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PubMed1981

The effects of acute administration of diazepam on the binding of [3H]-diazepam and [3H]-gaba to rat cortical membranes.

Specific [3H]-diazepam binding and [3H]-GABA binding were measured in cortical membranes of untreated rats and rats which had been administered unlabeled diazepam (5.0 mg/kg, IP) thirty minutes prior to sacrifice. Washed and unwashed membranes from control animals showed identical levels of [3H]-diazepam binding. Unwashed membranes of diazepam-treated animals showed consistently and significantly lower binding of [3H]-diazepam than membranes derived from control animals and treated similarly. [3H]-GABA was almost non-existent in unwashed membranes of either group of animals. The binding capability of membranes of treated animals for [3H]-diazepam returned to control levels upon washing with buffer prior to the binding assay. The specific binding of [3H]-GABA in membranes derived from either group of animals also improved after the buffer washes. However, no difference could be detected in [3H]-GABA binding between control and diazepam-treated animals. The failure of diazepam to modulate [3H]-GABA binding in unwashed membranes and the participation of an endogenous inhibitory material repressing [3H]-GABA binding are discussed.

Animals↗
PubMed1995

Daily variations in GABA receptor function in Syrian hamster cerebral cortex.

The existence of diurnal changes in postsynaptic expression of gamma-aminobutyric acid (GABA) type A receptors was assessed in cerebral cortex of Syrian hamsters by measuring [3H]GABA binding and the influx of 36Cl- in synaptoneurosomes. A diurnal variation in dissociation constant of [3H]GABA binding to cerebral cortex membranes, and the absence of diurnal differences in maximal number of sites, were found. When the nycthemeral changes in muscimol-stimulated 36Cl- uptake by cortical synaptoneurosomes were assessed, a maximum occurred late at night (i.e. 0400 h). At 1600 h, micromolar concentrations of flunitrazepam potentiated significantly the influx of chloride induced by muscimol, while at 0400 h flunitrazepam did not exert any significant effect on 36Cl- uptake. The results indicate that postsynaptic type A GABAergic activity peaked at nocturnal hours in the cerebral cortex of Syrian hamsters.

Animals↗
PubMed2006

Effects of peripheral-type benzodiazepine receptor ligands on Ehrlich tumor cell proliferation.

Peripheral-type benzodiazepine receptors have been found throughout the body, and particularly, in high numbers, in neoplastic tissues such as the ovary, liver, colon, breast, prostate and brain cancer. Peripheral-type benzodiazepine receptor expression has been associated with tumor malignity, and its subcellular localization is important to define its function in tumor cells. We investigated the presence of peripheral-type benzodiazepine receptors in Ehrlich tumor cells, and the in vitro effects of peripheral-type benzodiazepine receptors ligands on tumor cell proliferation. Our results demonstrate the presence of peripheral-type benzodiazepine receptor in the nucleus of Ehrlich tumor cells (85.53+/-12.60%). They also show that diazepam and Ro5-4864 (peripheral-type benzodiazepine receptor agonists) but not clonazepam (a molecule with low affinity for the peripheral-type benzodiazepine receptor) decreased the percentage of tumor cells in G0-G1 phases and increased that of cells in S-G2-M phases. The effects of those agonists were prevented by PK11195 (a peripheral-type benzodiazepine receptor antagonist) that did not produce effects by itself. Altogether, these data suggest that the presence of peripheral-type benzodiazepine receptor within the nucleus of Ehrlich tumor cells is associated with tumor malignity and proliferation capacity.

Animals↗
PubMed1998

Characterization of chloride efflux from GT1-7 neurons: lack of effect of ethanol on GABAA response.

The purpose of this study of GT1-7 neurons was to partially characterize basal Cl- transport and GABAA mediated Cl- efflux and to test the effect of ethanol on a GABAA receptor that lacks a gamma subunit. We measured GABAA function and Cl- transport with 36Cl-. Our results show that basal 36Cl- efflux varied with temperature at 4 degrees C, 23 degrees C, and 37 degrees C. At 23 degrees C, DIDS, an inhibitor of anion exchange, reduced basal 36Cl- efflux maximally by 79.6% with an IC50 of 42.1 microM, whereas bumetanide, an inhibitor of (Na-K-Cl) cotransport, had no effect on basal 36Cl- efflux at concentrations up to 150 microM. At 4 degrees C, muscimol, a GABAA receptor agonist, stimulated 36Cl- efflux with an EC50 of 1.47 microM. Bicuculline, a GABAA receptor antagonist, completely reversed the effect of 20 microM muscimol with an IC50 of 6.08 microM. Ethanol, at concentrations up to 87 mM (0.4% (w/v)), had no effect on muscimol-induced 36Cl- efflux at 4 degrees C or at 32 degrees C. Our results indicate that stimulation of GABAA receptors causes an efflux of Cl- from GT1-7 neurons. This finding is consistent with the concept that stimulation of GABAA receptors produces depolarization of the plasma membrane, increase in cytosolic [Ca2+], and GnRH release. Our results represent the first description of chloride transport in GT1-7 neurons and suggest the presence of a Cl- exchange, but not (Na-K-Cl), transporter mechanism. Furthermore, the lack of an effect of ethanol observed in this study is consistent with the idea that a gamma 2L subunit may be necessary for the effects of low concentrations of ethanol at GABAA receptors.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2001

