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PubMed1998

Gamma-hydroxybutyrate is a GABAB receptor agonist that increases a potassium conductance in rat ventral tegmental dopamine neurons.

gamma-Hydroxybutyric acid (GHB) is an abused substance that occurs naturally in the basal ganglia. Electrophysiological recordings of membrane voltage and current were made to characterize the effects of GHB on dopamine neurons in the ventral tegmental area of the rat midbrain slice. Perfusate containing GHB caused a concentration-dependent membrane hyperpolarization (EC50 = 0.88 +/- 0.21 mM) and a reduction in input resistance (EC50 = 0.74 +/- 0.21 mM). The highest concentration of GHB studied (10 mM) hyperpolarized neurons by 20 +/- 3 mV and reduced input resistance by 58% +/- 9%. Changes in membrane potential and input resistance were blocked by the gamma-aminobutyric acid antagonist CGP-35348 (300 microM), but neither bicuculline (30 microM) nor strychnine (10 microM) was an effective antagonist. Voltage-clamp recordings demonstrated that GHB (1 mM) evoked 80 +/- 6 pA of outward current (at -60 mV) that reversed at -110 mV (in 2.5 mM K+). Increasing concentrations of extracellular K+ progressively shifted the reversal to more depolarized potentials. In tetrodotoxin (0.3 microM) and tetraethylammonium (10 mM), depolarizing voltage steps (to -30 mV) evoked calcium-dependent current spikes that were completely blocked by GHB (1 mM). These data suggest that GHB is an agonist at gamma-aminobutyric acid receptors and would be expected to inhibit DA release by causing K+-dependent membrane hyperpolarization.

Animals↗
PubMed1995

Dopamine modulates GABAc receptors mediating inhibition of calcium entry into and transmitter release from bipolar cell terminals in tiger salamander retina.

Using optical recording techniques, we directly monitored pre- and postsynaptic calcium dynamics at bipolar cell terminals while inhibiting synaptic release with applied GABA and modulating inhibition with dopamine. To monitor pre-synaptic activity, individual bipolar cells in the retinal slice were filled with either fura-2 or fluo-3 through a patch electrode. Calcium entry into bipolar terminals, elicited by depolarization from -60 mV to 0 mV, was reduced to 36% of control in the presence of 200 microM bath-applied GABA. Further addition of 100 microM dopamine to the bath relieved the GABAergic inhibition and nearly doubled the calcium entry. Yet dopamine alone had no apparent direct effect upon calcium entry. The relief from GABAergic inhibition could be reproduced with SKF-38393, a dopamine D1 receptor agonist, and with forskolin, an adenylyl cyclase activator, suggesting that dopamine acts through a cAMP second-messenger pathway. To monitor transmitter release from bipolar cells, slices were loaded with fura-2AM, a membrane permeable form of the dye. Puffs of 110 mM KCl at bipolar dendrites depolarized bipolar cells and elicited calcium signals that could be monitored both at bipolar terminals and in postsynaptic cells. Consistent with the results above, GABA inhibited calcium entry at bipolar terminals and also reduced transmitter release, measured as a decrease in calcium entry in amacrine and ganglion cells. The addition of dopamine relieved this inhibition and increased transmitter release. Our results show the spatiotemporal correlation between the GABAergic inhibition of calcium entry at bipolar terminals, the resulting reduction in postsynaptic activity, and the relief of this inhibition with dopamine.

Animals↗
PubMed1999

The modulation of calcium current by GABA metabotropic receptors in a sub-population of pallidal neurons.

