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PubMed1999

Modulation of bistratified cell IPSPs and basket cell IPSPs by pentobarbitone sodium, diazepam and Zn2+: dual recordings in slices of adult rat hippocampus.

Simultaneous intracellular recordings from presynaptic Stratum pyramidale interneurons and postsynaptic pyramidal cells in adult rat hippocampal slices were performed to investigate the strength of the modulation of single-axon inhibitory postsynaptic potentials (IPSPs) by the GABAA receptor modulators pentobarbitone, diazepam and zinc. The processing of biocytin-filled interneurons for light microscopy revealed that these single-axon IPSPs were generated by basket cells (n = 33), bistratified cells (n = 18) and axo-axonic cells (n = 2). The IPSPs generated by these three groups of interneurons had amplitudes and widths at half amplitude with similar ranges, but when bistratified cell IPSPs were compared with basket cell IPSPs with similar half widths their rise times were slower. Pentobarbitone sodium (250 microM) powerfully enhanced 13 tested IPSPs generated by all three cell types. Amplitudes were enhanced by 82 +/- 56%, 10-90% rise times by 150 +/- 101% and the widths at half amplitude by 71 +/- 29%. Diazepam (1-2 microM) also increased all IPSPs tested, although the changes were more moderate in basket cell IPSPs (amplitudes increased by 19 +/- 11%, n = 8) than in bistratified cell IPSPs (amplitudes increased by 66 +/- 48%, n = 5). Basket cell IPSP 10-90% rise times and widths at half amplitude were not significantly increased. Bistratified cell IPSP 10-90% rise times were increased by 44 +/- 24% and the widths at half amplitude by 32 +/- 35%. The one tested IPSP generated by an axo-axonic cell was also diazepam-sensitive. Zinc, 250 microM, decreased four out of 10 IPSPs generated by basket cells and four out of five IPSPs generated by bistratified cells. The one tested axo-axonic cell IPSP was zinc-insensitive. These data suggest that IPSPs generated in CA1 pyramidal cells by basket and bistratified cells display different pharmacologies and may be mediated by different receptors or receptor combinations.

Age Factors↗
PubMed1996

Cannabinoid modulation of rat pup ultrasonic vocalizations.

The present study investigated the effects of the cannabinoid receptor agonist CP 55,940 (1-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl) phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol) and the cannabinoid receptor antagonist SR 141716A (N-(piperidin-l-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1 H-pyrazole-3-carboxamide hydrochloride) on ultrasonic vocalizations, body temperature and activity in 11-13-day-old rat pups. Testing occurred in a 5-min session 30 min following drug administration. CP 55,940 produced a dose-dependent decrease in ultrasonic vocalizations, with a 1000-micrograms/kg dose causing an almost complete inhibition of calls. Doses of 100 and 1000 micrograms/kg of CP 55,940, but not 10 micrograms/kg, caused significant hypothermia in the pups and the 1000 micrograms/kg dose also inhibited activity. The cannabinoid receptor antagonist SR 141716A (20 mg/kg) reversed the effects of 1000 micrograms/kg CP 55,940 on ultrasonic vocalizations and body temperature, but the benzodiazepine receptor antagonist flumazenil (20 mg/kg), the dopamine D1 receptor antagonist SCH 23390 (0.5 mg/kg) and the opioid receptor antagonist naloxone (1 mg/kg) did not. When administered alone, SR 141716A (20 mg/kg) increased pup ultrasonic vocalizations without affecting body temperature or activity. These results indicate that cannabinoids modulate ultrasonic vocalization production in rat pups in a manner that is independent of hypothermia. The increase in ultrasonic vocalizations produced by SR 141716A is one of the first reported behavioural effects of this drug and suggests that the endogenous cannabinoid ligand anandamide may be involved in the regulation of ultrasonic vocalizations.

Analysis of Variance↗
PubMed2003

Characterization of wild-type (R100R) and mutated (Q100Q) GABAA alpha 6 subunit in Sardinian alcohol non-preferring rats (sNP).