Involvement of benzodiazepine binding sites in an antiaggressive effect by 5-HT(1A) receptor activation in isolated mice.

The effect of the benzodiazepine receptor antagonist flumazenil was examined on an antiaggressive effect of (S)-5-[3-[(1,4-benzodioxan-2-ylmethyl)amino]propoxy]-1,3- benzodioxole HCl (MKC-242), a 5-HT(1A) receptor agonist. MKC-242 (0.1-1.0 mg/kg, p.o.) selectively reduced isolation-induced aggressive behavior in a dose-dependent manner. Flumazenil (10 mg/kg, i.p.) antagonized the antiaggressive effects of MKC-242 and diazepam, although it alone did not affect the behaviors of isolated mice. These findings suggest that a gamma-aminobutyric acid(A) (GABA(A)) receptor system is involved in the antiaggressive effect by 5-HT(1A) receptor activation.

Aggression↗
PubMed2003

Effects of propofol on GABAA channel conductance in rat-cultured hippocampal neurons.

Channels were activated, in ripped-off patches from rat-cultured hippocampal neurons, by propofol alone, propofol plus 0.5 microM GABA (gamma-aminobutyric acid) or GABA alone. The propofol-activated currents were chloride-selective, showed outward-rectification and were enhanced by 1 microM diazepam. The maximum propofol-activated channel conductance increased with propofol concentration from less than 15 pS (10 microM) to about 60 pS (500 microM) but decreased to 40 pS in 1 mM propofol. Fitting the data from 10 to 500 microM propofol with a Hill-type equation gave a maximum conductance of 64 pS, an EC50 value of 32 microM and a Hill coefficient of 1.1. Addition of 0.5 microM GABA shifted the propofol EC50 value to 10 microM and increased the maximum channel conductance to about 100 pS. The Hill coefficient was 0.8. The maximum channel conductance did not increase further when 1 microM diazepam was added together with a saturating propofol concentration and GABA. The results are compared to effects other drugs have on GABAA channels conductance.

Anesthetics, Intravenous↗
PubMed1998

Stereoselective actions of halothane at GABA(A) receptors.

Isoflurane anesthesia exhibits stereoselectivity, and a corresponding stereoselectivity ((+)->(-)-isomer) has been reported at GABA(A) receptors in vitro. The objective of the present study was to determine if the positive modulatory actions of halothane at GABA(A) receptors exhibited a similar stereoselectivity. Both (R)- and (S)-halothane ((+)- and (-)- isomers, respectively) enhanced [3H]flunitrazepam binding to brain membranes in a concentration dependent manner without a significant difference in either potency (EC50) or efficacy (Emax). While both (R)- and (S)-halothane enhanced [3H]muscimol binding, the potency of the (+)-isomer was slightly greater than the corresponding (-)-isomer (0.91 +/- 0.17 versus 1.45 +/- 0.04% atmospheres, respectively (P < 0.02)). Thus, subtle structural differences between inhalational anesthetics can have a significant impact on the degree of stereoselectivity at the receptor level and may provide insights for the development of more specific drugs.

Anesthetics, Inhalation↗
PubMed1997

Size-exclusion chromatographic reconstitution of the bovine brain benzodiazepine receptor. Effects of lipid environment on the binding characteristics.

