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PubMed2001

Evidence for the formation of functionally distinct alphabetagammaepsilon GABA(A) receptors.

1. We transiently introduced the human GABA(A) receptor epsilon subunit cDNA into a human embryonic kidney (HEK) cell line stably expressing alpha1beta3gamma2 receptors (WSS-1 cells) to establish whether the subunit competes with the gamma2 subunit for assembly into receptors. GABA-evoked currents were recorded using the patch-clamp technique from cells transfected with cDNA encoding green fluorescent protein (GFP) alone or in combination with the epsilon subunit cDNA. 2. The epsilon subunit did not change the potency of GABA: the GABA EC(50) was 34 +/- 6 microM in control WSS-1 cells and 37 +/- 6 microM in cells expressing the epsilon subunit. The introduction of the epsilon subunit reduced the peak current amplitude activated by GABA (1 mM) from 1.8 +/- 0.2 nA in control cells to 0.9 +/- 0.2 nA in cells expressing the epsilon subunit (P < 0.05). 3. The epsilon subunit caused the appearance of leak currents recorded in the absence of GABA. Outside-out patches excised from epsilon subunit-containing WSS-1 cells exhibited spontaneously opening GABA(A) channels not seen in patches excised from control GFP-expressing WSS-1 cells. Introduction of the epsilon subunit did not alter the GABA-evoked single-channel cord conductance. 4. The anaesthetic 2,6-diisopropylphenol (propofol, 3 microM) and the benzodiazepine flunitrazepam (1 microM) potentiated GABA-evoked currents recorded from control cells labelled with GFP. The epsilon subunit reduced potentiation by both agents 48-96 h after transfection. 5. The introduction of the epsilon subunit had no effect on the ability of propofol (3-30 microM) relative to GABA (1 mM) to activate GABA(A) receptors in WSS-1 cells. High concentrations of propofol (> or = 100 microM) produced a more marked desensitization of GABA(A) receptor activity in WSS-1 cells transfected with cDNA for the epsilon subunit than in control cells. 6. There was no difference in the potency of Zn(2+) as an inhibitor of currents recorded from control cells (IC(50) = 165 +/- 34 microM) or cells expressing the epsilon subunit (IC(50) = 179 +/- 11 microM). 7. GABA-activated currents recorded both from control cells and cells expressing the epsilon subunit reversed in sign at the Cl- equilibrium potential and exhibited outward rectification. 8. The introduction of the epsilon subunit changes the functional properties of GABA(A) receptors in WSS-1 cells. The resulting receptors have a unique combination of properties indicative of the co-assembly of alpha, beta, gamma and epsilon subunits.

Anesthetics, Intravenous↗
PubMed1998

Photoaffinity labeling of the benzodiazepine binding site of alpha1beta3gamma2 gamma-aminobutyric acidA receptors with flunitrazepam identifies a subset of ligands that interact directly with His102 of the alpha subunit and predicts orientation of these within the benzodiazepine pharmacophore.

Photoincorporation of ligands into the benzodiazepine site of native gamma-aminobutyric acidA (GABAA) receptors provides useful information about the nature of the benzodiazepine (BZ) binding site. Photoincorporation of flunitrazepam into a single population of GABAA receptors, recombinant human alpha1beta3gamma2, was investigated to probe further the mechanism and orientation of flunitrazepam and other ligands in the BZ binding site. It was concluded that the receptor is primarily derivatized with the entire, unfragmented, flunitrazepam molecule, which undergoes a conformational change during photolysis and largely vacates the benzodiazepine binding site. Investigation of the BZ site after photoincorporation of [3H]flunitrazepam confirmed that binding of other radioligands was unaffected by incorporation of flunitrazepam. This did not correlate with their efficacy but depended on the presence of particular structural features in the molecule. It was observed that affected compounds have a pendant phenyl moiety, analogous to the 5-phenyl group of flunitrazepam, which are proposed to overlap and interact with the same residue or residues in the BZ binding site. Because the major site of flunitrazepam photoincorporation has been shown to be His102, we propose that this group of compounds interacts directly with His 102, whereas compounds of other structural types have no direct interaction with this amino acid. The orientation of ligands within the BZ binding site and their specific interaction with identified amino acids are not well understood. The data in the current study indicate that His102 interacts directly with the pendant phenyl group of diazepam, and further implications for the pharmacophore of the BZ binding site are discussed.