Sardinian alcohol non-preferring (sNP) rats, selected for their low ethanol preference and consumption, carry a point mutation (R100Q) in the gene coding for GABA(A) receptor alpha(6) subunit, which becomes more sensitive to diazepam-evoked GABA currents. We performed binding studies in the cerebellum of normal (RR) and mutated (QQ) sNP rats using [3H]Ro 15-4513, an inverse agonist for the benzodiazepine site which binds both diazepam insensitive and diazepam sensitive sites. Saturation curves performed on cerebellar membrane from genotyped rats indicated an higher affinity of [3H]Ro 15-4513 for GABA(A) receptors in QQ with respect to RR rats (K(d) values 4.0+/-0.67 and 6.24+/-0.95 nM, respectively), with similar B(max) values (3.5+/-0.25 and 3.9+/-0.39 pmol/mg protein, respectively). Diazepam displacement curves showed a two component model for both genotypes, with similar K(i1) values for QQ and RR (3.6+/-0.62 and 4.9+/-0.33 nM, respectively). In QQ rats diazepam is able to completely displace [3H]Ro 15-4513 (K(i2)=1.48+/-0.27 microM), while in RR rats the diazepam sensitive sites are still present (K(i2)>10 microM). The basal mRNA and protein expression level of the alpha(6) subunit were similar in RR and QQ rats. The electrophysiological profile of oocytes of Xenopus laevis injected with cerebellar synaptosomes showed that ethanol positively modulated GABA-evoked currents significantly more in QQ than in RR rats. These data contribute to the characterization of the function of GABA(A) alpha(6) subunit and its involvement in determining alcohol related behavior.

Alcohol Drinking↗
PubMed2006

Temazepam triggers the release of vasopressin into the rat hypothalamic paraventricular nucleus: novel insight into benzodiazepine action on hypothalamic-pituitary-adrenocortical system activity during stress.

We investigated the influence of a representative classical benzodiazepine on the regulation of the hypothalamic-pituitary-adrenocortical (HPA) axis activity both under basal conditions and stress. Adult male Wistar rats were intravenously administered with temazepam (0.5, 1, and 3 mg/kg body weight) and plasma concentrations of corticotropin (ACTH) and vasopressin (AVP) were measured in blood samples collected via chronically implanted jugular venous catheters. Simultaneously, the release of AVP within the hypothalamic paraventricular nucleus (PVN) was monitored via microdialysis. Plasma AVP levels remained unaffected by the different treatment conditions. Temazepam blunted the stressor exposure-induced secretion of ACTH in a dose-dependent manner. Concurrently, and also in a dose-dependent manner temazepam enhanced the intra-PVN release of AVP, known to originate from magnocellular neurons of the hypothalamic neurohypophyseal system. Furthermore, temazepam did not affect the in vitro secretion of ACTH from the adenohypophyseal cells. Taken together, the results of this study suggest that temazepam modulates the central nervous regulation of the HPA axis by altering intra-PVN AVP release. An increasingly released AVP of magnocellular origin seems to provide a negative tonus on ACTH secretion most probably via inhibiting the release of ACTH secretagogues from the median eminence into hypophyseal portal blood.

Adrenal Cortex Hormones↗
PubMed2003

Changed vesicular GABA transporter immunoreactivity in the gerbil hippocampus following spontaneous seizure and vigabatrin administration.

To identify the roles of vesicular gamma-aminobutyric acid (GABA) transporter (VGAT) in epileptogenesis and the recovery mechanisms in spontaneous seizure, we conducted a chronological and comparative analysis of VGAT expression. VGAT immunoreactivity was stronger in the seizure resistant group than that in the pre-seizure group of seizure sensitive (SS) gerbils. In 3 h postictal group, the density of VGAT immunoreactivity was significantly increased in the hippocampus, as compared to pre-seizure group. In 24 h postictal group, VGAT immunodensity had recovered to its pre-seizure level. In addition, VGAT immunoreactivity in the hippocampus was also increased by vigabatrin (GVG) administration. These results suggest that decreased VGAT expression in the SS gerbil hippocampus may affect epileptogenesis in this animal, and that the subsequent alteration in its expression induced by seizure and the administration of GVG may reflect a modulation of GABA release to alleviate seizure activity.