The benzodiazepine receptor from calf brain was solubilized with sodium deoxycholate (2 mg/ml) in the presence of 0.5 M KCl and protease inhibitors, and bound flunitrazepam with an equilibrium dissociation constant (Kd) of 2.7 +/- 1.2 nM and with 0.40 +/- 0.04 pmol binding sites per mg protein (Bmax). Up to 60% of the benzodiazepine binding sites (average 25%) could be reconstituted in lipid vesicles, upon size-exclusion chromatography of protein-detergent-lipid mixtures on Sephadex G-50 Medium for detergent depletion. The flunitrazepam affinity for the reconstituted receptor varied with the lipid composition (Kd 1.4-4 nM). Freezing and thawing increased the size of the small proteoliposomes obtained by chromatographic reconstitution and, on the average, doubled the number of operative flunitrazepam binding sites. When the proteoliposomes were stored at -20 degrees C or -80 degrees C or in lyophilized state, the receptor retained its benzodiazepine binding affinity and Bmax over a period of 2 months.

Animals↗
PubMed1999

GABA(B) receptor activation protects GABA(A) receptor from cyclic AMP-dependent down-regulation in rat cerebellar granule cells.

Interaction between GABAA and GABA(B) receptors was studied in rat cerebellar granule cells in culture, by the whole-cell patch-clamp approach. Our data show that the GABA(B) agonist (-)baclofen is not able, per se, to significantly change the muscimol-activated chloride current. However, (-)baclofen dose-dependently prevents the reduction of GABA(A) receptor function by forskolin, an activator of adenylate cyclase. The effect of baclofen is mediated by a pertussis toxin-sensitive G protein. In fact, in cells treated with pertussis toxin, baclofen and forskolin, the toxin is able to block baclofen action, allowing forskolin to act fully. The protective effect by GABA(B) receptor activation under these circumstances is most probably related to the prevention of cyclic AMP increases after forskolin treatment. In fact, in these neurons cyclic AMP and protein kinase A activation result in a down-regulation of GABA(A) receptor function. On the whole, the data indicate the presence of complex modulation of GABA(A) receptors by GABA(B) receptor types in cerebellum granule cells.

Adenylate Cyclase Toxin↗
PubMed1999

Review of the clinical pharmacology and use of the benzodiazepines.

Benzodiazepines are commonly used in the perioperative period for the anxiolytic and amnestic effects they provide. The purpose of this article is to provide an understanding of the clinical pharmacology and mechanism of action for these agents, as well as the knowledge needed for the safe administration of benzodiazepines. The benzodiazepines most commonly used in the perioperative period are presented along with important facts and information regarding their use. The effected organ systems and drug interactions are also presented. Discussion of the benzodiazepine reversal agent, flumazenil, is included, followed by a discussion of nursing interventions.

Anti-Anxiety Agents↗
PubMed2002

Synthesis and biological evaluation of 7,8,9,10-tetrahydroimidazo[1,2-c]pyrido[3,4-e]pyrimdin-5(6H)-ones as functionally selective ligands of the benzodiazepine receptor site on the GABA(A) receptor.

Benzodiazepines are allosteric modulators of the GABA(A) receptor. The traditionally prescribed benzodiazepines are nonselective and suffer from numerous side effects. Upon the identification of receptor subtypes, we set out to discover selective agents with the anticipation that these agents would have superior therapeutic potential. Herein, we describe the synthesis and biological evaluation of substituted 7,8,9,10-tetrahydroimidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-ones and disclose that these compounds exhibit functional selectivity at the benzodiazepine receptor of GABA(A) receptor subtypes. The alpha(2)/alpha(3)-selective partial agonist 42 exhibited potent in vivo activity.

Animals↗
PubMed1995

The inhibitory effect of beta-endorphin on LH release in ovariectomized rats does not involve the preoptic GABAergic system.

In rats, beta-endorphin (beta-END) and gamma-aminobutyric acid (GABA) suppress LH secretion by hypothalamic mechanisms involving the preoptic area (POA). Systemic injection of naloxone (NAL) increases LH secretion in male rats, an effect which can be prevented by coadministration of GABA agonists. Application of NAL into the POA of ovariectomized (ovx), progesterone substituted sheep modulates preoptic GABA release. These findings have been interpreted such that the endogenous opioids act via the preoptic GABAergic system to regulate LH release. To evaluate this hypothesis we implanted ovx rats with push pull cannula into the POA and measured GABA secretion prior to and during the preoptic application of either NAL or beta-END. Blood samples were collected to assess the effects of the drugs on LH secretion. In addition, ovx rats were substituted with estradiol (E2) to induce a negative feedback effect on LH release. Intrapreoptic application of beta-END caused a rapid decline of LH release in ovx rats which was completely reversible after termination of beta-END perfusion. Though LH levels were clearly suppressed, no change of GABA release in the POA was observed. During preoptic NAL perfusion both LH secretion and GABA release remained unaffected. Likewise, during beta-END perfusion into the POA of E2 treated rats neither LH nor GABA secretion changed. In contrast, NAL perfusion rapidly increased LH release but again this action of the opioidergic drug was not accompanied by alterations of GABA release. We conclude from these data: 1) Intrapreoptically applied beta-END inhibits LH release only in the absence of steroids. In turn, blockade of opioid receptors is effective only in the presence of steroids. Both findings indicate that in the POA opioidergic activity is low in ovx rats, but high during negative feedback of E2. 2) No changes of GABA secretion were observed during manipulations of the opioidergic tonus in the POA suggesting that both beta-END and GABA do not interact to regulate LH release. Thus, beta-END may directly inhibit the activity of GnRH neurons located in the POA or acts via a neurotransmitter other than GABA.

