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PubMed2004

Pharmacology of catamenial epilepsy.

Catamenial epilepsy is a menstrual cycle-related seizure disorder characterized by an increase in seizures at the time of menstruation. Catamenial epilepsy affects up to 70% of women with epilepsy. Catamenial seizures are common among women with focal or generalized epilepsy, which affects an estimated 1 million women in the United States. Presently, there is no specific, FDA-approved drug treatment for catamenial epilepsy. Despite the increased use of wide-ranging antiepileptic and hormonal drugs, catamenial seizures are often refractory to many treatments. Recent studies have provided an improved understanding of the pathophysiology of catamenial epilepsy. Cyclical changes of ovarian hormones estrogens and progesterone are now widely believed to be essential for the genesis of catamenial seizures. Generally, progesterone has antiseizure effects, while estrogens facilitate seizure susceptibility. The progesterone metabolite allopregnanolone has been identified as a key endogenous neurosteroid with powerful antiseizure activity. Allopregnanolone is a potent, positive allosteric modulator of GABA(A) receptors. Progesterone and allopregnanolone exposure and withdrawal affects GABA(A) receptor plasticity. In animal models, withdrawal from chronic progesterone and, consequently, of allopregnanolone levels in brain, has been shown to increase seizure susceptibility. Natural progesterone therapy is proven to be effective in women with epilepsy. Consequently, synthetic neurosteroids that are devoid of hormonal side effects represent a novel class of antiepileptic drugs for women with catamenial epilepsy. Our studies suggest that ganaxolone, a GABA(A) receptor-modulating synthetic neuroactive steroid, is a particularly promising treatment for catamenial epilepsy. Future studies are clearly warranted to determine the molecular pathophysiology and an effective treatment of catamenial epilepsy.

Animals↗
PubMed2002

GABA(A) receptor-modulating neuroactive steroid composition in patients with panic disorder before and during paroxetine treatment.

OBJECTIVE: Previous studies have shown that neuroactive steroids modulate anxiety and stress reactivity. However, no data on the possible role of these gamma-aminobutyric acid(A) (GABA(A)) receptor-modulating neuroactive steroids in patients with anxiety disorders are available. METHOD: The concentrations of 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-THP), 3alpha,5beta-THP, 3beta,5alpha-THP, and their precursors were studied in the plasma of 10 patients with panic disorder and 10 matched healthy comparison subjects. In addition, the effects of paroxetine treatment on neuroactive steroid concentrations were studied in the panic disorder patients over a 24-week period. RESULTS: Unexpectedly, patients with panic disorder had significantly greater concentrations of the positive allosteric modulators 3alpha,5alpha-THP and 3alpha,5beta-THP and significantly lower concentrations of 3beta,5alpha-THP (a functional antagonist for GABA(A) agonistic steroids), which might result in greater GABA(A) receptor-mediated neuronal activity. Paroxetine treatment did not affect neuroactive steroid concentrations, which were highly stable over 24 weeks. CONCLUSIONS: Differences in neuroactive steroid composition in patients with panic disorder were the opposite of those seen in patients with major depression and may reflect counterregulative mechanisms against the occurrence of spontaneous panic attacks.

Adult↗
PubMed1998

Antisense oligonucleotide to GABA(A) receptor gamma2 subunit induces limbic status epilepticus.

Gamma-Aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the brain. A deficiency of GABAergic inhibition mediated via the GABAA receptor complex has for a long time been suspected to be a central factor in epileptogenesis. Status epilepticus is a condition of sustained and prolonged excitation of neuronal circuits, as detected by epileptiform discharges in the electroencephalogram (EEG). Reduction of GABAA receptor-mediated hippocampal inhibition has been implicated in the development of status epilepticus. The present study provides direct evidence of a link between the GABAA receptor and epilepsy. We show that selective inhibition of the expression of the GABAA receptor gamma2 subunit in the rat hippocampus by means of antisense oligonucleotides leads to spontaneous electrographic seizures that evolve into profound limbic status epilepticus, ultimately resulting in severe neurodegenerative changes. Concurrent treatment with diazepam prevents the development of status epilepticus and markedly reduces neuronal cell loss. These findings strongly support the hypothesis that the GABAA receptor is critically involved in the pathogenesis of seizures and status epilepticus.

