltage-sensitive fluorescent indicator dye (oxonol), we have identified and separated embryonic hippocampal cells according to the sensitivity of their functionally expressed GABAA receptors to zolpidem. Immunocytochemical and RT-PCR analysis of sorted zolpidem-sensitive (ZS) and zolpidem-insensitive (ZI) subpopulations identified ZS cells as postmitotic, differentiating neurons expressing alpha2, alpha4, alpha5, beta1, beta2, beta3, gamma1, gamma2, and gamma3 GABAA receptor subunits, whereas the ZI cells were neuroepithelial cells or newly postmitotic neurons, expressing predominantly alpha4, alpha5, beta1, and gamma2 subunits. Fluctuation analyses of macroscopic Cl- currents evoked by GABA revealed three kinetic components of GABAA receptor/Cl- channel activity in both subpopulations. We focused our study on ZI cells, which exhibited a limited number of subunits and functional channels, to directly correlate subunit composition with channel properties. Biophysical analyses of GABA-activated Cl- currents in ZI cells revealed two types of receptor-coupled channel properties: one comprising short-lasting openings, high affinity for GABA, and low sensitivity to diazepam, and the other with long-lasting openings, low affinity for GABA, and high sensitivity to diazepam. Both types of channel activity were found in the same cell. Channel kinetics were well modeled by fitting dwell time distributions to biliganded activation and included two open and five closed states. We propose that short- and long-lasting openings correspond to GABAA receptor/Cl- channels containing alpha4beta1gamma2 and alpha5beta1gamma2 subunits, respectively.

Animals↗
PubMed1997

Key amino acids in the gamma subunit of the gamma-aminobutyric acidA receptor that determine ligand binding and modulation at the benzodiazepine site.

Pharmacological analyses of gamma-aminobutyric acidA (GABAA) receptor subtypes have suggested that both the alpha and gamma subunits, but not the beta subunit, contribute to the benzodiazepine binding site. We took advantage of the different pharmacological properties conferred by the inclusion of different gamma subunits in the receptor macromolecule to identify amino acids gamma2Phe77 and gamma2Met130 as key determinants of the benzodiazepine binding site. gamma2Phe77 was required for high affinity binding of the benzodiazepine site ligands flumazenil, CL218,872, and methyl-beta-carboline-3-carboxylate but not flunitrazepam. This amino acid was, however, required for allosteric modulation by flunitrazepam, as well as other benzodiazepine site ligands. In contrast, gamma2Met130 was required for high affinity binding of flunitrazepam, clonazepam, and triazolam but not flumazenil, CL218, 872, or methyl-beta-carboline-3-carboxylate and did not affect benzodiazepine efficacy. Introduction of the phenylalanine and methionine into the appropriate positions of gamma1 was not sufficient to confer high affinity for the benzodiazepine site ligand zolpidem. These data show that gamma2Phe77 and gamma2Met130 are necessary for high affinity binding of a number of benzodiazepine site ligands. Although most previous studies have focused on the contribution of the alpha subunit, we demonstrated a critical role for the gamma subunit at the benzodiazepine binding site, indicating that this modulatory site is located at the interface of these two subunits. Furthermore, gamma2Phe77 is homologous to alpha1Phe64, which has been previously shown to be a key determinant of the GABA binding site, suggesting a conservation of motifs between different ligand binding sites on the GABAA receptor.

Amino Acid Sequence↗
PubMed1997

Allopregnanolone affects sleep in a benzodiazepine-like fashion.

Recent research in rats and humans has shown that exogenous progesterone evokes a sleep profile similar to that induced by agonistic modulators of gamma-aminobutyric acid(A) receptors, such as benzodiazepines. This finding suggests the involvement of the neuroactive metabolite of progesterone, allopregnanolone. In the vehicle-controlled study reported here, we assessed the sleep effects of two doses of allopregnanolone (7.5 and 15 mg/kg), mixed with oil, administered intraperitoneally at light onset in 8 rats. The electroencephalogram (EEG) and electromyogram were recorded during the first 6 postinjection hr. Compared with vehicle, both doses of allopregnanolone reduced the latency to non-rapid eye movement sleep (non-REMS) and 15 mg/kg allopregnanolone significantly increased the time spent in pre-REMS, an intermediate state between non-REMS and REMS. Furthermore, allopregnanolone dose-dependently influenced EEG activity during non-REMS and REMS. In non-REMS, EEG activity was decreased in the lower frequencies (< or =7 Hz) and enhanced in the frequencies of > or =13 Hz. In REMS, allopregnanolone enhanced high-frequency EEG activity (> or =17 Hz). The effects were most pronounced during the first postinjection hours and gradually diminished thereafter. Analysis of the plasma and brain concentrations of allopregnanolone in 45 rats revealed long-lasting increases, which reached maximal levels during the first postinjection hour. The sleep effects of allopregnanolone are very similar to those elicited by larger doses of progesterone, which produce comparable brain levels of allopregnanolone. These data indicate that the steroid allopregnanolone has benzodiazepine-like effects on sleep.

