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PubMed2005

Radioligand binding studies of caloporoside and novel congeners with contrasting effects upon [35S] TBPS binding to the mammalian GABA(A) receptor.

Caloporoside is a natural active fungal metabolite, which was isolated from Caloporous dichrous and was described to exhibit antibacterial, antifungal and phospholipase C inhibitory activity. We have previously reported evidence that related beta-linked compounds, lactose and octyl-beta-d-mannoside, bind and functionally modulate rodent GABA(A) receptors, respectively. We have characterized the binding pharmacology of synthetic caloporoside and two further congeners, 2-hydroxy-6-([(16R)-(beta-d-mannopyranosyloxy)heptadecyl]) benzoic acid and octyl-beta-d-glucoside on GABA(A) receptors using a [35S]-t-butylbicyclophosphoorothionate (TBPS) radioligand binding assay. Caloporoside and 2-hydroxy-6-([(16R)-(beta-d-mannopyranosyloxy)heptadecyl]) benzoic acid produced concentration-dependent complete inhibition of specific [35S] TBPS binding with overall apparent IC50 values of 14.7+/-0.1 and 14.2+/-0.1 microM, respectively. In contrast, octyl-beta-d-glucoside elicited a concentration-dependent stimulation of specific [35S] TBPS binding (E(max)=144+/-4%; EC50=39.2+/-22.7 nM). The level of stimulation was similar to that elicited by diazepam (E(max)=147+/-6%; EC50=0.8+/-0.1 nM), and was occluded by GABA (0.3 microM). However, the three test compounds failed to elicit any significant effect (positive or negative) upon [3H] flunitrazepam or [3H] muscimol binding, indicating that they did not bind directly, or allosterically couple, to the benzodiazepine or agonist binding site of the GABA(A) receptor, respectively. The constituent monosaccharide, glucose, and both the closely related congeners octyl-beta-d-glucoside or hexyl-beta-d-glucoside have no significant effect upon [35S] TBPS binding. These data, together, provide strong evidence that a beta-glycosidic linkage and chain length are crucial for the positive modulation of [35S] TBPS binding to the GABA(A) receptor by this novel chemical class.

Animals↗
PubMed1992

Effects of gender and gonadectomy on responses to chronic benzodiazepine receptor agonist exposure in rats.

Gonadal steroid hormones or their derivatives have been shown to modulate the GABA receptor complex and GABA-mediated responses in a manner similar to the benzodiazepines. The present study examines if hormonal status modulates the development of tolerance and/or the neural adaptations in GABAA receptors associated with chronic benzodiazepine exposure. Anticonvulsant effects of diazepam were compared in groups of male, female, orchidectomized, and ovariectomized rats following acute (3 day) and chronic (3 week) exposure to diazepam-filled silastic implants. Results indicated that hormonal status did not significantly modify either the neural levels of drug resulting from the diazepam implants or the diazepam-induced increases in bicuculline seizure thresholds following acute (3 day) exposure. Unlike males and gonad-intact females, ovariectomized rats continued to display elevated seizure threshold values due to the diazepam released from the implants even after chronic diazepam exposure. This suggests that the tolerance to benzodiazepine actions observed in male and intact female rats was prevented by ovariectomy. Analysis of the anticonvulsant effects of additional challenge doses of diazepam in chronic diazepam-treated rats paradoxically suggested that benzodiazepine tolerance developed in all hormone groups. The discrepancies between these two tests of anticonvulsant tolerance may be related to the divergent neural GABAA receptor adaptations seen between hormone groups. Ovariectomized rats displayed a reduction in GABA IC50 values for [3H]bicuculline-thiocyanate binding in cortex following chronic diazepam exposure that was not observed in males or intact females. These results suggest that the diminution of ovarian steroid hormones may modulate the neural GABAergic changes associated with the development of tolerance to benzodiazepine actions during chronic agonist exposure.

Animals↗
PubMed1990

Endogenous GABAergic modulators in the pathogenesis of hepatic encephalopathy.

Theories on the neurochemical etiology for hepatic encephalopathy have recently focussed on activation of inhibitory neurotransmitter GABA systems. Modulators of the GABAA receptor complex, including diazepam binding inhibitor, are significantly and selectively altered in hepatic encephalopathy. In animals and humans, benzodiazepine receptor antagonists rapidly ameliorate this syndrome suggesting the possible existence of an endogenous benzodiazepine-like substance. Endogenous GABAergic modulators may contribute to the neurochemical pathogenesis of hepatic encephalopathy.