Animals↗
PubMed2004

Changes of [3H]muscimol, [3H]flunitrazepam and [3H]MK-801 binding in rat brain by prolonged ventricular infusion of 7-nitroindazole.

In the present study, we have investigated the effects of prolonged inhibition of nitric oxide synthase (NOS) by infusion of neuronal NOS (nNOS) inhibitor, 7-nitroindazole (7-NI), to examine modulation of NMDA and GABAA receptor binding in rat brain. The duration of sleeping time was significantly increased by the pre-treatment with 7-NI (100 mg/kg) 30 min before pentobarbital (40 mg/kg) treatment in rats. However, the duration of pentobarbital-induced sleep was shortened by the prolonged infusion of 7-NI into cerebroventricle for 7 days. We have investigated the effect of NOS inhibitor on NMDA and GABAA receptor binding characteristics in discrete areas of brain regions by using autoradiographic techniques. The GABAA receptors were analyzed by quantitative autoradiography using [3H]muscimol and [3H]flunitrazepam binding, and NMDA receptor binding was analyzed by using [3H]MK-801 binding in rat brain slices. Rats were infused with 7-NI (500 pmol/10 microl/h, i.c.v.) for 7 days, through pre-implanted cannula by osmotic minipumps. The levels of [3H]muscimol were markedly elevated in cortex, caudate putamen, and thalamus while the levels of [3H]flunitrazepam binding were only elevated in cerebellum by NOS inhibitor. However, there was no change in the level of [3H]MK-801 binding except decreasing in the thalamus. These results show that the prolonged inhibition of NOS by 7-NI-infusion highly elevates [3H]muscimol binding in a region-specific manner and decreases the pentobarbital-induced sleep.

Animals↗
PubMed2007

Preclinical and clinical pharmacology of alcohol dependence.

In recent years, advances in neuroscience led to the development of new medications to treat alcohol dependence and especially to prevent alcohol relapse after detoxification. Whereas the earliest medications against alcohol dependence were fortuitously discovered, recently developed drugs are increasingly based on alcohol's neurobiological mechanisms of action. This review discusses the most recent developments in alcohol pharmacotherapy and emphasizes the neurobiological basis of anti-alcohol medications. There are currently three approved drugs for the treatment of alcohol dependence with quite different mechanisms of action. Disulfiram is an inhibitor of the enzyme aldehyde dehydrogenase and acts as an alcohol-deterrent drug. Naltrexone, an opiate antagonist, reduces alcohol craving and relapse in heavy drinking, probably via a modulation of the mesolimbic dopamine activity. Finally, acamprosate helps maintaining alcohol abstinence, probably through a normalization of the chronic alcohol-induced hyperglutamatergic state. In addition to these approved medications, many other drugs have been suggested for preventing alcohol consumption on the basis of preclinical studies. Some of these drugs remain promising, whereas others have produced disappointing results in preliminary clinical studies. These new drugs in the field of alcohol pharmacotherapy are also discussed, together with their mechanisms of action.

Acamprosate↗
PubMedDate not supplied

Endogenous neuroprotective factors: neurosteroids.

Neurosteroids are a group of steroid hormones synthesized by the brain in the presence of steroidogenic enzymes. Specific neurosteroids modulate function of several receptors, and also regulate growth of neurons, myelinization and synaptogenesis in the central nervous system. Some neurosteroids have been shown to display neuroprotective properties, which may have important implications for their potential use in the treatment of various neuropathologies such as: age-dependent dementia, stroke, epilepsy, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease (PD) and Niemann-Pick type C disease (NP-C). This paper focuses on neuroprotection afforded by neurosteroids.