Animals↗
PubMed2001

Benzodiazepine receptor antagonists for acute and chronic hepatic encephalopathy.

BACKGROUND: The pathogenesis of hepatic encephalopathy is unknown. It has been suggested that liver failure leads to the accumulation of substances that bind to a receptor-complex in the brain resulting in neural inhibition which may progress to coma. Several trials have assessed benzodiazepine receptor antagonists for hepatic encephalopathy, but the results are conflicting. OBJECTIVES: To evaluate the efficacy and safety of benzodiazepine receptor antagonists for patients with acute or chronic hepatic encephalopathy. SEARCH STRATEGY: Eligible trials were identified through The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Controlled Trials Register, MEDLINE, EMBASE, reference lists of relevant articles, authors of trials, and the pharmaceutical company known to produce benzodiazepine receptor antagonists. SELECTION CRITERIA: Randomised trials comparing any benzodiazepine receptor antagonist versus placebo or no intervention for hepatic encephalopathy were included, regardless of language or publication status. DATA COLLECTION AND ANALYSIS: Trial inclusion and data extraction were made independently by two contributors. Depending on the presence or absence of significant heterogeneity (P<0.1) a random or fixed effect model was used. Potential causes for heterogeneity were explored by sensitivity analyses. MAIN RESULTS: Twelve randomised trials with 765 patients were included. Eight trials used a crossover design. All trials were double-blind and assessed flumazenil versus placebo. Data on all outcomes could not be extracted from all trials. The included patients had a favourable prognosis (341/370 (92%) survived in the flumazenil group versus 325/356 (91%) in the placebo group). Flumazenil had no significant effect on full recovery (two trials), survival (nine trials), or on the occurrence of adverse events (five trials). However, flumazenil was associated with a significant effect on improvement of hepatic encephalopathy compared to placebo at the end of treatment (103/346 (30%) versus 23/332 (7 %), risk difference 0.23, 95% confidence interval 0.18 to 0.28, five trials). REVIEWER'S CONCLUSIONS: Flumazenil had no significant effect on recovery or survival from hepatic encephalopathy. However, flumazenil had a significant effect on short-term improvement of hepatic encephalopathy in some patients with chronic liver disease and a highly favourable prognosis. Considering the fluctuating nature of hepatic encephalopathy, future trials should use a parallel design and assess if treatment with flumazenil leads to a sustained improvement or increased recovery and survival. Until this has been demonstrated, flumazenil may be considered for patients with chronic liver disease and hepatic encephalopathy, but cannot be recommended for routine clinical use.

Acute Disease↗
PubMed2004

Benzodiazepine receptor antagonists for hepatic encephalopathy.