Animals↗
PubMed2004

Low-dose diazepam primes motivation for alcohol and alcohol-related semantic networks in problem drinkers.

Considerable research with animals indicates that the GABA-benzodiazepine (BZ) system plays a key role in alcohol reinforcement. However, only limited research appears to have assessed this issue directly in humans. The present study investigated whether low-dose diazepam would cross-prime motivation for alcohol in problem drinkers. Twelve male problem drinkers (Alcohol Dependence Scale; ADS score > or =9) received oral diazepam (5 mg) and placebo, in a counterbalanced manner on separate sessions. There were three measures of primed motivation for alcohol: self-reported desire for alcohol, consumption of placebo beer in an ostensible taste test procedure, and automatically executed vocal reading responses to Alcohol versus Neutral words on a computer-based task. Diazepam significantly increased beer consumption, and produced a marginally significant increase in reported desire for alcohol. On the reading task, diazepam significantly decreased response latency to Alcohol words relative to Neutral words. Latency to Alcohol words correlated significantly with beer consumption under the drug. Moreover, response latency to Alcohol words under the drug also predicted ADS scores. Thus, severity of dependence was directly linked with vulnerability to a BZ priming effect on motivation for alcohol. These findings provide direct evidence that the GABA-BZ system plays an important role in alcohol reinforcement in problem drinkers.

Administration, Oral↗
PubMed2005

A study of the effects of lorazepam and dextromethorphan on the response to cortical 1 Hz repetitive transcranial magnetic stimulation.

We studied the effects of lorazepam and dextromethorphan on the responses to 1 Hz repetitive transcranial magnetic stimulation applied to the left human motor cortex. Lorazepam, dextromethorphan or placebo was administered to 45 normal controls in a double-blind fashion 2.5 h before the repetitive transcranial magnetic stimulation procedure. Motor cortical excitability was measured with single transcranial magnetic stimulation pulses before and after 15 min of 1 Hz repetitive transcranial magnetic stimulation applied at supra-threshold intensity. 1 Hz repetitive transcranial magnetic stimulation resulted in a decrease in motor cortical excitability in the placebo group but not in the groups taking lorazepam or dextromethorphan. These results suggest that cortical responses to 1 Hz repetitive transcranial magnetic stimulation are dependent on activity at both gamma-aminobutyric acid and N-methyl-D-asparate receptor systems.

Adult↗
PubMed1999

Response kinetics and pharmacological properties of heteromeric receptors formed by coassembly of GABA rho- and gamma 2-subunits.

Two of the gamma-aminobutyric acid (GABA) receptors, GABAA and GABAC, are ligand-gated chloride channels expressed by neurons in the retina and throughout the central nervous system. The different subunit composition of these two classes of GABA receptor result in very different physiological and pharmacological properties. Although little is known at the molecular level as to the subunit composition of any native GABA receptor, it is thought that GABAC receptors are homomeric assemblies of rho-subunits. However, we found that the kinetic and pharmacological properties of homomeric receptors formed by each of the rho-subunits cloned from perch retina did not resemble those of the GABAC receptors on perch bipolar cells. Because both GABAA and GABAC receptors are present on retinal bipolar cells, we attempted to determine whether subunits of these two receptor classes are capable of interacting with each other. We report here that, when coexpressed in Xenopus oocytes, heteromeric (rho 1B gamma 2) receptors formed by coassembly of the rho 1B-subunit with the gamma 2-subunit of the GABAA receptor displayed response properties very similar to those obtained with current recordings from bipolar cells. In addition to being unresponsive to bicuculline and diazepam, the time-constant of deactivation, and the sensitivities to GABA, picrotoxin and zinc closely approximated the values obtained from the native GABAC receptors on bipolar cells. These results provide the first direct evidence of interaction between GABA rho and GABAA receptor subunits. It seems highly likely that coassembly of GABAA and rho-subunits contributes to the molecular organization of GABAC receptors in the retina and perhaps throughout the nervous system.