Analysis of Variance↗
PubMed2005

Participation of dorsal raphe nucleus in the behavioral alteration observed after discontinuation of chronic diazepam administration: possible neural circuitry involved.

Previous findings from our laboratory have demonstrated a positive correlation between the development of tolerance to diazepam (DZ) 5 mg/kg/day over 4 days, and increased hippocampal synaptic plasticity. It seems likely that a similar plastic phenomenon may occur on hippocampal formation after chronic (18 days) DZ administration. We postulate hippocampal long-term potentiation (LTP) underlying substrate to the behavioral alteration observed after chronic DZ administration. In the present study, we investigated the involvement of the serotonergic (5-HT) system in the possible neural circuitry recruited during DZ withdrawal and in the increased hippocampal synaptic plasticity associated with the discontinuation of chronic DZ administration. The results of the current research demonstrate an increased neuronal activity in the dorsal raphe nucleus (DRN) during withdrawal. Previous MK-801 administration impairs the development of anxiety signs observed during withdrawal and the concomitant increased electrical activity on 5-HT neurons on DRN. These results are discussed in terms of the participation of 5-HT system in the modulation of hippocampal plasticity developed on DZ withdrawal.

Action Potentials↗
PubMed2001

Vesicular neurotransmitter transporters in Huntington's disease: initial observations and comparison with traditional synaptic markers.

Markers of identified neuronal populations have previously suggested selective degeneration of projection neurons in Huntington's disease (HD) striatum. Interpretations are, however, limited by effects of compensatory regulation and atrophy. Studies of the vesicular monoamine transporter type-2 (VMAT2) and of the vesicular acetylcholine transporter (VAChT) in experimental animals indicate that they are robust markers of presynaptic integrity and are not subject to regulation. We measured dopamine and acetylcholine vesicular transporters to characterize the selectivity of degeneration in HD striatum. Brains were obtained at autopsy from four HD patients and five controls. Autoradiography was used to quantify radioligand binding to VMAT2, VAChT, the dopamine plasmalemmal transporter (DAT), benzodiazepine (BZ) binding sites, and D2-type dopamine receptors. The activity of choline acetyltransferase (ChAT) was determined as an additional marker of cholinergic neurons. Autoradiograms were analyzed by video-assisted densitometry and assessment of atrophy was made from regional structural areas in the coronal projection. Striatal VMAT2, DAT, and VAChT concentrations were unchanged or increased, while D2 and BZ binding and ChAT activity were decreased in HD. After atrophy correction, all striatal binding sites were decreased. However, the decrease in ChAT activity was 3-fold greater than that of VAChT binding. In addition to degeneration of striatal projection neurons, there are losses of extrinsic nigrostriatal projections and of striatal cholinergic interneurons in HD on the basis of vesicular transporter measures. There is also markedly reduced expression of ChAT by surviving cholinergic striatal interneurons.

Adult↗
PubMed2006

Increased levels of pregnenolone and its neuroactive metabolite allopregnanolone in autopsied brain tissue from cirrhotic patients who died in hepatic coma.

It has been suggested that neurosteroids with agonist properties at the central GABA-A receptor are implicated in the pathogenesis of hepatic encephalopathy (HE) in chronic liver disease. In order to address this issue, gas chromatography/mass spectrometry was used to measure the neurosteroids pregnenolone, allopregnanolone, and tetrahydrodeoxycorticosterone (THDOC) in postmortem brain tissue from controls, cirrhotic patients who died without HE, a patient who died in uremic coma, and cirrhotic patients who died in hepatic coma. Exposure of rat cerebral cortical membranes to brain extracts from hepatic coma patients resulted in a 53% (p < 0.001) increase in binding of [3H]muscimol, a GABA-A receptor ligand. Subsequent GC/MS analysis showed that concentrations of the GABA-A receptor agonist neurosteroid allopregnanolone were significantly increased in brain tissue from hepatic coma patients compared to patients without HE or controls (p < 0.001). Brain allopregnanolone concentrations were significantly correlated with the magnitude of induction of [3H]muscimol binding (r2 = 0.82, p < 0.0001). Concentrations of allopregnanolone comparable to those observed in hepatic coma brains are pathophysiologically relevant. Concentrations of the neurosteroid precursor pregnenolone were also increased in brain tissue from hepatic coma patients, while those of a second neurosteroid THDOC were below the levels of detection in all groups. Brain concentrations of benzodiazepine receptor ligands estimated by radioreceptor assay were not significantly increased in cirrhotic patients with or without hepatic coma. These findings suggest that increased levels of allopregnanolone rather than "endogenous benzodiazepines" offer a cogent explanation for the phenomenon of "increased GABAergic tone" previously proposed in HE.