Globus pallidus (GP) receives an abundant GABAergic (gamma-aminobutyric acid) pathway from the corpus striatum. Several evidences suggested that alterations of this pathway might underlie the development of movement disorders. Classical models on Parkinsonism are centred on the increased excitability of GABAergic striatofugal neurons impinging GP and, therefore, on the presumed hypoactivity of GP neurons, but very few electrophysiological studies have addressed the activation of GABA receptors in mammalian GP. We have isolated calcium currents in GP neurons dissociated from the adult rat brain and analysed GABA-mediated responses. In the presence of bicuculline, the fast, chloride-mediated, ionotropic responses were obscured and GABA produced a large (>/= 35%) inhibition of calcium currents. The GABA-induced inhibition of calcium currents strongly desensitized was mimicked by baclofen and prevented by hydroxy-saclofen, supporting the involvement of GABAB receptors. The baclofen-mediated modulation was: (i) associated with slowing of activation kinetics; (ii) relieved by prepulse facilitation; and (iii) G-protein-mediated. The response was slow in onset, requiring the mobilization of intracellular cAMP, and was abolished by the combination of N-type and P-type calcium channel blockers. The GABAB-mediated effect, however, was confined to a particular subtype of GP neurons, identified by relatively small to medium soma. Differently, in cells characterized by larger somata and capacitance, the baclofen response was negligible. Intriguingly, these baclofen-resistant, larger neurons manifested a consistent low-voltage-activated (LVA) calcium current, not detected in baclofen-sensitive cells, at least when recorded in whole-cell mode. This study demonstrates that GP neurons express functional GABAA and GABAB receptors. In a subset of GP neurons, the activation of GABAB receptors induces a large modulation of high-voltage-activated (HVA) calcium currents, which may strongly influence basal ganglia circuitry and partially explain some discrepancies of classical models of extrapyramidal disorders.

Animals↗
PubMed2001

Alcohol, allopregnanolone and aggression in mice.

RATIONALE: Aggressive behavior of certain individual animals can be greatly increased when under the influence of low doses of alcohol. One of alcohol's neurochemical actions that may be relevant to alcohol-heightened aggression (AHA) is its positive modulation of the GABA(A) receptor complex. OBJECTIVE: The objective of this study was to investigate whether alcohol interacts with an endogenous modulator of the GABA(A) receptor complex, the neurosteroid allopregnanolone, in stimulating/heightening aggressive behavior. METHODS AND RESULTS: The first experiment was designed to test the hypothesis that neurosteroid modulators of the GABA(A) receptor complex will increase aggression and to compare these effects with alcohol. Male CFW mice were injected with allopregnanolone, alphaxalone (3-30 mg/kg, i.p.), or alcohol (1.0 g/kg, p.o.) 15 min prior to a 5-min confrontation with an intruder. Moderate doses of alcohol and the neurosteroids increased aggression by ca. 50% above baseline; impaired locomotion was seen only at the highest doses. A second experiment compared AHA and ANA (i.e. alcohol-non-heightened aggression) mice by giving allopregnanolone (1-10 mg/kg) with a simultaneous oral injection of alcohol (0.6 or 1.0 g/kg) or water. When administered with water and the 0.6 g/kg dose of alcohol, allopregnanolone increased the aggression of AHA and ANA mice. Administration of the 1.0 g/kg dose of alcohol in ANA mice prevented allopregnanolone-heightened aggression. In AHA mice, addition of allopregnanolone to 1.0 g/kg alcohol dose-dependently reduced alcohol-heightened aggression, suggesting potentiation of alcohol's suppressive effects on aggression. CONCLUSIONS: The neuroactive steroid allopregnanolone appears to play an important role in alcohol-heightened aggression. Moreover, the upward shift of the aggression-heightening effects of alcohol and the downward shift at the maximally effective alcohol dose by allopregnanolone point to a shared mechanism for both positive modulators of the GABA(A) receptor complex.

Aggression↗
PubMed1990

A bicarbonate-dependent increase in extracellular pH mediated by GABAA receptors in turtle cerebellum.

The gamma-aminobutyric acid (GABA)-gated anion channel has been found to have a significant permeability to bicarbonate in isolated nerve cells and crayfish muscle. We have studied the extracellular pH of the in vitro turtle cerebellum to determine whether the extracellular pH of vertebrate brain can be modulated by GABA. Exposure to 10(-3) M GABA produced an extracellular alkaline transient with a mean amplitude of 0.054 +/- 0.19 pH units (n = 49, range 0.018-0.091 pH units). The GABA-evoked alkaline shift was blocked by picrotoxin and was dependent on the presence of HCO3- in the bathing media. These data suggest that GABAA receptors gate an HCO3(-)-efflux which is sufficient to modulate brain pH.

Animals↗
PubMed2001

GABA(A) receptor cell surface number and subunit stability are regulated by the ubiquitin-like protein Plic-1.