Azides↗
PubMed2000

Evidence that long-lasting potentiation of amygdala efferents in the right hemisphere underlies pharmacological stressor (FG-7142) induced lasting increases in anxiety-like behaviour: role of GABA tone in initiation of brain and behavioural changes.

The hypothesis that long-lasting potentiation (LLP) in amygdala efferents to the periacqueductal gray (PAG) of the right hemisphere mediates initiation of lasting increases in defensive response to rats induced by FG-7142 was supported in this study. GABA transmission was potentiated with Vigabatrin (gamma vinyl GABA, GVG), a suicide inhibitor of GABA transaminase. It was predicted that increasing GABA transmission would interfere with LLP and behavioural changes. The hypothesis was confirmed, for the most part. GVG given 1 day prior to FG-7142 prevented increased defensive response to rats as well as LLP in right amygdala efferent transmission to the PAG. It did not prevent LLP in the left amygdalo-PAG pathway, although LLP duration was shortened. Nor did it prevent LLP in the right amygdalo-ventromedial hypothalamic (VMH) pathway, and LLP in this pathway was associated with a slightly increased response to vocal threat, but not to rats. GVG given without FG-7142 had no behavioural effects, although it did potentiate transmission in the left amygdalo-PAG pathway. The effects of increasing GABA transmission are consistent with the hypothesis that FG-7142 changes behaviour by inducing a failure of GABA transmission, which in turn facilitates NMDA transmission and NMDA dependent limbic LLP. Finally, the hypothesis that altering GABA tone would change the efficacy of Flumazenil from a neutral antagonist to an inverse agonist was tested on limbic transmission. The hypothesis was confirmed in the left amygdalo-VMH pathway, but no other. It was concluded that mechanisms other than a change in GABA tone account for the drug-dependent reversal of LLP in the right amygdalo-PAG by Flumazenil. The findings of the present study suggest that response to FG-7142 may be a useful model of the effects of traumatic stressors on limbic system function in anxiety.

Aggression↗
PubMed1995

Possible involvement of peripheral-type benzodiazepine receptors in erythroid differentiation of human leukemia cell line, K562.

Possible involvement of the peripheral-type benzodiazepine receptor (PBR) in hemin/protoporphyrin-induced erythroid differentiation of human leukemia K562 cells was investigated by the use of the ligands, diazepam and PK11195. Diazepam itself exhibited differentiation-inducing activity on K562 cells. The PBR-specific antagonist, PK11195, dose-dependently inhibited both diazepam-induced and hemin/protoporphyrin-induced K562 cell differentiation. The results imply that PBR is involved in the erythroid differentiation of K562 cells.

Cell Differentiation↗
PubMed1998

A possible therapeutic solution for stomatodynia (burning mouth syndrome).

Stomatodynia is a difficult disease for both patients and clinicians. When facing true stomatodynia, i.e., idiopathic burning mouth, patients are offered poorly effective treatment. This open study reports the results of local application of clonazepam (0.5 or 1 mg) two or three times daily in 25 subjects who suffered from idiopathic stomatodynia. At the first evaluation, 4 weeks after the beginning of treatment, a visual analogue scale (VAS) that represented the intensity of pain decreased significantly from 6.2 +/- 0.3 to 3.0 +/- 0.5. At the second evaluation, 3 to 29 months after the first consultation, the VAS scores dropped significantly further to 2.6 +/- 0.5. Analysis of the individual results showed that 10 patients were totally cured and needed no further treatment, 6 patients had no benefit at all, and the remaining 9 patients had some improvement but were not considered to be cured since they did not wish to stop the treatment. Blood level tests that were performed 1 and 3 hours after the topical application revealed the presence of small amounts of the drug (3.3 ng/mL +/- 0.66 and 3.3 ng/mL +/- 0.52, respectively). The hypothesis that clonazepam acts locally to disrupt the neuropathologic mechanism that underlies stomatodynia is proposed. The risk factors that are recognized for this condition could decrease the density and/or ligand affinity of peripheral benzodiazepine receptors. This, in turn, could cause spontaneous pain from the tissues concerned.