Animals↗
PubMed2006

Temperature: an important experimental variable in studying PKC modulation of ligand-gated ion channels.

Amphibian oocyte and mammalian heterologous expression systems are often used to investigate the function of recombinant ion channels using electrophysiological techniques. Although both systems have yielded important information, the results obtained in these systems are sometimes conflicting. Oocytes and mammalian cells differ in their physiological temperature requirements. While room temperature is within the physiological temperature range for oocytes, this temperature is far below that required by mammalian cells. Since electrophysiological studies are often performed in both oocytes and mammalian cells at room temperature, we sought to determine if recording temperature could be a factor in some disparate results obtained in these cell types. For these studies, we examined phorbol ester modulation of GABA(A) and glycine receptors. Consistent with the literature, at room temperature, PMA (phorbol 12-myristate 13-acetate) produced a large reproducible decrease in the peak amplitude of GABA and glycine-gated currents in Xenopus oocytes. In contrast, PMA was ineffective in modulating these heterologously expressed receptors at room temperature in human embryonic kidney (HEK) 293 cells. However, when electrophysiological experiments were performed at 35 degrees C in HEK 293 cells, PMA decreased the function of these receptors. Our results indicate that the temperature at which electrophysiological studies are conducted is an important experimental variable. To determine the extent to which electrophysiological recordings are performed at physiological temperatures in HEK 293 cells, a PubMed search was conducted using the search terms "patch clamp" and "HEK" for the years 2003-2004. This search revealed that only 15% of the patch clamp studies were reported to have been conducted in the temperature range of 32-37 degrees C. The results of our study indicate that temperature is an important experimental variable that requires rational consideration in the design of electrophysiological experiments.

Analysis of Variance↗
PubMed2001

Reversal of reserpine-induced vacuous chewing movements in rats by melatonin: involvement of peripheral benzodiazepine receptors.

Several reports have indicated that melatonin modulates striatal dopaminergic functions via its interaction with central and peripheral benzodiazepine (BZ) receptors. Clinical reports and animal studies speculated on the possible involvement of melatonin in the pathophysiology of tardive dyskinesia (TD). In view of this, the present experiment was performed to study the possible effect of melatonin in modulation of reserpine-induced dyskinesia. Melatonin (1-10 mg/kg) dose dependently suppressed the severity of vacuous chewing movements (VCMs) in rats. Prior administration of the putative melatonin receptor antagonists luzindole (2.5 and 5 mg/kg) or prazosin (2.5 and 5 mg/kg) failed to antagonize melatonin (2.5 mg/kg) reversal of reserpine-induced VCMs. However, the peripheral BZ receptor antagonist PK11195 (0.5 and 1 mg/kg) but not flumazenil (1 and 2 mg/kg), dose dependently antagonized melatonin's reversal of reserpine-induced VCMs. Taken together the present results demonstrate that melatonin reverses reserpine-induced VCMs and that this could be due to enhancement of GABAergic activity via peripheral BZ receptors.

Adrenergic Uptake Inhibitors↗
PubMed1996

Effects of benzodiazepine receptor inverse agonists and nicotine on behavioral vigilance in senescent rats.

Previous experiments demonstrated that, compared with 6-month-old rats, the performance of 20-month-old rats in a behavioral vigilance task was characterized by an impairment in their ability to detect visual signals, whereas their ability to discriminate between longer signals and nonsignal events was unaffected. The benzodiazepine receptor (BZR) agonist chlordiazepoxide potently and selectively interacted with the effects of age on the relative number of hits. However, negative modulators of GABAergic transmission (Zk 93 426, beta-CCtB, RU 33965) failed to attenuate the effects of age on behavioral vigilance. the present experiment tested the hypothesis that the performance of senescent animals (28 months) is further impaired and thus would allow the demonstration of beneficial effects of BZR inverse agonists or nicotine. However, administration of ZK 93 426 (0.39, 1.56, 6.25 mg/kg), Ru 33965 (0.1, 0.5 mg/kg), or nicotine (0.09, 0.287, 0.689 mg/kg) did not beneficially affect the performance of senescent animals; rather, detrimental effects were found. Considering the beneficial behavioral effects of these compounds in animals with experimentally induced impairments in cholinergic function, the present finding point to limitations of normal aging as a variable in animal experiments on BZR inverse agonist or nicotine-induced attenuation of cognitive impairments that result from cholinergic hypofunction.