Controlling the number of functional gamma-aminobutyric acid A (GABA(A)) receptors in neuronal membranes is a crucial factor for the efficacy of inhibitory neurotransmission. Here we describe the direct interaction of GABA(A) receptors with the ubiquitin-like protein Plic-1. Furthermore, Plic-1 is enriched at inhibitory synapses and is associated with subsynaptic membranes. Functionally, Plic-1 facilitates GABA(A) receptor cell surface expression without affecting the rate of receptor internalization. Plic-1 also enhances the stability of intracellular GABA(A) receptor subunits, increasing the number of receptors available for insertion into the plasma membrane. Our study identifies a previously unknown role for Plic-1, a modulation of GABA(A) receptor cell surface number, which suggests that Plic-1 facilitates accumulation of these receptors in dendritic membranes.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Novel plant substances acting as beta subunit isoform-selective positive allosteric modulators of GABAA receptors.

GABAA receptors are modulated by a large variety of compounds. A common chemical characteristic of most of these modulators is that they contain a cyclic entity. Three linear molecules of a polyacetylene structure were isolated from the East African medicinal plant Cussonia zimmermannii Harms and shown to allosterically stimulate GABAA receptors. Stimulation was not abolished by the absence of the gamma2 subunit, the benzodiazepine antagonist Ro15-1788 (8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid ethyl ester), or the point mutation beta2N265S that abolishes effects by loreclezole. At a concentration of 30 microM, the substances by themselves elicited only tiny currents. Maximal stimulation at alpha1beta2gamma2 amounted to 110 to 450% for the three substances, and half-maximal stimulation was observed at concentrations of 1 to 2 muM. Stimulation was subunit composition-dependent and was for the substance MS-1, alpha1beta2gamma2 approximately alpha1beta2 approximately alpha3beta2gamma2 > alpha2beta2gamma2 > alpha5beta2gamma2 approximately alpha1beta3gamma2 approximately alpha6beta2gamma2 > alpha1beta1gamma2, for MS-2 alpha1beta2gamma2 approximately alpha3beta2gamma2 approximately alpha1beta2 > alpha2beta2gamma2 approximately alpha6beta2gamma2 approximately alpha5beta2gamma2 > alpha1beta1gamma2, and for MS-4, alpha1beta2gamma2 approximately alpha1beta2 approximately alpha5beta2gamma2 approximately alpha3beta2gamma2 approximately alpha2beta2gamma2 > alpha6beta2gamma2 >> alpha1beta1gamma2. Maximal stimulation by MS-1 was 450% at alpha1beta2gamma2, 80% at alpha1beta1gamma2, and 150% at alpha1beta3gamma2. MS-1 was thus specific for receptors containing the beta2 subunit. The reversal potential was unaffected by 10 microM MS-1, whereas apparent picrotoxin affinity for current inhibition was increased approximately 3-fold. In summary, these positive allosteric modulators of GABAA receptors of plant origin have a novel unusual chemical structure and act at a site independent of that of benzodiazepines and loreclezole.

Allosteric Regulation↗
PubMed1991

Gamma-aminobutyric acidA (GABAA) receptor modulation of morphine inhibition of norepinephrine release.

Agents that enhance gamma-aminobutyric acid (GABA) neurotransmission can modulate certain effects of opioids, such as analgesia. In this study, the interaction between morphine and GABAergic agents on the release of [3H]norepinephrine ([3H]NE) from rat frontal cortical slices was examined. GABA (10(-4) M), enhanced potassium-stimulated [3H]NE release and reversed the inhibitory effect of 10(-6) M morphine. GABA and muscimol modulated the inhibitory effect of morphine in a noncompetitive manner. Bicuculline methiodide (10(-4) M) reduced the effect of GABA in the absence of morphine, and appeared to reduce the effect of GABA in the presence of morphine, although the latter effect was not statistically significant from the controls. While the GABAA agonist muscimol mimicked the effect of GABA, the GABAB agonist baclofen did not affect the release of [3H]NE in the absence or the presence of 10(-6) M morphine. These results support the involvement of GABAA receptors in modulating the action of opioids on the noradrenergic system in the cerebral cortex of the rat.

Animals↗
PubMed2006

[The GABA(A) receptor family: possibilities for the development of better anesthetics].

Clinically used anesthetics show amnestic, sedative, hypnotic and immobilizing properties. On a molecular level these drugs affect several receptors in the cell membrane of neurons. By using genetically engineered mice a linkage can now be made between actions on certain receptors and clinically desired and undesired effects. Experiments show that a certain GABA(A) receptor subtype mediates hypnosis and immobility, whereas another subtype is involved in side-effects like sedation and hypothermia. These findings form the basis for the development of new drugs, acting highly specific and with fewer side-effects.