BACKGROUND: Hepatic encephalopathy may be associated with accumulation of substances that bind to a receptor-complex in the brain resulting in neural inhibition. Benzodiazepine receptor antagonists may have a beneficial effect on patients with hepatic encephalopathy. OBJECTIVES: To evaluate the beneficial and harmful effects of benzodiazepine receptor antagonists for patients with hepatic encephalopathy. SEARCH STRATEGY: Eligible trials were identified through The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Controlled Trials Register on The Cochrane Library, MEDLINE and EMBASE (last search: January 2004), reference lists of relevant articles, authors of trials, and pharmaceutical companies. SELECTION CRITERIA: Randomised trials comparing any benzodiazepine receptor antagonist versus placebo or no intervention for hepatic encephalopathy. DATA COLLECTION AND ANALYSIS: Two reviewers independently included trials and extracted data. Binary outcomes are reported as risk difference (RD) with 95% confidence intervals (CI) based on a random effects model. Statistical heterogeneity was explored by a chi-squared test with significance set at P < 0.1. The inconsistency across trials was assessed by I(2). Potential sources of heterogeneity were explored through subgroup analyses. MAIN RESULTS: Thirteen randomised trials with 805 patients were included. Eight trials used a crossover design. All trials were double-blind and assessed flumazenil versus placebo. Data on all outcomes could not be extracted from all trials. The included patients had a favourable prognosis (361/390 [93%] survived in the flumazenil group versus 345/376 [92%] in the placebo group). Flumazenil had a significant beneficial effect on improvement of hepatic encephalopathy at the end of treatment (RD 0.28; 95% CI 0.20 to 0.37, eight trials). Flumazenil had no significant effect on recovery (RD 0.13; 95% CI -0.09 to 0.36, two trials) or mortality RD 0.01; 95% CI -0.05 to 0.07, 10 trials). Flumazenil may be associated with adverse events, but trial results were heterogeneous. REVIEWERS' CONCLUSIONS: Flumazenil had a significant beneficial effect on short-term improvement of hepatic encephalopathy in patients with cirrhosis and a highly favourable prognosis. Flumazenil had no significant effect on recovery or survival. Considering the fluctuating nature of hepatic encephalopathy, future trials should use a parallel design and assess if treatment with flumazenil leads to a sustained improvement or increased recovery and survival. Until this has been demonstrated, flumazenil may be considered for patients with chronic liver disease and hepatic encephalopathy, but cannot be recommended for routine clinical use.

Acute Disease↗
PubMed2000

Pharmacokinetics of the peripheral benzodiazepine receptor antagonist, PK 11195, in rats. The effect of dose and gender.

In spite of the extensive use of the peripheral benzodiazepine (BZ) receptor antagonist, PK 11195 (PK), in pharmacological studies, there is a lack of information of its pharmacokinetics in the rat. In this study the pharmacokinetics of PK were determined after bolus intravenous (i.v.) administration in rat. The effects of dose and gender were evaluated in Sprague-Dawley age-matched male and female rats after the injection of PK (5, 10, 20 mg kg(-1)). Plasma was collected at 5-300 min. Levels of PK in plasma and brain were determined by a novel HPLC method. The stability of PK in blood in vitro was determined. PK is stable in rat blood in vitro. The pharmacokinetics of PK are described by a two-compartment model. The half-lives for distribution ( approximately 0.14 h) and elimination ( approximately 5.4 h) are not related to dose. The large volume of distribution (9-24 l kg(-1)) indicates an extensive distribution outside plasma. Total plasma clearance increases with increasing dose (23-42 ml min(-1)kg(-1)). The brain/plasma ratio ( approximately 3) is not related to dose. These finding suggest that the pharmacokinetics of PK are related to dose (5-20 mg kg(-1)) and gender in rat.

Animals↗
PubMed1995

Benzodiazepine (omega) receptor partial agonists and the acquisition of conditioned fear in mice.

It is well established that benzodiazepines can produce anterograde amnesia in humans and interfere with the acquisition of passive avoidance and spatial responses in rodents. However, the extent to which the disruption of learning is a secondary effect of the sedation produced by these drugs has not been clearly established. In order to investigate this question, the effects of several BZ (omega) receptor partial agonists were studied on the acquisition of conditioned fear (passive avoidance learning) in mice. As these drugs have been shown to produce anticonvulsant and anxiolytic-like effects without sedation or depression of motor activity, it was of interest to see whether they could disrupt learning. Clear effects on the acquisition of conditioned fear were produced by imidazenil (0.01-1.0 mg/kg), divaplon (1-60 mg/kg), ZK 91296 (3-60 mg/kg), and Ro 17-1812 (0.1-10 mg/kg). However, bretazenil (0.1-10 mg/kg) did not produce statistically significant effects. Only the high dose of imidazenil (1.0 mg/kg) decreased levels of exploratory behaviour. These results show that BZ (omega) receptor partial agonists without apparent sedative actions can disrupt fear learning, indicating that the effects of this class of drugs on passive avoidance learning can be dissociated from sedation. The reasons for the observed differences between the different compounds studied are unclear at present and may be related to differences in intrinsic activity or receptor subtype selectivity.