Aging↗
PubMed1983

Influence of caffeine and midazolam on gamma-aminobutyric acid-evoked responses in the frog spinal cord.

The recently reported potentiation of gamma-aminobutyric acid (GABA) evoked depolarizations by caffeine in the frog spinal cord might involve an interaction with GABA-linked benzodiazepine receptors. This possibility was investigated using a new potent benzodiazepine, midazolam, and a benzodiazepine antagonist, Ro 147437. Caffeine or midazolam enhanced the amplitude of submaximal GABA responses by about 50%; when equieffective enhancing doses of these compounds were simultaneously applied, GABA depolarizations were usually depressed below control levels. It was however possible to detect a narrow range of concentrations of midazolam which had an additive effect to the enhancement by caffeine. Ro 147437 did not block caffeine-induced potentiations of GABA responses. It is suggested that caffeine and benzodiazepines have distinct modes of action in modulating GABA-induced depolarizations in the in vitro spinal cord of the frog.

Animals↗
PubMed1986

gamma-Aminobutyric acid-dependent motility induced by avermectin B1a in the isolated intestine of the guinea pig.

In the isolated ileum of the guinea pig, neurally mediated rhythmic longitudinal mechanical activity was induced by avermectin, a macrolide anthelmintic that releases gamma-aminobutyric acid (GABA) and modulates the GABAA-receptor-ionophore complex. This avermectin-induced activity was dependent on GABA, being reduced or abolished by bicuculline, a GABAA-receptor antagonist, and by 3-mercaptopropionic acid which prevents neural GABA release. These results provide additional direct evidence that GABA is a functional neurotransmitter in the myenteric plexus of the guinea pig intestine, evidently involved in the regulation of intestinal motility.

3-Mercaptopropionic Acid↗
PubMed1981

[Molecular mechanism of action of benzodiazepines].

Recently, binding sites with high affinity and high specificity for the benzodiazepines have been discovered in mammalian brain. The affinity of the various benzodiazepines for these sites correlates well with the pharmacological potencies of these drugs. It is mainly for this reason that these binding sites are believed to represent the pharmacologically relevant "benzodiazepine receptors". Investigation of the binding of prazepam and metabolites to benzodiazepine receptors in rat brain homogenates reveals that prazepam has only a weak affinity to the receptor(s) with a KD of 1 microM. Its metabolite, descyclopropylmethyl-prazepam (= norprazepam) binds about 100 times more strongly (KD congruent to 15 nM). This shows that norprazepam which is the main pharmacokinetic metabolite (greater than 80% of all metabolites in plasma after oral administration of prazepam) is at the same time the biochemically active substance. Hydroxylation of the 7-membered ring of prazepam or norprazepam in position 3 does not lead to a marked increase in affinity. There is strong electrophysiological and biochemical evidence that the benzodiazepines potentiate GABAergic mechanisms in the CNS (GABA is the major inhibitory transmitter in brain). The molecular events by which the benzodiazepines modulate the GABA system are, however, completely unknown. Also, we do not know whether all pharmacological actions of the benzodiazepines (e.g. anxiolytic action, sedation, muscle relaxation) may be explained by the GABA-hypothesis. The existence of an endogenous substance--which binds to the benzodiazepine receptors--is still open to debate.

Animals↗
PubMedDate not supplied

[New trends on biochemical mechanism of action of benzodiazepines (author's transl)].

The benzodiazepines (BZD) are widely used in clinical practice as anxiolytics, muscle relaxants, sedatives and anticonvulsants. Electrophysiological studies have shown a specific interaction of BZD with - aminobutyric acid (GABA), an inhibitory neurotransmitter, of which they enhance the physiological effects. The discovery of saturable and stereospecific binding sites with high affinity for BZD, and their brain distribution indicates a predominantly cortical action of BZD. Furthermore, BZD receptors seem to be linked to GABA receptors--modulating their inhibitory effects--and closely connected to the chloride conductance mechanism associated to the GABA receptor. The discovery of BZD receptors suggests the existence of endogenous ligands. Inosine, hypoxanthine or nicotinamide are reported to have BZD-like activities, in spite of a relative low affinity for their binding sites. Their putative role as endogenous anxiolytics needs to be supported by behavioral studies.

Animals↗
PubMed1998

Electrophysiological studies of neurohypophysial neurons and peptides.