Alzheimer Disease↗
PubMed2003

Practice and difficulty evoke anatomically and pharmacologically dissociable brain activation dynamics.

Brain activation is adaptive to task difficulty and practice. We used functional MRI to map brain systems activated by an object-location learning task in 24 healthy elderly volunteers each scanned following placebo and two of four active drugs studied. We distinguished a fronto-striatal system adaptive to difficulty from a posterior system adaptive to practice. Fronto-striatal response to increased cognitive load was significantly attenuated by scopolamine, sulpiride and methylphenidate; practice effects were not modulated by these drugs but were enhanced by diazepam. We also found enhancement by methylphenidate, and attenuation by sulpiride, of load response in premotor, cingulate and parietal regions comprising a spatial attention network. Difficulty and practice evoke anatomically and pharmacologically dissociable brain activation dynamics, which are probably mediated by different neurotransmitter systems in humans.

Adrenergic Uptake Inhibitors↗
PubMed1994

Cocaine inhibits GABA release in the VTA through endogenous 5-HT.

The ventral tegmental area (VTA) is thought to be involved in the addictive properties of many drugs, including cocaine. It has been hypothesized that cocaine exerts its actions in the VTA by blocking the reuptake of dopamine released from the dendrites of the A10 dopamine neurons, thus prolonging the actions of dopamine at D2 autoreceptors. However, cocaine also blocks the reuptake of the other monoamines, including serotonin (5-HT). Using intracellular recordings from midbrain dopamine neurons in a brain slice preparation, we have found that cocaine (0.1-10 microM) inhibited the GABAB IPSP in a dose-dependent manner. This effect was observed in the presence of the D2 dopamine receptor antagonists sulpiride (1 microM) and eticlopride (0.1 microM). 5-HT mimicked this effect, as did the selective 5-HT1D receptor agonist sumatriptan and the 5-HT-releasing agent fenfluramine. The actions of both 5-HT and cocaine were attenuated by the 5-HT1C/D antagonist metergoline. Pretreatment of slices with the 5-HT-depleting agent p-chloroamphetamine (pCA; 10 microM) abolished the inhibition of the GABAB IPSP by cocaine but failed to affect the actions of sumatriptan. We conclude that cocaine acts to modulate the GABA input to A10 dopamine neurons via inhibition of the 5-HT transporter, increasing the concentration of 5-HT at presynaptic 5-HT1D receptors. These actions of cocaine were apparent at lower concentrations than those required to act via inhibition of the dopamine transporter. This reduction of inhibitory synaptic input into the VTA would be expected to attenuate the GABA-mediated feedback inhibition from the nucleus accumbens, thus leading to increased activation of dopamine neurons.

Animals↗
PubMed1990

Molecular biology of GABAA receptors.

The major type of receptor for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), called the GABAA receptor, is a member of a gene superfamily of ligand-gated ion channels. This receptor is a hetero-oligomeric protein composed of several distinct polypeptide types (alpha, beta, gamma, and delta). Molecular cloning of these polypeptides reveals that they show 20-40% identity with each other, and 10-20% identity with polypeptides of the nicotinic acetylcholine receptors and strychnine-sensitive glycine receptor. Each polypeptide type is also represented by a family of genes whose members have 60-80% amino acid sequence identity. Regions of conserved and variable amino acid sequence suggest structural and functional domains within each polypeptide. All of the polypeptides when expressed in heterologous cells produce GABA-activated chloride channels, and the different subtypes express different pharmacological properties. The distributions of mRNAs for the different GABAA receptor polypeptides and their subtypes show significant brain regional variation consistent with pharmacological and biochemical evidence for receptor heterogeneity. Subpopulations of GABAA receptors with different cellular and regional locations show differential sensitivity to GABA, to modulators like steroids, to physiological regulation, to disease processes, and to pharmacological manipulation by drugs such as benzodiazepines. The properties of the different subpopulations of GABAA receptors are determined by which one or more of the different polypeptides and their subtypes are expressed in a given cell to produce a variety of different oligomeric protein structures. Molecular cloning techniques have produced rapid advances in understanding the GABAA receptor protein family.