Anesthetics↗
PubMed1998

Prolonged GABA(B) receptor-mediated synaptic inhibition in the cat spinal cord: an in vivo study.

In pentobarbitone-anaesthetised spinal cats, a comparison was made of the effects of intravenous bicuculline hydrochloride, a GABA(A)-receptor antagonist, and several (-)-baclofen (GABA(B)-receptor) antagonists (CGP 35348, 4638 , 56999A) on the prolonged inhibition of extensor-muscle monosynaptic reflexes, recorded from lumbar ventral roots, by brief or continuous tetanic stimulation of low-threshold afferent fibres of hindlimb flexor muscles. Two components of brief tetanus inhibition were detected. Whilst possibly of similar central latency, the inhibition associated with GABA(B) receptors had a longer time course than that reduced by bicuculline. Furthermore, whereas bicuculline reduced primary afferent depolarization, generated by the inhibitory volleys, and detected as dorsal-root potentials, such potentials were generally enhanced by intravenous baclofen antagonists. The inhibition of reflexes during and after continuous (333 Hz) tetanic flexor-nerve stimulation appeared to be predominantly associated with the activation of GABA(B) receptors. In the period following continuous tetanic flexor-nerve stimulation, during which monosynaptic extensor reflexes were reduced in amplitude, the action potentials of the intraspinal terminations of extensor-muscle group-Ia afferent fibres were reduced in duration, as detected by the time course of the recovery of the threshold to extracellular microstimulation following the arrival of an orthodromic impulse. A reduction in termination action-potential duration also accompanied the reduction by microelectrophoretic (-)-baclofen of the release of excitatory transmitter from group-Ia terminations, both presynaptic effects being blocked by microelectrophoretic baclofen antagonists. However, the reduction of the duration of the action potential of individual group-Ia terminations, which followed continuous flexor-nerve stimulation, was not sensitive to the baclofen antagonist CGP 55845A, but was diminished by bicuculline methochloride. Intravenously administered bicuculline hydrochloride, however, had little or no effect on the inhibition of reflexes following continuous flexor-nerve stimulation. These observations are discussed in the context of possible intraspinal pathways and pre- and postsynaptic mechanisms for GABA(A) and GABA(B) receptor-mediated inhibition of the monosynaptic excitation of spinal motoneurones and of the functional significance of central GABA(B) receptor-associated inhibitory processes, given the relatively minimal effects on motor activity and behaviour produced by baclofen antagonists that penetrate the mammalian blood-brain barrier.

Animals↗
PubMed1992

Barbiturate tolerance: effects on GABA-operated chloride channel function.

Male ICR mice were fed powdered laboratory chow containing phenobarbital for 7 days to induce tolerance. Mice were sacrificed and brains assayed for changes in GABA-mediated chloride flux into brain membrane vesicles (microsacs). Concentration-dependent stimulation of chloride flux by GABA alone was not affected by the development of tolerance to phenobarbital. Phenobarbital potentiation of GABA-mediated chloride flux was significantly attenuated in the membranes prepared from phenobarbital-tolerant mice compared with those from pair-fed control mice. Similarly, stimulation of GABA-mediated flux by the benzodiazepine, flunitrazepam was also depressed in membranes from tolerant mice. However, the ability of ethanol and the benzodiazepine inverse agonist FG-7142 to modulate GABA-gated chloride flux was not affected by the development of phenobarbital tolerance. No significant changes in saturation [3H]diazepam binding parameters were observed. These findings suggest that there is a degree of cross-tolerance between phenobarbital and benzodiazepine agonist at the level of the GABA-operated chloride channel. Furthermore, although some reports have demonstrated behavioral cross-tolerance between ethanol and barbiturates, the present data suggest different mechanisms of tolerance development for these intoxicants at the level of the GABAA receptor chloride channel complex.

Animals↗
PubMed1996

Effects of chronic morphine pretreatment on amygdaloid kindling development, postictal seizure and suppression and benzodiazepine receptor binding in rats.