We have used hypothalamic slices of the supraoptic nucleus (SON) to investigate synaptic control of magnocellular vasopressinergic and oxytocinergic neurons. With the use of perforated patch recording techniques we identified and isolated excitatory or inhibitory postsynaptic currents elicited by electrical stimulation of afferent fibers. Both inhibitory and excitatory afferent fibers displayed presynaptic GABAB receptors; the GABAB agonist, baclofen caused a dose-dependent suppression of the evoked potentials in the absence of any effects on postsynaptic input resistance. Further evidence for a presynaptic locus included an increase in paired pulse ratio and a lack of effect on currents elicited by exogenously applied muscimol (a GABAA receptor agonist) or AMPA (a glutamate agonist). With the use of an GABAB receptor antagonist we demonstrated an action of endogenously released GABA, acting at GABAB receptors on excitatory terminals, to reduce excitatory transmission. In addition to presynaptic modulation by GABA of afferent inputs, we also observed actions of vasopressin and oxytocin, released from dendrites of magnocellular SON neurons, to gate afferent, excitatory transmission in the SON. Exogenously applied vasopressin and oxytocin, or these peptides when released by depolarizing stimuli of magnocellular neurons, reduced the size of evoked excitatory postsynaptic potentials at a presynaptic locus. We have also observed actions of arginine vasopressin to modulate the action of glutamate in slices of the ventral septal area and to attenuate a glutamate-mediated excitatory postsynaptic current in slices of the parabrachial nucleus.

Animals↗
PubMed2004

Benzodiazepine receptor-dependent modulation of neutrophil (PMN) free amino- and alpha-keto acid profiles or immune functions.

We have examined the effects of midazolam, Ro 5-4864 (agonist for "peripheral" [p] benzodiazepine receptors [BR]), PK 11195 (antagonist for pBR), flumazenil (antagonist for "central" BR), naloxone (antagonist for opiate receptors) and the combination of midazolam and Ro 5-4864, PK 11195, flumazenil or naloxone on intracellular amino- and alpha-keto acids and the immune function markers superoxide anion (O(2)(-)), hydrogen peroxide (H(2)O(2)) and released myeloperoxidase (MPO) activity in neutrophils (PMN). Only midazolam and Ro 5-4864 led to significant changes in the dynamic PMN free amino- and alpha-keto acid pools. Concerning PMN immune function markers, midazolam and Ro 5-4864 significantly decreased O(2)(-) and H(2)O(2) formation and released MPO. When midazolam and Ro 5-4864 were applied together they appeared to act additively. Pre-incubation with PK 11195 partially neutralized the midazolam effects whereas flumazenil or naloxone showed no effects. We therefore believe that pBR are involved in the signal transmission of anesthetic-induced cellular metabolic changes in PMN.

Adult↗
PubMed2002

Metabotropic glutamate mGlu5 receptor-mediated modulation of the ventral striopallidal GABA pathway in rats. Interactions with adenosine A(2A) and dopamine D(2) receptors.

Interactions between subtypes of dopamine, glutamate and adenosine receptors seem to play an important integrative role in the function of striatal gamma-aminobutyric acid (GABA)ergic efferent neurons. Recent behavioral and biochemical studies suggest the existence of specific interactions between adenosine A2A receptors (A(2A)R), dopamine D2 receptors (D2R) and the group I metabotropic mGlu5 receptors (mGlu5R) in the dorsal striatum. The dual-probe approach in vivo microdialysis technique in freely moving rats was used to study the role of mGlu5R/A2AR/D2R interactions in the modulation of the ventral striopallidal GABA pathway. Perfusion of a selective mGlu5R agonist (CHPG) in the nucleus accumbens facilitated GABA release in the ipsilateral ventral pallidum. This effect was strongly potentiated by co-perfusion with the A2AR agonist CGS 21680. Co-perfusion with the D2R agonist quinpirole counteracted the increase in pallidal GABA levels induced by CGS 21680 and by CGS 21680 plus CHPG. These results demonstrate that mGlu5R/A2AR/D2R interactions play an important modulatory role in the function of the ventral striopallidal GABA pathway, which might have implications for the treatment of schizophrenia and drug addiction.

Adenosine↗
PubMed1995

Contribution of "diazepam-insensitive" GABAA receptors to the alcohol antagonist properties of Ro 15-4513 and related imidazobenzodiazepines.

