Gamma-aminobutyric Acid Benzodiazepine Research Articles

Efficacy and safety of lemborexant as an alternative drug for patients with insomnia taking gamma-aminobutyric acid-benzodiazepine receptor agonists or suvorexant.

Although gamma-aminobutyric acid-benzodiazepine (GABA-BZ) receptor agonists are used to treat insomnia, their long-term or high-dosage use causes adverse events. Nevertheless, evidence regarding the discontinuation and replacement of GABA-BZ receptor agonists with alternative agents is lacking. Suvorexant (SUX), an existing orexin receptor antagonist, is effective in preventing nocturnal awakening in 70%-75% of patients with insomnia. The novel dual orexin receptor antagonist lemborexant (LEM) has fewer adverse effects than GABA-BZ receptor agonists. Therefore, in this retrospective study, we categorised patients taking GABA-BZ receptor agonists and SUX into LEM-treated (switched) and non-treated (non-switched) groups and compared their outcomes over a 12-week period. The GABA-BZ group (N=59) comprised 34 'switched' and 25 'non-switched' and the SUX group (N=14) comprised 6 'switched' and 8 'non-switched' patients. A mixed model showed a significant diazepam equivalence reduction in patients taking GABA-BZ receptor agonists and improved Athens Insomnia Scale score in those taking SUX. The safety and tolerability of GABA-BZ receptor agonists and SUX were high, and no serious adverse effects were observed after switching to LEM. Lemborexant may be a useful alternative for long-term GABA-BZ receptor agonist users. For SUX, the number of cases (N=6) was insufficient to draw definite conclusions.

Bacopa monniera exerts antiamnesic effect on diazepam-induced anterograde amnesia in mice

As Benzodiazepines are known to produce amnesia by involvement of the GABAergic system, we examined Bacopa monniera, an herb known for memory enhancement for reversal of memory deficits caused by diazepam. The objective of the study was to study the effect of standardized extract of B. monniera on diazepam-induced amnesia in mice using Morris water maze. We used the rota rod test as a screening measure for muscle incoordination followed by the Morris water maze scale to evaluate the effect of B. monniera on amnesia. The index of acquisition and retrieval was recorded with varying doses of Bacopa. The results revealed antiamnesic effects of B. monniera (120 mg kg(-1) oral) on diazepam (1.75 mg kg(-1) intraperitoneal)-induced amnesia. The degree of reversal by Bacopa was significant as it progressively reduced escape latency time when mice treated with diazepam were subjected to acquisition trials. The antiamnesic effects of Bacopa suggest likely a gamma-aminobutyric acid-benzodiazepine pathway possibly affecting long-term potentiation.

ALCOHOL REINFORCEMENT AND NEUROPHARMACOLOGICAL THERAPEUTICS

The pleasant subjective effects produced by alcohol undoubtedly reinforce drinking behaviour. Alcohol positively reinforces or rewards drinking by producing a mild euphoria. Alcohol also has anxiolytic effects that negatively reinforce drinking. The reinforcing effects of alcohol are mediated by several neurochemical systems, with dopamine and serotonin playing major roles in reward and the gamma-aminobutyric acid-benzodiazepine receptor system playing a major role in negative reinforcement. Research from our laboratory suggests that the behavioural effects of alcohol change when blood alcohol levels are changing and that these changes correspond to alterations of specific neurochemical systems. Behavioural activation and reward effects appear to occur as blood alcohol concentrations (BACs) increase. Depressive and aversive effects of alcohol occur during the period when BACs decrease. The observed correlation between behavioural and neuropharmacological changes and alcohol consumption suggest that alcohol produces a unique cascade over time that may provide clues to its long-sought specific mechanisms of action. In alcohol-dependent individuals, chronic exposure to alcohol may alter the function and communication between the liver, brain and other vital organ systems involved in hunger and the maintenance of nutrition. Under such conditions, the importance of alcohol in the diet may be enhanced such that hunger signals in the alcohol-dependent individual motivate the consumption of alcohol. Therefore, hunger for alcohol may provide an additional source of reinforcement. Endogenous opioid mechanisms may be important in this form of alcohol reinforcement.

Neonatal caffeine exposure and seizure susceptibility in adult rats.