Effects of chronic morphine pretreatment on the development of amygdaloid kindling, seizure suppression and benzodiazepine (BDZ) receptor binding in rats were evaluated. The morphine-pretreated animals showed faster acquisition of seizure activity. Further evaluation of the postictal seizure suppression immediately after a fully kindled seizure demonstrated that morphine-pretreated rats had a decreased sensitivity to subsequent kindling stimulations. Twenty-four hours after the last electrical stimulation, saline-pretreated fully kindled rats showed enhanced BDZ receptor binding in dentate gyrus, and decreased binding in cingulate cortex ipsilateral to the stimulation site, compared to saline controls. Morphine-pretreated amygdala-kindled rats had significantly higher BDZ binding in piriform, entorhinal and sensorimotor cortices, basolateral and cortical amygdaloid nuclei, dentate gyrus, CAI-3 areas, substantia nigra pars reticulata and periaqueductal gray. The present study indicates that the previous experience with chronic morphine modifies the kindling process and that the enhanced BDZ receptor binding detected in our experiments may be involved in the enhanced postictal seizure suppression observed in these animals.

Amygdala↗
PubMed2005

gamma-Aminobutyric acid-serotonin interactions in healthy men: implications for network models of psychosis and dissociation.

BACKGROUND: This study tested the hypothesis that deficits in gamma-aminobutyric acid type A (GABA(A)) receptor function might create a vulnerability to the psychotogenic and perceptual altering effects of serotonergic (5-HT(2A/2C)) receptor stimulation. The interactive effects of iomazenil, an antagonist and partial inverse agonist of the benzodiazepine site of the GABA(A) receptor complex, and m-chlorophenylpiperazine (m-CPP), a partial agonist of 5-HT(2A/2C) receptors, were studied in 23 healthy male subjects. METHODS: Subjects underwent 4 days of testing, during which they received intravenous infusions of iomazenil/placebo followed by m-CPP/placebo in a double-blind, randomized crossover design. Behavioral, cognitive, and hormonal data were collected before drug infusions and periodically for 200 min after. RESULTS: Iomazenil and m-CPP interacted in a synergistic manner to produce mild psychotic symptoms and perceptual disturbances without impairing cognition. Iomazenil and m-CPP increased anxiety in an additive fashion. Iomazenil and m-CPP interacted in a synergistic manner to increase serum cortisol. CONCLUSIONS: Gamma-aminobutyric acid-ergic deficits might increase the vulnerability to the psychotomimetic and perceptual altering effects of serotonergic agents. These data suggest that interactions between GABA(A) and 5-HT systems might contribute to the pathophysiology of psychosis and dissociative-like perceptual states.

Analysis of Variance↗
PubMed2005

Novel anellated pyrazoloquinolin-3-ones: synthesis and in vitro BZR activity.

A series of pyrazolo[4,3-c]pyrrolo[3,2-f]quinolin-3-one derivatives 6, 7a-c, 8a,b, 9a,b and 10-12 were synthesized as modified pyrazoloquinolinone analogs (PQs) and evaluated for their ability to inhibit radioligand to central and peripheral benzodiazepine receptors (BZRs) and their effect on GABA(A) alpha1beta2gamma2L receptors expressed in Xenopus laevis oocytes. Multistep synthesis starting from 5-nitroindole, via the Gould-Jacobs reaction to the quinoline nucleus, yielded key intermediates 9-chloro-3H-pyrrolo[3,2-f]quinoline-8-carboxylates. The reaction of the latter with methyl-hydrazine and various phenyl-hydrazines furnished the final compounds. In order to confirm the expected tetracyclic 2-substituted-2H-pyrazolopyrroloquinolin-3-one structure, IR spectrophotometric, mono-1H and 13C and bi-dimensional spectrometric and HRMS analyses were carried out: all compounds were found to be 2-substituted 3-keto tautomers; compound 6 only differed because it turned out to be 1-methyl-2H-pyrazolo[4,3-c]pyrrolo[3,2-f]quinolin-3-olo. The results of this work are consistent with those previously reported for PQs: 7-9 show high potency in displacing specific [3H]flunitrazepam from its receptor site; no compound was active in inhibiting the binding of [3H]PK 11195. They all act as antagonists at central BZR.

Animals↗
PubMed2005

Effect of chronic administration of ethanol on GABAA receptor assemblies derived from alpha2-, alpha3-, beta2- and gamma2-subunits in the rat cerebral cortex.