Both in vivo and in vitro studies have shown that Ro 15-4513 can antagonize many of the pharmacologic actions of ethanol. In contrast to many benzodiazepine receptor (BzR) ligands, Ro 15-4513 binds with high affinity to a novel GABAA receptor subtype, referred to as "diazepam-insensitive" (DI). This study examined the contribution of DI GABAA receptors to the modulation of ethanol-induced sleep time by Ro 15-4513 and related imidazobenzodiazepines [e.g., Ro 19-4603, Ro 16-6028, and ZG-63 (t-butyl-8-chloro-5,6-dihydro-5-methyl-6-oxo-imidazo[1,5,a] [1,4]benzodiazepine-3-carboxylate)] that possess high affinities for this GABAA receptor subtype. Ro 15-4513 (0.6-5 mg/kg) significantly reduced ethanol (3.5 g/kg, i.p.) sleep time in mice (p < 0.001, analysis of variance). This effect was not blocked by BzR antagonists ZK 93426 (5 mg/kg) and Ro 14-7437 (5 mg/kg), which possess low affinities for DI but bind with high affinities to other "diazepam-sensitive" (DS) GABAA receptor isoforms. Although Ro 19-4603 (2.5 mg/kg) also reduced ethanol sleep time (p < 0.01), this effect was attenuated by coadministration of ZK 93426 (2.5 mg/kg). Ro 16-6028 (2.5 mg/kg) prolonged (p < 0.01) ethanol sleep time. However, in the presence of either Ro 19-7437 (5 mg/kg) or ZK 93426 (2.5 mg/kg) ethanol-induced sleep time was reduced to values approaching those obtained with ethanol in the presence of Ro 15-4513. A low dose (2.5 mg/kg) of ZG-63 did not significantly affect alcohol sleep time. However, in the presence of ZK 93426, ZG-63 increased sleep time (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Deterrents↗
PubMed1998

Improvement of chronic hepatic encephalopathy in dogs by the benzodiazepine-receptor partial inverse agonist sarmazenil, but not by the antagonist flumazenil.

Therapeutic modulation of the increased GABAergic tone in chronic hepatic encephalopathy (HE) by the benzodiazepine receptor (BR) antagonist flumazenil (F) has led to conflicting results in humans and animal models for HE. The BR inverse agonist sarmazenil (S) has only been used in animal models of acute HE. Therefore we investigated the effects of intravenous injection of F and S in dogs with chronic HE 8 to 12 weeks after placement of a portocaval shunt and 40% hepatectomy (n=7), compared to sham-operated pair-fed controls (n=7). The HE dogs had hyperammonemia (298 +/- 48 microM v 33 +/- 3 before surgery (mean +/- SEM)) and signs of HE at the start of the experiments (0.9 +/- 0.1 (scale 0-4)). Three (S3) and 8 (S8) mg/kg of S resulted in a significant improvement of encephalopathy (grade 0.9 +/- 0.2 immediately before v 0.5 +/- 0.1 after injection (S3) and 0.7 +/- 0.1 v 0.3 +/- 0.1 (S8)) and increase in mean dominant frequency of the EEG (MDF; 9.1 +/- 0.7 Hz v 11.1 +/- 0.3 (S3) and 8.9 +/- 0.5 v 11.0 +/- 0.3 (S8)) in HE dogs, whereas 15 mg/kg of S, 3 and 8 mg/kg of F, and the vehicle had no significant effects. The efficacy of S in these dogs is consistent with an increased GABAergic tone in the pathogenesis of chronic HE. The lack of effects of F makes a role for endogenous benzodiazepines herein unlikely.

Ammonia↗
PubMed1990

Calcium-independent GABA release from striatal slices: the role of calcium channels.

We have investigated the role of Ca2+ and Ca2+ channels in the modulation of GABA release. Brain slices prepared from rat striatum were preincubated with [3H]GABA, superfused with Krebs bicarbonate buffer, and exposed to electrical field stimulation (2 Hz for 3 min). Tritium efflux was measured as an index of GABA release. Both resting and evoked efflux were greatly accelerated by deleting Ca2+ from the medium and adding EGTA (1 mM). However, when the concentration of Mg2+ in the buffer was elevated to 10 mM, no effect of the Ca2(+)-deficiency was observed on resting release and its impact on evoked overflow was diminished. Moreover, addition of verapamil (10 microM), a Ca2+ channel blocking agent, reduced evoked overflow even in the absence of external Ca2+, while 4-aminopyridine (10 microM), a K+ channel inhibitor, enhanced GABA efflux in normal buffer but had no effect in the absence of Ca2+. Finally, we have shown previously that nipecotic acid, an inhibitor of high affinity GABA transport, increases GABA overflow in normal buffer, but blocks it in Ca2(+)-free buffer. Collectively, these results suggest that Ca2+ channels may play two roles in the regulation of depolarization-induced GABA release. Firstly, these channels permit a depolarization-induced influx of Ca2+ which then promotes GABA release. In addition, these channels influence GABA release through a mechanism that does not involve external Ca2+. Although the precise nature of this latter involvement is unclear, we propose that the Ca2+ channels serve to permit an influx of Na+, which in turn promotes Ca2(+)-independent release through an influence on the high affinity GABA transport system.