Adult↗
PubMed2000

Pharmacophore/receptor models for GABA(A)/BzR alpha2beta3gamma2, alpha3beta3gamma2 and alpha4beta3gamma2 recombinant subtypes. Included volume analysis and comparison to alpha1beta3gamma2, alpha5beta3gamma2, and alpha6beta3gamma2 subtypes.

Pharmacophore/receptor models for 6 recombinant GABA(A)/BzR subtypes (alphax beta3gamma2, x = 1-6) have been established via an SAR ligand mapping approach. This study was based on the affinities of 166 BzR ligands at 6 distinct (alpha1-6beta3gamma2) recombinant GABA(A)/BzR receptor subtypes from at least twelve different structural families. Examination of the included volumes indicated that the shapes of binding pockets for alpha1, alpha2 and alpha3 subtypes are very similar to each other. Region L2 for the alpha5 containing subtype appeared to be larger in size than the analogous region of the other receptor subtypes. Region L(Di), in contrast, appeared to be larger in the alpha1 subtype than in the other subtypes. Moreover, region L3 in the alpha6 subtype is either very small or nonexistent in this diazepam insensitive "DI" subtype as compared to the other subtypes. Preliminary results for the alpha4-containing receptor subtype (DI) indicate that L3 in the alpha4 subtype suffers a similar fate. Use of the pharmacophore/receptor models for these subtypes have resulted in the design of novel BzR ligands selective for the alpha5beta3gamma2, receptor subtype.

Animals↗
PubMedDate not supplied

[State of GABA-benzodiazepine receptor complex in diabetic neuropathy: effect of nicotinamide and nicotinoyl-GABA].

An increase in GABA uptake by isolated rat brain synaptic endings as well as a decrease of pharmacologically active GABA analogue muscimol specific binding have indicated a physiologically drastic failure in realization of GABA-mediated inhibitory effects in CNS induced by diabetic encephalopathy. In spite of the impairment of inhibitory function of GABAergic transmission in diabetes a crucial activation of benzodiazepine receptors was determined, as it is tested by the increase in specific binding of flunitrazepam by synaptic membranes. This increase may play an important role in endogenous control of neural activity associated with the factors undefined so far. Using the approach that GABA, and several synthetic GABA agonists, appear to increase the affinity of the benzodiazepine recognition sites for such ligands, presumably by some allosteric mechanism, the findings concerning the in vitro binding assay technique confirm at least some of the functional characteristics observed between GABA and benzodiazepine receptors in vivo under pathological conditions. Indeed, the absence of activating effect on the affinity of flunitrazepam specific binding in the presence of micromolar concentrations of exogenous GABA implicate diabetes-induced alterations in coupling GABA- and benzodiazepine receptors that might be linked to changes in conformantial state of this membrane-bound complex and could partially explain diabetes-induced impairments of GABAergic transmission evaluated in the present study. Our study suggests that nicotinamide and especially GABA play an important role in improving the functioning of brain GABA-benzodiazepine complex impaired in diabetes through specific ligand-mediated mechanism and can be useful in the management of diabetes-associated brain failures.

Animals↗
PubMed1995

New 2,3-substituted 4,7-dihydro-6-(1'H-pyrazol-3'-yl)pyrazolo[1,5-a] pyrimidin-7-ones and related compounds: synthesis and benzodiazepine receptor binding study.