Chronic administration of ethanol decreased the immunoprecipitation of the [(3)H]flunitrazepam binding activity for GABA(A) receptor assemblies derived from alpha(2)-, alpha(3)- and gamma(2)-subunits in the rat cerebral cortex. However, the [(3)H]muscimol binding sites derived from these subunits were not affected. Thus, chronic ethanol causes the down-regulation of the benzodiazepine sites derived from the alpha(2)-, alpha(3)- and gamma(2)-subunits without affecting the GABA binding sites.

Alcoholism↗
PubMed2005

Changes in hippocampal GABAA receptor subunit composition in bipolar 1 disorder.

Postmortem CNS studies have suggested an uncoupling of the gamma-aminobutyric acid (GABA) and benzodiazepine binding sites on the hippocampal GABA(A) receptor in schizophrenia. The GABA(A) receptor is an assembly of discrete subunits that form a ligand-gated ion channel, the binding characteristics of which are defined by receptor subunit composition. Thus, a likely explanation for an uncoupling between the GABA and benzodiazepine binding sites on the GABA(A) receptor would be a change in receptor subunit composition. To test this hypothesis we measured the density of GABA ([(3)H]muscimol) and benzodiazepine ([(3)H]flumazenil) binding sites on the GABA(A) receptor in hippocampi, obtained postmortem, from schizophrenic, bipolar I disorder and control subjects. In addition, we measured the amount of [(3)H]flumazenil binding that could be displaced with zolpidem and clonazepam. Levels of both [(3)H]muscimol and [(3)H]flumazenil binding were significantly decreased in part of the CA2 from subjects with schizophrenia; the decrease in [(3)H]flumazenil being due to decreases in both zolpidem-sensitive and -insensitive radioligand binding. There were complex regionally specific changes in [(3)H]muscimol binding in the hippocampus from subjects with bipolar I disorder but there were no significant changes in the overall levels of [(3)H]flumazenil binding. There were significant decreases in zolpidem-sensitive and increases in zolpidem-insensitive [(3)H]flumazenil binding in most regions of the sections of the hippocampal formation studied in bipolar I disorder. Unlike [(3)H]flumazenil, zolpidem does not bind to the alpha5 subunit of the GABA(A) receptor; therefore, we postulate that there is an increase in GABA(A) receptors containing alpha5 subunit in the hippocampus from subjects with bipolar I disorder.

Adult↗
PubMed2003

Effects of pentobarbital on GABA-activated currents in acutely-isolated rat dentate gyrus granule neurons.

Granule neurons from the rat dentate gyrus were acutely isolated and whole-cell currents recorded. Maximal enhancement of 7 microM gamma-aminobutyric acid (GABA; EC30) evoked currents was obtained with 100 microM pentobarbital where the peak-current was 2.1+/-0.2 of control. One hundred microM pentobarbital alone evoked no current response whereas 1 mM pentobarbital elicited a current response that was 0.4+/-0.2 of the 100 microM GABA-activated peak current. In 100 microM pentobarbital, the GABA EC50 value shifted from 14 to 3 microM but the peak-saturating-current value was not altered. An off-current was recorded on removal of 100 microM and higher pentobarbital concentrations. Ten mM pentobarbital abolished the peak-current response to 7 and 100 microM GABA. The results show that in the granule neurons the drug potency differs for the different effects of pentobarbital at GABAA receptors with the modulatory and inhibitory effects requiring lower concentrations than the direct activation of the receptors.

Animals↗
PubMed2002

Benzodiazepine receptors in the medial-posterior hypothalamus mediate the reduction of hippocampal theta frequency by chlordiazepoxide.

Separate sub-populations of benzodiazepine receptors are involved in determining hippocampal theta frequency in freely moving rats. Systemic injection of the benzodiazepine chlordiazepoxide (CDP) reduced the frequency of theta elicited by stimulation of the brainstem reticular formation, and theta recorded during fixed interval (FI) bar pressing. Infusion of the benzodiazepine receptor antagonist flumazenil into the supramammillary nucleus (mSuM) or the posterior hypothalamic nucleus (PH) antagonised CDP in both cases. Flumazenil was similarly effective in mSuM and PH, suggesting that these nuclei are jointly involved in the coding of theta frequency during FI and during high levels of reticular activation. However, benzodiazepine receptors in other brain regions probably participate in determining the frequency of theta at other times.

Animals↗