Early developmental exposure to caffeine in rats results in changes in brain excitability that persist to adulthood. The mechanism of these alterations is unknown. To identify potential neurotransmitter systems involved, we exposed neonatal rats to caffeine and determined seizure thresholds for chemoconvulsants active at different CNS receptors in the adult animal. Rats were unhandled (NH) or received by gavage (0.05 ml/10 g) either vehicle (water) or caffeine (15-20 mg/kg/day) for postnatal days 2-6. At age 70-90 days, each rat was infused intravenously (i.v.) with picrotoxin (PIC), bicuculline (BIC) [convulsants acting at the gamma-aminobutyric acid/benzodiazepine (GABA/BDZ) receptor], pentylenetetrazol [PTZ, possibly acting at both GABA/BDZ and N-methyl-D-aspartate (NMDA) receptors], caffeine (acting at adenosine receptors), strychnine (STR, acting at glycine receptors), or kainic acid (KA, acting at the NMDA receptor). Seizure thresholds were analyzed as a function of neonatal treatment and sex. Thresholds for caffeine, PTZ, PIC, and KA were increased as a function of neonatal caffeine exposure (p = 0.01, 0.02, 0.02, and 0.005, respectively). The thresholds for BIC and STR were not altered. There were also gender differences in seizure susceptibility. Thresholds for seizures produced by BIC, caffeine, PIC, and STR were higher in females (p = 0.005, 0.005, 0.001, and 0.0001, respectively), but were not different for seizures caused by PTZ. These results suggest that early developmental exposure to caffeine affects later seizure susceptibility. Moreover, some of these effects are gender specific.

Involvement of gamma-aminobutyric acid and N-methyl-D-aspartate receptors in the inhibitory effect of ethanol on pentylenetetrazole-induced c-fos expression in rat brain.

The expression of c-fos mRNA in rat brain was induced by intraperitoneal administration of pentylenetetrazole (PTZ) and picrotoxin, which act on the picrotoxin binding site of the gamma-aminobutyric acid-benzodiazepine (GABA-BZ) receptor complex, by N-methyl-D-aspartate (NMDA) and kainic acid, agonists of different classes of glutamate receptors and by caffeine, an antagonist of adenosine receptors. The actions of PTZ and picrotoxin but not that of NMDA were blocked by ethanol and the NMDA-receptor antagonist, MK-801. Ro 15-4513 partially reversed the inhibitory effect of ethanol on PTZ-induced c-fos mRNA synthesis. Acute ethanol administration blocked the actions of PTZ and NMDA without affecting the response to kainic acid or caffeine. Taken together, these data suggest that ethanol blocks c-fos gene activation by noncompetitive antagonists of the GABA-BZ receptor via actions on both the NMDA and GABA receptors.

Alcohol and the brain: recent advances in biomedical research

Considerable progress has been made in our understanding of the cellular mechanisms of action of alcohol on the brain, particularly in relation to tolerance and dependence. Tolerance is associated with changes in the composition of the gamma-aminobutyric acid-benzodiazepine receptor, making it less sensitive to alcohol. An increased density of excitatory glutamate receptors may underlie certain withdrawal manifestations. Other neuroadaptive mechanisms include an increase in presynaptic calcium influx on depolarization and effects on adenylate cyclase. Alcohol also influences the expression of a proto-oncogene which plays an important role in neural development. Further advances in neurobiology offer the prospect of elucidating the mechanisms of tolerance and brain damage.

Biochemical Characterization of an Isolated and Functionally Reconstituted γ‐Aminobutyric Acid/Benzodiazepine Receptor

We have solubilized, affinity-purified, and functionally reconstituted the gamma-aminobutyric acid/benzodiazepine (GABA/BDZ) receptor from rat brain into natural brain lipid liposomes. The detergent, 3-[(3-cholamidopropyl)-dimethylammonio] 1-propanesulphonate, was employed for the isolation of the receptor in the presence of a whole rat brain lipid extract supplemented with cholesteryl hemisuccinate. The soluble and reconstituted protein showed a homogeneous [3H]flunitrazepam binding population and the allosteric modulation of this binding site by GABA, by the pyrazolopyridine, cartazolate, and by the depressant barbiturate, pentobarbital. The purified GABA/BDZ receptor when incorporated into liposomes has been visualized by electron microscopy and reveals rosette structures, 8-9 nm in diameter, which appear to have a central pore. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis of the reconstituted GABA/BDZ receptor reveals three major protein bands of 41, 52-56, and 59-62 kDa, the latter two of which appears as doublets. Functional receptor reconstitution is demonstrated by the measurement of GABA-stimulated 36Cl- flux into the purified GABA/BDZ receptor incorporated liposomes and its modulation by the BDZs, barbiturates, and pyrazolopyridines.