Animals↗
PubMed1996

The effects of a benzodiazepine receptor antagonist beta-carboline ZK-93426 on scopolamine-induced impairment on attention, memory and psychomotor skills.

The effects of a single dose of scopolamine alone and in combination with ZK 93426 (a beta-carboline antagonist at the GABAA/BZ receptor complex with weak inverse agonist activity) were tested in two studies. In one study (study 1) the emphasis of enquiry was on different stages of information processing measured by a psychometric battery; in the second study (study 2) performance at different stages of memory and psychomotor abilities was tested and electroencephalogram recordings and video-tracking were also performed. Each study consisted of two parts, part I in which scopolamine (0.5 mg; 1 ml) or placebo were administered subcutaneously, and part II in which scopolamine (0.5 mg; 1 ml) was administered subcutaneously followed by an intravenous injection of ZK 93426 (0.04 mg; 0.04 ml/kg) or placebo. Thirty-six volunteers, who were randomly allocated to receive one of the two treatments (n = 18 per treatment), participated in each part. In study 1 attention was measured by a continuous attention task and a rapid information processing task, vigilance was measured by a visual vigilance task, and working memory and reasoning were evaluated by a logical reasoning task. A visual memory task was also included to measure acquisition and retention. In study 2 acquisition and short term storage and retrieval were measured by a word lists-Buschke restricted reminding procedure, and retention was tested by delayed recall and recognition. Psychomotor performance was assessed by measuring tapping speed (related to gross motoric abilities) and a pegboard task (related to fine motoric abilities). A task to measure working memory, the Pauli test, was also included. In study 1 scopolamine significantly impaired performance in the attentional and vigilance tasks (P < 0.05), but there was no effect in the logical reasoning task main measurements of time and accuracy. In study 2, scopolamine also impaired performance in the psychomotor tasks (P < 0.05) and the Pauli test. ZK 93426 partially antagonised most of the effects of scopolamine on memory and attention, suggesting that an interaction between the GABA-ergic and cholinergic systems is reflected in measurements of both attention and memory. In general a dissociation was found in the effects of scopolamine on memory, i.e. scopolamine impaired performance during all acquisition measurements but left retention unaffected.

Adult↗
PubMedDate not supplied

Contribution of presynaptic dopaminergic receptors to the mechanism of the reactivating effects of blockade of the GABA-benzodiazepine-ionophore complex.

Changes in the reactivating efficiency of blockade of components of the GABA-benzodiazepine-ionophore complex were analyzed in conditions of preliminary activation and inhibition of dopamine autoreceptors using (+)ZRRR and haloperidol respectively. A conditioned passive escape reflex was used, along with amnesia produced by detaining mice in the danger sector of a chamber immediately after imposition of a painful stimulus. Doses of bicuculline (1 mg/kg), picrotoxin (1 mg/kg), and flumazenil (10 mg/kg) given before testing restored performance of the conditioned response without altering the neurochemical background. Reductions and increases in dopaminergic activity during the training period prevented restoration of the conditioned passive escape response by blockade of GABAa and benzodiazepine receptors and chloride channels. It is suggested that the neurochemical mechanisms involved in restoring the damaged memory trace are based on the formation of te optimal balance in the activities of the various components of the GABA-benzodiazepine-ionophore complex and the dopaminergic system.

Animals↗
PubMed2005

Benzodiazepine system is involved in hyperalgesia in rats induced by the exposure to extremely low frequency magnetic fields.