4-Aminopyridine↗
PubMed1996

The hyperphagic effect of 3 alpha-hydroxylated pregnane steroids in male rats.

Like benzodiazepines receptor (BDZR) ligands, 3 alpha-hydroxylated, 5 alpha, or 5 beta pregnane steroids are sedative, anticonvulsant, and anxiolytic. BDZR ligands also modulate the feeding response. Therefore, in this study we have investigated the effects of four 3 alpha-hydroxylated pregnane steroids-Pregnanolone (3 alpha-hydroxy-5 beta-pregnan-20-one), allopregnanolone (3 alpha-hydroxy-5 alpha-pregnan-20-one), alphaxalone (3 alpha-hydroxy-5 alpha-pregnan-11,20-dione), and 5 beta-pregnanediol (5 beta-pregnan-3 alpha,20 alpha-diol) on food intake. In non-food deprived male rats, all four steroids increased the consumption of a palatable diet. For pregnanolone (1-10 mg/kg), hyperphagia was found at lower doses than its anxiolytic effect (5-10 mg/kg) as determined using the elevated plus maze test. The presumed steroid antagonists, isopregnanolone (3 beta-hydroxy-5 alpha-pregnan-20-one) (10 mg/kg) and pregnenolone sulfate (2 mg/kg), and the BDZ antagonist, Ro15-1788 (20 mg/kg), did not reverse the hyperphagic effect of pregnanolone. Picrotoxin, a GABAA receptor antagonist, dose dependently and at a subconvulsive dose (1.5 mg/kg), reversed the hyperphagic effect of pregnanolone and alphaxalone, but had no effect on allopregnanolone- and 5 beta-pregnanediol-induced hyperphagia. These results indicate that the hyperphagic effects of pregnanolone and alphaxalone are mediated by the GABAA receptor but not by direct interaction with BDZ receptors. However, allopregnanolone- and 5 beta-pregnanediol-induced hyperphagia may be mediated by other receptor systems. Because some 3 alpha-hydroxylated pregnane steroids are endogenous progesterone metabolites, they may play an important role in appetite control.

Animals↗
PubMed1996

Medial septal benzodiazepine receptors modulate hippocampal evoked responses and long-term potentiation.

Infusion of benzodiazepine (BDZ) receptor ligands into the medial septum (MS) produces a bidirectional modulation of spatial memory retention. The present experiments sought to determine the effects of BDZ ligands upon synaptic responses and long-term potentiation (LTP) in the dentate gyrus following electrical stimulation of the angular bundle. Intraseptal infusion of the BDZ agonist, chlordiazepoxide, decreased the amplitude of the evoked population spike and increased paired-pulse facilitation at a 150-ms interstimulus interval (ISI) in a dose-dependent manner. Intraseptal infusion of the BDZ antagonist, flumazenil (10 nmol), enhanced the amplitude of the dentate population spike and also increased paired-pulse facilitation at the 150-ms ISI. There was no effect of either BDZ receptor ligand upon the slope of the rising phase of the evoked population excitatory postsynaptic potential (pEPSP). Intraseptal flumazenil also significantly enhanced the magnitude of dentate LTP induced by high-frequency stimulation of the angular bundle. Intraseptal chlordiazepoxide failed to alter LTP induction. These results indicate that intraseptal infusion of an amnestic dose of the BDZ ligand, chlordiazepoxide, decreases the excitatory responsiveness of the dentate gyrus to its synaptic input from entorhinal cortex. In contrast, the promnestic BDZ ligand, flumazenil, enhances dentate granule cell responsivity, and facilitates synaptic plasticity in the dentate gyrus network. Taken together these data suggest that the memory impairing and memory enhancing action of these compounds may be a function of their ability to alter hippocampal physiology during a critical phase of memory. The potential role of septodentate cholinergic and GABAergic projections in the present observation is discussed.

Animals↗