Amino Acid Sequence↗
PubMed1999

Pre- versus postinjury effects of intravenous GABAergic anesthetics on formalin-induced Fos immunoreactivity in the rat spinal cord.

UNLABELLED: We evaluated the suppression of spinal Fos-like immunoreactivity (FLI) by i.v. anesthetics in the rat formalin model. Preformalin injection (1.5% subcutaneously) treatment groups included i.v. saline controls and three i.v. GABAergic anesthetic groups (pentobarbital 20 mg/kg, propofol 10 mg/kg, or alphaxalone 1.5 mg/kg; n = 12 per group). After perfusion 2 h postformalin, spinal cords were dissected, sliced at 30 microm, and processed by immunoperoxidase staining with an antibody against the Fos protein. Quantification and determination of the laminar distribution of Fos-labeled nuclei were performed at the L4-5 spinal level ipsilateral to formalin injection. Drug groups demonstrating FLI suppression were comparatively studied in a 5-min postformalin treatment group. Pentobarbital pretreatment failed to suppress FLI. However, significant reductions (percent decrease) of FLI were observed with propofol (63%) and alphaxalone (30%) compared with saline controls. Pre- versus postformalin comparison studies showed that propofol, but not alphaxalone, suppressed FLI more effectively when given preformalin. Given the observed inconsistencies between this study of Fos expression and our previous behavioral study, it is questionable whether anesthetic modulation of noxious stimulus-induced FLI parallels that of behavioral responses. IMPLICATIONS: In this study, we examined whether i.v. general anesthetics (propofol, alphaxalone, and pentobarbital) prevent injury-induced spinal cord changes. We measured spinal Fos protein after rats received anesthetics before versus after a formalin injection. Fos inhibition patterns were inconsistent with behavioral studies of these anesthetics, suggesting that Fos inhibition does not always correlate with behavioral analgesia.

Adjuvants, Anesthesia↗
PubMed2006

GABA(B) receptor-mediated modulation of glutamate signaling in cerebellar Purkinje cells.

Since Purkinje cells are the sole output neurons of the cerebellar cortex, the postsynaptic integration of excitatory and inhibitory synaptic inputs in this cell type is a pivotal step for cerebellar motor information processing. In Purkinje cells, Gi/o protein-coupled B-type gamma-aminobutyric acid receptor (GABABR) is expressed at the annuli of the dendritic spines that are innervated by the glutamatergic terminals of parallel fibers. The subcellular localization of GABABR suggests the possibility of postsynaptic interplay between GABABR and glutamate signaling. It has recently been demonstrated that GABABR indeed modulates alpha amino-3-hydroxy-5-methyl-4-isoxalone propionate-type ionotropic glutamate receptor (AMPAR)-mediated and type-1 metabotropic glutamate receptor (mGluR1)-mediated signaling. Interestingly, GABABR exerts modulatory actions not only via the classical Gi/o protein-dependent signaling cascade but also via a Gi/o protein-independent interaction between GABABR and mGluR1. In this review, we compare the physiological nature, underlying mechanisms, and possible functional significance of these modulatory actions of GABABR.

Animals↗
PubMed1996

Progesterone modulation of diazepam withdrawal syndrome in mice.

The influence of progesterone and oestrogens on the benzodiazepine withdrawal syndrome in mice was studied. The intraperitoneal administration of 15 mg/kg of flumazenil induced a withdrawal syndrome in chronic diazepam-treated mice, characterized by jerks, usually accompanied by tail lifts, and seizures. The principal finding of the present work is that the intensity of diazepam withdrawal syndrome was significantly reduced by acute administration of progesterone as revealed by a low incidence of jerks and seizures. The action of progesterone could be due to a modulatory role of the hormone on neuronal activity as an anxiolytic agent. The modulatory activity of progesterone appears to be related to changes in the pharmacological properties of benzodiazepine receptors.