Etude Electro-Encephalographique De L'Effet D'un Antagoniste Des Benzodiazepines Dans L'Encephalopathie Hepatique

Observing animal models of fulminant hepatic failure lead to the hypothesis of a GABAergic origin of the comatose state in hepatic encephalopathy (HE). The hypothesis of hyperstimulation of gamma-aminobutyric acid-benzodiazepine (GABA-BZ) receptors in HE has been tested with a BZ antagonist (flumazenil, Anexate) on 7 patients suffering from severe HE. The standard EEG has been recorded 30 min before and after slow IV perfusion of 1 mg flumazenil. Although we did not observe a complete EEG normalization, a significant improvement of EEG was observed after only a few minutes in 6 out of the 7 cases studied. Modification of the reactivity parallels clinical improvement of encephalopathy. These effects persist mostly 4 h after perfusion. The results are consistent with the hypothesis of hyperstimulation of GABA-BZ receptors in HE. The positive effect of flumazenil on vigilance level should encourage its use in chronic hepatic encephalopathy.

Solubilisation of the gamma-aminobutyric acid/benzodiazepine receptor from rat cerebellum: optimal preservation of the modulatory responses by natural brain lipids.

We have solubilised the gamma-aminobutyric acid/benzodiazepine (GABA/BDZ) receptor from rat cerebellum using 3-[(3-cholamidopropyl)dimethylammonio] 1-propane sulphonate (CHAPS) in the presence of a natural brain lipid extract and cholesteryl hemisuccinate. The soluble material shows a homogeneous [3H]flunitrazepam ([3H]FNZ) binding population with an equilibrium dissociation constant (KD) of 4.4 +/- 0.2 nM compared to a KD of 2.3 +/- 0.2 nM in cerebellar synaptosomal membranes. The receptor complex in solution retains the characteristic facilitation of [3H]flunitrazepam binding induced by GABA, the pyrazolopyridine cartazolate, and the depressant barbiturate pentobarbital to the same extent as that observed in synaptosomal membranes. Furthermore, these responses are retained both quantitatively and qualitatively when this preparation is stored for 48 h at 4 degrees C. This is contrary to the results obtained with a CHAPS-soluble preparation including asolectin in which these responses are anomalous and extremely labile on storage.

35S]-t-butylbicyclophosphorothionate binding sites are constituents of the gamma-aminobutyric acid benzodiazepine receptor complex

t- Butylbicyclophosphorothionate ( TBPS ), a derivative of potent GABA antagonistic cage convulsants, has recently been introduced ( Squires , R. F., J.E. Casida , M. Richardson, and E. Saederup (1983) Mol. Pharmacol. 13:326-336) as ligand for a GABA-A receptor-linked drug receptor. Using conventionally prepared washed membrane fractions from rat cerebral cortex, we have confirmed that in the presence of 200 mM NaBr [35S] TBPS binds to a high affinity population of binding sites (Kd 26 +/- 5 nM) and that muscimol inhibits [35S] TBPS binding (IC50 0.32 microM) allosterically. In 200 mM NaCl the apparent affinity of [35S] TBPS binding sites is lower (Kd 60 +/- 5 nM), and muscimol has biphasic effects with stimulation at low concentrations of muscimol (EC50 0.023 microM) followed by inhibition at high concentrations (IC50 0.72 microM). Both base line [35S] TBPS binding (in 200 mM NaCl) and muscimol inhibition of [35S] TBPS binding (in 200 mM NaBr) are bidirectionally modulated by the occupancy of benzodiazepine receptors with its ligands. Benzodiazepine receptor agonists, regardless of their structure, enhance and inverse benzodiazepine receptor agonists inhibit base line [35S] TBPS binding and muscimol inhibition of [35S] TBPS binding. Fourteen ligands for benzodiazepine receptors display a similar in vitro profile as benzodiazepine receptor agonists or inverse benzodiazepine receptor agonists on [35S] TBPS binding as their anti- or proconvulsive effects in vivo suggest (Jensen, L. H., E. N. Petersen, and C. Braestrup (1983) Life Sci. 33: 393-399). That [35S] TBPS binding sites are constituents of a GABA benzodiazepine receptor complex is also suggested by a number of membrane pretreatments.(ABSTRACT TRUNCATED AT 250 WORDS)