Adult↗
PubMed1999

An investigation on the role of nitric oxide in the modulation of the binding characteristics of various radioligands of GABAA receptors by 5alpha-pregnan-3alpha-ol-20-one in the rat brain regions.

Chronic administration of Nomega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase, diminished the ability of 5alpha-pregnan-3alpha-ol-20-one, a neurosteroid, to potentiate the [3H]muscimol (5 nM) binding in the rat hippocampus but not in the cerebellum or cerebral cortex. This effect of NAME was stereospecific and susceptible to reversal by the pre-treatment of rats with L-arginine. However, chronic administration of L-NAME did not affect the modulation of the [3H]flunitrazepam (2 nM) or [35S]TBPS (4 nM) binding by the neurosteroid in any of the brain regions investigated in this study. These results suggest that nitric oxide may be involved in some of the effects of neurosteroids in hippocampus.

Animals↗
PubMed1996

Allopregnanolone acts as an inhibitory modulator on alpha1- and alpha6-containing GABA-A receptors.

Allopregnanolone, known so far to act as a gamma-aminobutyric acid (GABA) agonist, allosterically decreased the affinity of the GABA agonist muscimol for recombinant alpha1beta2gamma2 and alpha6beta2gamma2 GABA-A receptors. Pregnenolone sulfate, a GABA antagonist, had a similar effect. Both of these neuroactive steroids also reduced the time constant of desensitization (tau) of GABA-induced chloride currents. The effect on desensitization was demonstrated for native receptors of hypothalamic neurons as well as for the recombinant GABA-A receptors. Hence neuroactive steroids may differentially modulate distinct assemblies of GABA-A receptors and thus induce a more subtle modulation of GABAergic synaptic transmission than previously thought possible.

Animals↗
PubMed2000

Abnormal GABAA receptor-mediated currents in dorsal root ganglion neurons isolated from Na-K-2Cl cotransporter null mice.

We have recently disrupted Slc12a2, the gene encoding the secretory Na-K-2Cl cotransporter in mice (NKCC1) (Delpire et al., 1999). Gramicidin perforated-patch and whole-cell recordings were performed to study GABA-induced currents in dorsal root ganglion (DRG) neurons isolated from wild-type and homozygote NKCC1 knock-out mice. In wild-type DRG neurons, strong GABA-evoked inward current was observed at the resting membrane potential, suggesting active accumulation of Cl(-) in these cells. This GABA-induced current was blocked by picrotoxin, a GABA(A) receptor blocker. The strong Cl(-) accumulation that gives rise to depolarizing GABA responses is caused by Na-K-2Cl cotransport because reduction of external Cl(-) or application of bumetanide induced a decrease in [Cl(-)](i), whereas an increase in external K(+) caused an apparent [Cl(-)](i) accumulation. In contrast to control neurons, little or no net current was observed at the resting membrane potential in homozygote NKCC1 mutant DRG neurons. E(GABA) was significantly more negative, demonstrating the absence of Cl(-) accumulation in these cells. Application of bumetanide induced a positive shift of E(GABA), suggesting the presence of an outward Cl(-) transport mechanism. In agreement with an absence of GABA depolarization in DRG neurons, behavioral analysis revealed significant alterations in locomotion and pain perception in the knock-out mouse. Our results clearly demonstrate that the Na-K-2Cl cotransporter is responsible for [Cl(-)](i) accumulation in DRG neurons and that via regulation of intracellular Cl(-), the Na-K-2Cl cotransporter participates in the modulation of GABA neurotransmission and sensory perception.

Animals↗
PubMed2001

Evidence for a role of GABA interneurones in the cortical modulation of midbrain 5-hydroxytryptamine neurones.