Many reports demonstrate that extremely low frequency magnetic fields (ELF MFs, 60 Hz) may be involved in hyperalgesia. In a previous investigation, we suggested that MFs may produce hyperalgesia and such a response may be regulated by the benzodiazepine system. In order to further confirm this effect of MFs, we used diazepam and/or flumazenil with MFs exposure. When testing the pain threshold of rats using hot plate tests, MFs or diazepam (0.5 microg, i.c.v.; a benzodiazepine receptor agonist) induced hyperalgesic effects with the reduction of latency. These effects were blocked by a pretreatment of flumazenil (1.5 mg/kg, i.p.; a benzodiazepine receptor antagonist). When the rats were exposed simultaneously to MFs and diazepam, the latency tended to decrease without statistical significance. The induction of hyperalgesia by co-exposure to MFs and diazepam was also blocked by flumazenil. However, the pretreatment of GABA receptor antagonists such as bicuculline (0.1 microg, i.c.v.; a GABA(A) antagonist) or phaclofen (10 microg, i.c.v.; a GABA(B) antagonist) did not antagonize the hyperalgesic effect of MFs. These results suggest that the benzodiazepine system may be involved in MFs-induced hyperalgesia.

Animals↗
PubMed2002

Role of GABAA/benzodiazepine receptors containing alpha 1 and alpha 5 subunits in the discriminative stimulus effects of triazolam in squirrel monkeys.

RATIONALE: Conventional benzodiazepines (BZs), clinically used for treatment of anxiety and insomnia, bind to GABA(A) receptors containing alpha(1), alpha(2), alpha(3), or alpha(5) subunits. The role of these different GABA(A) receptor subtypes in mediating the subjective effects of BZs remains largely unknown. OBJECTIVE: The purpose of the present study was to evaluate the role of GABA(A) receptors containing the alpha(1) or alpha(5) subunits in the discriminative stimulus (DS) effects of the conventional BZ agonist triazolam. METHODS: Squirrel monkeys were trained to discriminate triazolam (0.03 mg/kg, i.v.) from vehicle under a fixed-ratio 10 schedule of food reinforcement. RESULTS: The GABA(A)/alpha(1)-preferring agonists zolpidem and zaleplon engendered responses predominantly on the triazolam lever (73-80% drug-lever responding), and the GABA(A)/alpha(1) partial agonist CL 218,872 engendered an average maximum of less than 50% triazolam-lever responding. The GABA(A)/alpha(1)-preferring antagonists beta-carboline-3-carboxylate-t-butyl ester (betaCCT) and 3-(propyloxy)-beta-carboline (3-PBC) blocked the DS effects of triazolam and zolpidem in a surmountable manner. Schild analyses for betaCCT and 3-PBC in combination with triazolam and zolpidem suggest that the interactions between these compounds were competitive in nature and mediated by a common population of receptors, presumably GABA(A)/alpha(1) receptors. In contrast, the GABA(A)/alpha(5)-preferring agonist QH-ii-66 did not engender triazolam-lever responding regardless of dose and did not alter the DS effects of triazolam when administered in combination. CONCLUSIONS: The results are consistent with GABA(A)/alpha(1) receptor involvement in mediating the DS effects of triazolam. In contrast, binding to GABA(A)/alpha(5) receptors may not play a critical role in mediating triazolam's DS effects.

Animals↗
PubMed2002

Selective antagonism of the ataxic effects of zolpidem and triazolam by the GABAA/alpha1-preferring antagonist beta-CCt in squirrel monkeys.