The reaction between two series of 7-dimethylaminovinyl pyrazolo[1,5-a]pyrimidines 4(a-r) 7a, 7d, 7f, 7(h-j) and hydrazine in acetic acid is investigated. The structure of 4,7-dihydro-6-(1'H-pyrazol-3'-yl)pyrazolo[1,5-a]pyrimidin-7- ones 5(a-r) and 7-methyl-6-(1'H-pyrazol-3'-yl)pyrazolo[1,5-a]pyrimidines 8a, 8d, 8f, 8(h-j) are attributed to the isolated products and the pathway of this reaction is suggested. The in vitro benzodiazepine receptor (BzR) affinity of the title compounds are determined by testing their ability to displace 3H-flunitrazepam from its specific binding in bovine brain membranes. The IC50 and GABA (gamma-aminobutyric acid) ratio values give valuable indications about affinity and behavioural profile of these new BzR ligands. Included in this investigation are indicated several structure-affinity relationships of the title compounds.

Animals↗
PubMed1997

Silent GABAA synapses during flurazepam withdrawal are region-specific in the hippocampal formation.

Whole-cell patch-clamp recordings were made from CA1 pyramidal and dentate gyrus granule cells (GCs) in hippocampal slices to assess the effects of withdrawal from chronic flurazepam (FRZ) treatment on the function of synaptic GABAA receptors. In slices from control rats, acute perfusion of FRZ (30 microM) increased the monoexponential decay time constant of miniature IPSCs (mIPSCs) in CA1 and GCs (from 3.4 +/- 0.6 to 7.6 +/- 2.1 msec and from 4.2 +/- 0. 6 to 7.1 +/- 1.8 msec, respectively) but did not change their mean conductance, 10-90% rise time, or frequency of occurrence. Withdrawal (2-5 d) from chronic in vivo FRZ treatment (40-110 mg/kg per day, per os) resulted in a dramatic loss of mIPSCs in CA1 neurons. On day 5 of withdrawal, no mIPSCs could be recorded in 40% of CA1 pyramidal cells. In the remaining 60% of the neurons, mIPSCs had a reduced mean conductance (from 0.78 +/- 0.12 nS in vehicle-treated controls to 0.31 +/- 0.05 nS) and a diminished frequency of occurrence (from 20.7 +/- 7.9 to 4.1 +/- 0.6 Hz). We have estimated that >80% of GABAA synapses on CA1 pyramidal cells had become silent, whereas at still-active synapses the number of functional GABAA receptor channels decreased by 60%. This reduction rapidly reverted to control levels on day 6 of withdrawal. FRZ withdrawal did not alter mIPSC properties in GCs. Our results are consistent with the hypothesis that chronic benzodiazepine treatment leads to a reduced number of functional synaptic GABAA receptors in a region-specific manner that may stem from differences in the subunit composition of synaptic GABAA receptors.

Animals↗
PubMedDate not supplied

Alterations of benzodiazepine receptor binding potential in anxiety and somatoform disorders measured by 123I-iomazenil SPECT.

123I-iomazenil (IMZ), a newly developed radioligand which acts on benzodiazepine receptors (BZR) as a partial inverse agonist, made it possible to evaluate the function of central BZR by single photon emission tomography (SPECT). To examine the alterations of the binding potential (BP) in the anxiety state, 123I-IMZ SPECT was performed in five patients with anxiety and somatoform disorders, and five epileptic patients without anxiety symptoms served as a reference. The BP of BZR was determined by using a table look-up procedure based on a three-compartment, two-parameter model in the bilateral superior frontal, inferior frontal, temporal, parietal, occipital, and cerebellar cortex. The mean BP of patients with anxiety and somatoform disorders was significantly decreased in the superior frontal, temporal, and parietal cortex, in comparison with that of epileptic patients. A significant correlation was observed between the anxiety levels scored on the Hamilton anxiety scale and BP in the right temporal cortex and left superior frontal cortex. These changes in BZR revealed by SPECT suggest the usefulness of 123I-IMZ SPECT to objectively evaluate anxiety levels in patients with anxiety symptoms.

Adult↗
PubMed2000

Mice lacking the long splice variant of the gamma 2 subunit of the GABA(A) receptor are more sensitive to benzodiazepines.