Animals↗
PubMed2003

Flumazenil attenuates development of tolerance to diazepam after chronic treatment of mice with either isoflurane or diazepam.

UNLABELLED: In an effort to clarify the mechanism of action of isoflurane, we studied the effect of flumazenil on mice chronically treated with isoflurane or diazepam. Mice were pretreated with diazepam, isoflurane, or saline, with and without flumazenil. After 2 wk, responses to isoflurane and diazepam were assessed, and central benzodiazepine receptor (CBR) binding characteristics were assayed. Mice pretreated with isoflurane failed the horizontal wire test at a larger isoflurane concentration (0.5%) compared with saline-pretreated mice (0.4%) (P < 0.05). These differences did not occur when flumazenil was added to the pretreatment. After the administration of diazepam, 20% of diazepam- and 11% of isoflurane-pretreated mice failed the horizontal wire test, versus 50% and 44% when flumazenil was added to either drug (P < 0.002) and 80% and 100% in the saline and saline plus flumazenil-treated mice. The increased CBR density due to flumazenil was attenuated by the coadministration of isoflurane or diazepam. Flumazenil attenuated the development of tolerance to diazepam after chronic treatment with diazepam or isoflurane and attenuated the development of tolerance to isoflurane. Isoflurane, like diazepam, attenuated the effect of flumazenil on CBR ligand binding. These findings suggest that isoflurane shares a mechanism of action with diazepam, probably via the gamma-aminobutyric acid system, most probably the CBR. IMPLICATIONS: Flumazenil attenuates the development of tolerance to isoflurane and diazepam after chronic isoflurane pretreatment. Isoflurane, like diazepam, attenuates the increase in central benzodiazepine receptor (CBR) density caused by flumazenil. These findings suggest that isoflurane and diazepam share a mechanism of action, most probably via the gamma-aminobutyric acid system and the CBR.

Anesthetics, Inhalation↗
PubMed1995

GABA neurotransmission in the hypothalamus: developmental reversal from Ca2+ elevating to depressing.

GABA is the primary inhibitory transmitter of the adult hypothalamus, synthesized by many neurons and found in 50% of the presynaptic boutons. GABA causes a decrease in Ca2+ in mature hypothalamic neurons in vitro by depressing cellular activity through opening Cl- channels. Despite the early expression of GABAA receptors in the embryonic hypothalamus (E15), the cellular function of GABA in the developing hypothalamus has received little attention. In the present study the role of GABA in modulating intracellular Ca2+ in developing hypothalamic neurons was studied with fura-2 digital imaging. GABA (0.5-500 microM) applied to embryonic hypothalamic neurons elicited a dramatic and rapid increase in intracellular Ca2+ This Ca2+ rise could be completely blocked by the GABAA antagonist bicuculline (20 microM) and persisted in the presence of tetrodotoxin (1 microM). The Ca2+ elevation induced by GABA was greater than that of equimolar concentrations of the excitatory transmitter glutamate in early development. The number of E15 neurons that responded to GABA with a Ca2+ rise increased during the first few days of culture, reaching 78% after 4 d in vitro. The Ca2+ rise was 87% blocked by cadmium (100 microM) and 85% blocked by nimodipine (1 microM), indicating that the mechanism of Ca2+ increase was primarily via L-type voltage operated Ca2+ channels. Addition of bicuculline to synaptically coupled cultures caused a significant decrease in Ca2+ 4-10 d after culturing, indicating hypothalamic neurons were secreting GABA at an early age of development, and that sufficient GABA was released to elicit an increase in Ca2+. This effect was seen even after blocking all glutamatergic activity with glutamate receptor antagonists. In contrast, GABA elicited no Ca2+ rise in older neurons (> 18 d in vitro), and the action of bicuculline reversed and caused a large increase in Ca2+ in spontaneously active neurons. Similar findings were obtained in cultures enriched in GABAergic neurons from the suprachiasmatic nucleus. To determine if the Ca2+ stimulating role of GABA on developing neurons was restricted to the hypothalamus and a few other regions, or whether it might exist throughout the brain, we examined the Ca2+ responses in cultured olfactory bulb, cortex, medulla, striatum, thalamus, hippocampus, and colliculus. The majority (75%) of developing neurons from each region showed a Ca2+ rise in response to GABA. Together these data suggest that GABA elevates Ca2+ in developing, but not mature, neurons from the hypothalamus and all other brain regions examined.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