RATIONALE: Delineation of the receptor mechanisms underlying the behavioral effects of benzodiazepines should allow for the development of drugs with improved clinical utility and reduced side effects. OBJECTIVES. The purpose of the present study was to investigate the role of GABAA/alpha1 receptors in the sedative and motor-impairing effects of benzodiazepines. METHODS: Squirrel monkeys were tested with the GABAA/alpha1-preferring agonist zolpidem and the nonselective benzodiazepine agonist triazolam alone and in combination with the GABAA/alpha1-preferring antagonist beta-CCt and the nonselective benzodiazepine antagonist flumazenil. During 30-min experimental sessions, all occurrences of normal behaviors like locomotion, environment- and self-directed behaviors, as well as side effects such as ataxia, rest and procumbent postures were scored. RESULTS: Zolpidem and triazolam produced dose-dependent reductions in locomotion and environment-directed behavior and increased ataxia and procumbent posture. Triazolam, but not zolpidem, also engendered species-typical rest posture at some doses. Flumazenil antagonized all of the behavioral effects of zolpidem and triazolam, whereas beta-CCt antagonized only zolpidem- and triazolam-induced ataxia. CONCLUSIONS: GABAA/alpha1 receptor mechanisms appear to play a key role in the ataxic effects of benzodiazepine agonists in squirrel monkeys, similar to recent results with transgenic mice. In contrast to the findings of these recent studies, GABAA mechanisms other than or in addition to those mediated at the alpha1 subunit may play a more important role in the sedative/hypnotic effects of benzodiazepines in squirrel monkeys.

Animals↗
PubMed2006

An inverse agonist selective for alpha5 subunit-containing GABAA receptors improves encoding and recall but not consolidation in the Morris water maze.

RATIONALE: Compounds selective for the GABAA receptors containing an alpha5 subunit have been reported to enhance performance in the hippocampally mediated delayed-matching-to-position version of the Morris water maze, in which reduction in the time required to find a hidden platform relative to an initial trial is used as an index of learning and memory. OBJECTIVE: In the present study, we have used one such compound, alpha5IA-II, to examine whether these effects occur during the encoding, consolidation or recall phases of this paradigm. METHODS: alpha5IA-II was administered in the absence or presence of the benzodiazepine site antagonist flumazenil, so as to limit its action to periods associated with encoding, consolidation and recall. Drug doses and timings of administrations were defined using occupancy data derived from an in vivo [3H]flumazenil binding assay. Similar experiments were carried out to study the memory-disruptive properties of chlordiazepoxide (CDP). RESULTS: The trial 1 to trial 2 difference was increased when alpha5IA-II was given before either trial 1 or trial 2, indicating an effect on the encoding and recall phases, respectively, of learning and memory. Conversely, alpha5IA-II had no effect on performance when given immediately after trial 1, suggesting that it had no effect on the consolidation phase. In contrast to the facilitation of performance produced by the alpha5-selective inverse agonist alpha5IA-II given during the encoding and recall but not the consolidation phase, the non-selective agonist CDP impaired performance when given during the encoding and recall phases, whilst having no effect on the consolidation phase. CONCLUSIONS: These data further highlight the cognition-enhancing properties of GABAA alpha5-selective inverse agonists and define the functional specificity of these effects in terms of encoding and recall processes in the Morris water maze.

Animals↗
PubMed2000

Flumazenil induces benzodiazepine partial agonist-like effects in BALB/c but not C57BL/6 mice.

RATIONALE: Some anxiety disorders may be treated in a different way than normal anxiety. OBJECTIVE: This study was aimed at investigating the action of the benzodiazepine receptor antagonist flumazenil, compared to that of the benzodiazepine receptor full agonist chlordiazepoxide, in an animal model of generalised anxiety disorder (the BALB/c mouse). METHODS: Flumazenil (0.0001, 0.001, 0. 01, 0.1 and 1 mg/kg) or chlordiazepoxide (5 mg/kg) were administered to BALB/c or C57BL/6 mice subjected to the light/dark test, the elevated plus maze or a passive avoidance step-through paradigm. RESULTS: Chlordiazepoxide and flumazenil (at all doses tested in the elevated plus maze and at the doses of 0.001 and 0.01 mg/kg in the light/dark test) induced a strong anxiolytic effect in BALB/c mice. Flumazenil did not induce anxiolysis in C57BL/6 mice, whatever the behavioral test or the dose used. However, chlordiazepoxide elicited anxiolysis in this strain in both procedures. In the passive avoidance test, chlordiazepoxide was amnesic in both strains but flumazenil had no effect. CONCLUSION: Flumazenil induces partial agonist-like effects in BALB/c and not in C57BL/6 mice, suggesting a possible benzodiazepine receptor set point shift toward the agonistic direction in some pathological anxiety states such as generalised anxiety disorder.