Animals↗
PubMed1996

Quantitative determination of imidazenil, a novel imidazobenzodiazpine carboxamide derivative, by normal phase high-performance liquid chromatography.

Imidazenil, an imidazobenzodiazepine carboxamide derivative, is a novel anxiolytic and anti-convulsant agent recently characterized as a partial allosteric modulator of GABAA receptors. Owing to the pharmacological and pharmacokinetic importance of plasma-level determination, a HPLC method has been developed. Imidazenil was extracted from a plasma sample after a partition with diethyl ether, using alprazolam as internal standard. The analysis was performed by a normal-phase HPLC method with UV detection at 255 nm. The limit of quantitation was 6 ng corresponding to 30 ng/ml of plasma concentration. This procedure has been successfully applied to the quantitation of imidazenil plasma levels in primarily pharmacokinetic studies after a single i.v. and an oral administration of the compound to the rat.

Administration, Oral↗
PubMed1996

Diazepam modulates the period of locomotor rhythm in mice (Mus booduga) and attenuates light-induced phase advances.

Experiments were carried out on the continuous action of diazepam (benzodiazepine) offered through drinking water in 2% ethanol on psi and tau of the activity rhythms under LD (12:12) and DD conditions. Under entraining conditions diazepam failed to evoke striking changes in psi. On the other hand, under free-running conditions period-lengthening and period-shortening effects were observed. Further experiments conducted on the continuous effect of diazepam on light pulse evoked phase shifts revealed that phase advances were attenuated significantly in diazepam-treated animals at CT 20 and 24. These results were discussed with regard to the action of diazepam on the light sensitivity of the circadian pacemaker.

Animals↗
PubMed2000

Imidazenil prevention of alprazolam-induced acquisition deficit in patas monkeys is devoid of tolerance.

The partial allosteric modulators (PAMs) of gamma-aminobutyric acid-gated Cl(-) current intensities at gamma-aminobutyric acid type A receptors have high affinity but low intrinsic efficacy on benzodiazepine recognition sites. Unlike the full allosteric modulators (FAM), like alprazolam, triazolam, and diazepam, PAMs are virtually devoid of unwanted side effects, including tolerance. Imidazenil (IMD) is a PAM that elicits potent anxiolytic and anticonvulsant actions in rodents and nonhuman primates and retains its anticonvulsant and anxiolytic effects, even in rodents that are tolerant to FAMs. IMD antagonizes the side effects of FAMs in rodents and nonhuman primates. Using patas monkeys and a multiple schedule with repeated acquisition and performance of chain responses, we report that IMD administration for 17 days antagonized without showing tolerance ALP-induced disruption of acquisition.

Alprazolam↗
PubMed2004

Sex differences in effects of mild chronic stress on seizure risk and GABAA receptors in rats.

Social stress is a common occurrence in our society that can negatively impact health. Therefore, we wanted to study the effects of a mild stressor designed to model social stress on seizure susceptibility and GABAA receptors in male and female rats. The mild chronic stress of individual housing consistently decreased bicuculline (but not pentylenetetrazol, PTZ) seizure thresholds by 10-15% in both sexes. Housing conditions did not alter the anticonvulsant activity of diazepam or ethanol, although the anticonvulsant effect of ethanol was significantly greater against PTZ-induced seizures. Experiments testing the addition of an acute restraint stress unmasked sex differences in seizure induction. The acute stress also selectively decreased the potency of GABA to modulate GABAA receptor-mediated chloride uptake in group-housed females. There were additional sex differences by housing condition for GABAA receptor-gated chloride uptake but no differences in [3H]flunitrazepam binding. We also found significant effects of sex and housing on ethanol-induced increases in corticosterone (CORT) levels. In summary, there were complex and sex-selective effects of mild chronic stress on seizure induction and GABAA receptors. Gaining a better understanding of mechanisms underlying interactions between sex and stress has important implications for addressing health concerns about stress in men and women.

Animals↗