The gamma 2 subunit is required for benzodiazepine modulation of the GABA(A) receptor. Alternate splicing of precursor GABA(A) gamma 2 mRNA results in two splice variants, a short (gamma 2S) and a long (gamma 2L) variant. We investigated the roles of these splice variants in benzodiazepine pharmacology using mice lacking genes for the gamma 2L splice variant. Sleep time responses to midazolam and zolpidem were 20 and 18% greater, respectively, in null allele mice compared with wild-type mice, while responses to nonbenzodiazepine agents such as etomidate and pentobarbital were unchanged. Although the GABA(A) receptor number was not altered in null allele mice, there was a corresponding increase in affinity of brain membranes for benzodiazepine agonists (midazolam, diazepam, and zolpidem), while affinity for benzodiazepine inverse agonists (beta CCM and Ro15-4513) was decreased. These changes were not observed in inbred mice of the parental strains (C57BL/6J and 129/SvJ) used to create the genetically altered mice, indicating that differences between gamma 2L null allele and wild-type mice were unlikely to be simply due to cosegregation of linked alleles. Absence of the gamma 2L splice variant increases the affinity of receptors for benzodiazepine agonists, and is associated with a modest increase in behavioral sensitivity to benzodiazepine agonists. Lack of the gamma 2L subunits may shift the GABA(A) receptor from an inverse agonist-preferring toward an agonist-preferring configuration.

Alternative Splicing↗
PubMed2003

Involvement of GABA-A receptor chloride channel complex in isolation stress-induced free choice ethanol consumption in rats.

The present study revealed the effect of diazepam, a benzodiazepine, and progesterone, a pregnane precursor of neurosteroids, which act via modulating GABA-A chloride channel complex on the isolation stress-induced free choice ethanol consumption in adult rats. Isolation stress for 24 hr over a period of 6 days produced a significant increase in ethanol consumption, which persisted during the 6-day recovery period. Pretreating the animals with diazepam (5 mg/kg, i.p.), or progesterone (5 mg/kg, i.p.), blocked the isolation stress-induced increase in ethanol consumption. Bicuculline (2 mg/kg, i.p.), a GABA-A receptor antagonist significantly attenuated the effect of both diazepam and progesterone on stress-induced modulation of ethanol consumption. Isolation stress also caused an increase in total fluid consumption, which was antagonised by both diazepam and progesterone. Like ethanol consumption, this effect of diazepam and progesterone on isolation stress-induced increase in total fluid consumption was attenuated by bicuculline. Neither diazepam nor progesterone produced an increase in ethanol consumption in non-stressed rats. However, unlike diazepam, progesterone administration to non-stressed rats caused a significant increase in total fluid consumption. Results of the present study thus show that GABAergic mechanisms may be playing an important role in isolation stress-induced increase in ethanol consumption.

Animals↗
PubMed2006

Cyclodextrins sequester neuroactive steroids and differentiate mechanisms that rate limit steroid actions.

BACKGROUND AND PURPOSE: Neuroactive steroids are potent modulators of GABA(A) receptors and are thus of interest for their sedative, anxiolytic, anticonvulsant and anaesthetic properties. Cyclodextrins may be useful tools to manipulate neuroactive effects of steroids on GABA(A) receptors because cyclodextrins form inclusion complexes with at least some steroids that are active at the GABA(A) receptor, such as (3alpha,5alpha)-3-hydroxypregnan-20-one (3alpha5alphaP, allopregnanolone). EXPERIMENTAL APPROACH: To assess the versatility of cyclodextrins as steroid modulators, we investigated interactions between gamma-cyclodextrin and neuroactive steroids of different structural classes. KEY RESULTS: Both a bioassay based on electrophysiological assessment of GABA(A) receptor function and optical measurements of cellular accumulation of a fluorescent steroid analogue suggest that gamma-cyclodextrin sequesters steroids rather than directly influencing GABA(A) receptor function. Neither a 5beta-reduced A/B ring fusion nor a sulphate group at carbon 3 affected the presumed inclusion complex formation between steroid and gamma-cyclodextrin. Apparent dissociation constants for interactions between natural steroids and gamma-cyclodexrin ranged from 10-60 microM. Although gamma-cyclodextrin accommodates a range of natural and synthetic steroids, C(11) substitutions reduced inclusion complex formation. Using gamma-cyclodextrin to remove steroid not directly bound to GABA(A) receptors, we found that cellular retention of receptor-unbound steroid rate limits potentiation by 3alpha- hydroxysteroids but not inhibition by sulphated steroids. CONCLUSIONS AND IMPLICATIONS: We conclude that gamma-cyclodextrins can be useful, albeit non-specific, tools for terminating the actions of multiple classes of naturally occurring neuroactive steroids.