Animals↗
PubMed1996

Assessment of benzodiazepine receptor heterogeneity in vivo: apparent pA2 and pKB analyses from behavioral studies.

The purpose of this review was to establish in vivo apparent pA2 and pKB values for antagonism of the discriminative stimulus effects of benzodiazepine ligands, and to compare these values to those obtained from other behavioral procedures. Articles were chosen from the Medline data base from January 1976 to August 1995. This literature consisted of studies with flumazenil (Ro 15-1788) as the antagonist, as well as other benzodiazepine ligands (beta-carbolines, CGS 9896, CGS 8216). The dose which occasioned 50% of the maximal response (ED50) was obtained from values estimated from the graphs presented in each article. These ED50 values were used to conduct apparent pKB and apparent pA2 analyses. Apparent pA2 values for antagonism of the discriminative stimulus effects of diazepam in rats were the following (antagonist, pA2, slope): flumazenil, 4.7, -1.5; beta-CCE, 4.0, -3.0; beta-CCtB, 5.0, -2.2. The apparent pA2 value for CGS 8216 antagonism of the discriminative stimulus effects of diazepam in rats was 5.74, -2.22 (reported in Shannon and Davis 1984). The mean apparent pA2 value for flumazenil antagonism of the discriminative stimulus effects of diazepam in rhesus monkeys was 6.55, with a mean slope of -1.42. Analysis of baboon data from Ator and Griffiths (1986) revealed apparent pKB values for flumazenil antagonism of the discriminative stimulus effects of lorazepam that were lower than the pKB values for either zopiclone or CL 218,872. Analyses of the pKB data also revealed the following: no effect of route of administration (rat, PO versus IP; baboon, PO versus IM), no effect of pretreatment time (grouped into two categories: 10-20 min and 40-70 min, in rats and non-human primates), and a species effect (pKB values for rats were reliably lower than either non-human primates or pigeons, rhesus monkeys were lower than baboons). The apparent pA2 and pKB values obtained in the present review were similar across behavioral assays, except that, in squirrel monkeys, flumazenil pKB values for antagonism of benzodiazepine-induced decreases in schedule-controlled behavior were lower than pKB values obtained from drug discrimination studies. This review provides apparent pA2 values for antagonism of the discriminative stimulus effects of benzodiazepine ligands and provides evidence from pKB analyses consistent with functional heterogeneity of benzodiazepine receptors in vivo.

Animals↗
PubMed1997

Comparison of abstinence syndromes precipitated by flumazenil and PK 11195 in female diazepam-dependent rats.

The abilities of the central (CBR) and the peripheral (PBR) benzodiazepine receptor antagonists, flumazenil (FLU) and PK 11195 (PK), to precipitate an abstinence syndrome in diazepam (DZ)-dependent rats have been evaluated. Female rats were exposed for 5 weeks to DZ slowly released from SC implanted silastic capsules (90 mg/capsule per week) and thereafter they were challenged in weekly intervals with IV injections of FLU (10, 20, 40 mg/kg) or PK (5, 10, 20 mg/kg), respectively. The maximum abstinence scores tended to increase with the dose of FLU but not with the dose of PK. Although FLU and PK precipitated some common abstinence signs, there were marked differences between these antagonists. FLU evoked dose-related tonic-clonic and clonic convulsions (five out of six rats), whereas PK (10 mg/kg) induced convulsions in only one rat (out of five); tachypnea tended to increase with the dose of both FLU and PK; twitches and jerks, backing and writhing had a significant regression on the dose of FLU; rearing tended to decrease with the dose of PK whereas FLU-evoked head bobbing and PK-evoked twitches and jerks had inverse U-shaped dose-response curves. In comparison to FLU, similar doses of PK (10 and 20 mg/kg) induced a lower precipitated abstinence score (P < 0.05) and a less intense tachypnea (P < 0.05). The data indicate that the chronic continuous exposure to DZ (and/or its active metabolites) affects both CBR and PBR in the rat; however, the abstinence syndromes produced by the CBR and PBR antagonists, FLU and PK, differ in overall intensities and in the diversity of evoked abstinence signs.