Recent electrophysiological studies demonstrate that the ventral medial prefrontal cortex has a powerful inhibitory influence on 5-hydroxytryptamine (5-HT) neurones in the dorsal raphe nucleus. Here we utilised a combination of anatomical and electrophysiological methods to characterise the cellular substrate underlying this effect.Anterograde tracing (Phaseolus vulgaris leucoagglutinin) using electron microscopy demonstrated a pathway from the ventral medial prefrontal cortex that makes neuronal contacts throughout the dorsal raphe nucleus. These contacts were predominantly asymmetrical synapses adjoining GABA immunoreactive dendrites and spines. In vivo extracellular recordings were made in the dorsal raphe nucleus of the anaesthetised rat from a subpopulation of non-5-HT neurones. These neurones were fast-firing, irregular and with short spike width, properties strongly reminiscent of immunochemically identified GABA interneurones in other brain regions. Recordings of classical 5-HT neurones were also included. Electrical stimulation of the ventral medial prefrontal cortex elicited a rapid onset (16 ms latency), orthodromic excitation of the non-5-HT neurones (13/25 neurones). This stimulation also caused a pronounced inhibition of most 5-HT neurones tested, with a longer latency (30 ms), and this was partially blocked by locally applied bicuculline. These data provide the first evidence that the ventral medial prefrontal cortex influences the activity of large numbers of raphe 5-HT neurones by targeting a local network of GABA neurones. This circuitry predicts that physiological and pathological changes in the ventral medial prefrontal cortex will impact on significant parts of the forebrain 5-HT system.

Action Potentials↗
PubMed1996

Evaluation of in vivo interactions in mice between flurazepam and two neuroactive steroids.

The development of neuroactive steroids as anticonvulsant medications may be useful both as a primary treatment and as an adjuvant to other anticonvulsants. They may be limited, however, by sedative and ataxic side effects. In the current study, 3 alpha-hydroxy-5 beta-pregnan-20-one and alfaxalone, two prototypic neuroactive steroids, were shown to potentiate the ability of flurazepam to antagonize electrically precipitated tonic hindlimb extension in mice at doses that by themselves had little antiseizure efficacy. While alfaxalone alone lacked motor incoordinating effects at a dose (18.0 mg/kg) that potentiated the antiseizure efficacy of flurazepam, the same dose of 3 alpha-hydroxy-5 beta-pregnan-20-one possessed both the ability to potentiate flurazepam's anticonvulsant effect and disrupt mouse rotorod performance. The data suggest that allosteric interactions that have been described in vitro between neuroactive steroids and other modulators of the GABAA receptor complex may have relevance for the intact animal. Finally, the data also suggest that neuroactive steroids could be developed as short-lived adjuvant antiseizure medications in certain critical situations (e.g., medication-refractory status epilepticus). However, the motor incoordinating effects resulting from the combination of neuroactive steroids and flurazepam suggest that their usefulness as adjuvant medications in the chronic therapy of seizure disorders may be limited.

Animals↗
PubMed2001

Neuroactive steroids: molecular mechanisms of action and implications for neuropsychopharmacology.

Besides their binding to cognate intracellular receptors gonadal steroids may also act as functional antagonists at the 5-HT3 receptor. A structure-activity relationship for the actions of a variety of steroids at the 5-HT3 receptor was elaborated that differed considerably from that known for GABA(A) receptors. Steroids appear to interact allosterically with ligand-gated ion channels at the receptor membrane interface. The functional antagonism of gonadal steroids at the 5-HT3 receptor may play a role for the development and course of nausea during pregnancy and of psychiatric disorders. Moreover, we could demonstrate that 3alpha-reduced neuroactive steroids concurrently modulate the GABA(A) receptor and regulate gene expression via the progesterone receptor after intracellular oxidation. Animal studies showed that progesterone is converted rapidly into GABAergic neuroactive steroids in vivo. Progesterone reduces locomotor activity in a dose dependent fashion in male Wister rats. Moreover, progesterone and 3alpha,5alpha-tetrahydroprogesterone produce a benzodiazepine-like sleep EEG profile in rats and humans. In addition, there is a dysequilibrium of such 3alpha-reduced neuroactive steroids during major depression which is corrected by successful treatment with antidepressants. Neuroactive steroids may further be involved in the treatment of depression and anxiety with antidepressants in patients during ethanol withdrawal. First studies in patients with panic disorder suggest that neuroactive steroids may also play a pivotal role in human anxiety. The genomic and non-genomic effects of steroids in the brain contribute to the pathophysiology of psychiatric disorders and the mechanisms of action of antidepressants. Neuroactive steroids affect a broad spectrum of behavioral functions through their unique molecular properties and may constitute a yet unexploited class of drugs.

Animals↗