Animals↗
PubMed1997

Anxiolytic and anticonvulsant activity of a synthetic neuroactive steroid Co 3-0593.

Endogeneously occurring neuroactive steroids, metabolites of progesterone and deoxycorticosterone, have been shown previously to interact with the GABAA receptor with great specificity in vitro and to have anticonvulsant, anxiolytic and sedative activity in vivo. However, these endogenously occurring steroids are not useful as therapeutic agents due to their potential metabolism to hormonally active steroids and their poor oral bioavailability. In an attempt to develop therapeutic agents which would maintain the pharmacological profiles of endogeneous neuroactive steroids but with increased oral bioavailability and reduced metabolic liability, we explored simple substitutions at the 3 beta-position of the endogenous neuroactive steroid, 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha, 5 alpha-P). This report describes part of the in vitro and in vivo pharmacological profile of a 3 beta-substituted analog, 3 beta-ethenyl-3 alpha-hydroxy-5 alpha-pregnan-20-one (Co 3-0593). The compound exhibited anticonvulsant activity against pentylenetrazol-induced seizures in mice and rats (ED50 = 5.6 and 11.5 mg/kg, i.p., respectively). Co 3-0593 showed robust anxiolytic effects, comparable to benzodiazepines in the Geller-Seifter test after both SC and oral administration. Furthermore, the anxiolytic activity was maintained after chronic administration suggesting an absence of tolerance. The compound did not affect the acquisition of a learned response at both anticonvulsant and anxiolytic doses. However, at higher doses the compound showed rotorod deficit which was further enhanced by ethanol. In summary, 3 beta-ethenyl-substituted 3 alpha, 5 alpha-P appeared to maintain the pharmacological activities of the endogenous neuroactive steroid with apparent oral activity.

Animals↗
PubMed1998

Mg2+ reduces ACTH secretion and enhances spindle power without changing delta power during sleep in men -- possible therapeutic implications.

Disturbances of Mg2+ metabolism have been reported in association with affective disorders, seizures in eclampsia, and alcohol withdrawal. Mg2+ has been reported to have N-methyl-D-aspartate (NMDA)-antagonistic and gamma-aminobutyric acid (GABA)-agonistic properties and modulation of GABA(A)- and NMDA-dependent systems is involved in pharmacological treatment of affective disorders and seizures. We studied the effect of Mg2+ on sleep electroencephalogram (EEG) and nocturnal hormonal secretion in men. Ten normal controls were given MgSO4 (3 g MgSO4 between 2030 hours and 2100 hours, followed by 0.5 g MgSO4 per hour until 0700 hours) or placebo i.v. according to a randomized schedule. The sleep EEG was recorded from 2300 hours to 0700 hours. Blood samples were taken from 2000 hours to 0700 hours for analysis of plasma corticotropin (ACTH), cortisol, growth hormone, prolactin and melatonin. The sleep-EEG power within the spindle frequency range (11.0-12.9 Hz) showed a significant increase in the third sleep cycle, but delta power was unchanged throughout the night. ACTH concentration was suppressed between 2200 hours and 0700 hours. No changes in cortisol, growth hormone prolactin or melatonin release were found. The findings are consistent with the assumption that Mg2+ has GABA(A)-agonistic or NMDA-antagonistic effects on sleep and nocturnal hormonal secretion and hence may be useful in controlling depressive symptoms and seizures.

Adrenocorticotropic Hormone↗