Animals↗
PubMed1998

GABA receptors and benzodiazepine binding sites modulate hippocampal acetylcholine release in vivo.

In the present study, the regulation of acetylcholine release from the ventral hippocampus by gamma-aminobutyric acid (GABA) was investigated in vivo. GABA receptor agonists and antagonists were administered locally in the medial septum and the adjacent vertical limb of the diagonal band of Broca, or in the hippocampus by retrograde dialysis. Acetylcholine release was measured in the ventral hippocampus. In addition, the modulation of acetylcholine release via septal benzodiazepine binding sites was assessed by intraseptal administration of an agonists and an antagonist at the benzodiazepine binding site. Intraseptal administration of the GABA(A) receptor agonist muscimol and the GABA(B) receptor agonist baclofen, but not the agonist of the benzodiazepine binding site midazolam, decreased acetylcholine release in the hippocampus. The GABA(A) receptor antagonist bicuculline and the antagonist of the benzodiazepine binding site flumazenil, but not the GABA(B) receptor antagonist 3-N-(3,4,-dichlorobenzyl) aminopropyl-P-diethoxymethyphosphinic acid (CGP 52432) increased acetylcholine release in the hippocampus upon intraseptal administration. The same GABA receptor ligands were administered in the ventral hippocampus. CGP 52432 induced a small increase in acetylcholine release, whereas baclofen, muscimol and bicuculline did not affect local acetylcholine release. Thus, endogenous GABA causes tonic inhibition of acetylcholine release in the ventral hippocampus via septal GABA(A) receptors and, to a lesser extent, via GABA(B) receptors in the medial septum and hippocampus. The GABAergic inhibition in the medial septum is reduced by antagonists of the benzodiazepine binding site.

Acetylcholine↗
PubMed1991

Excitotoxic index--a biochemical marker of selective vulnerability.

We have previously demonstrated that elevated intraischemic glutamate levels are insufficient, of themselves, to engender ischemic damage. Glycine and gamma-aminobutyric acid (GABA), which modulate glutamatergic activity, may also play a significant role. We compared ischemia-induced changes in glutamate, glycine, and GABA release in a selectively vulnerable region (dorsolateral striatum) to the changes occurring in a region, although rendered ischemic, is usually spared with 20 min ischemia (anterior thalamus). Regional extracellular neurotransmitter levels were measured by microdialysis before, during, and after 20 min of global ischemia induced by 2-vessel occlusion plus systemic hypotension in the rat (n = 5). Similar ischemia-induced increases in glutamate, GABA, and glycine were observed in both striatum and thalamus (19-25 fold, 43-52 fold, and 3-4 fold, respectively). During recirculation, both glutamate and GABA returned to baseline in both regions by 30 min of reperfusion. Glycine levels remained two-fold higher than baseline in the striatum but fell to baseline in the thalamus. To derive a quantitative descriptor reflecting the composite magnitude of aminoacid neurotransmitter changes with ischemia, we defined the 'excitotoxic index' as: [glutamate] x [glycine]/[GABA]. While increases in the excitotoxic index during ischemia were similar for striatum and thalamus, a marked and highly significant increase was found in the striatum compared to the thalamus at early (1 h = 91.5 +/- 27.4 and 25.1 +/- 6.3, P less than 0.01, ANOVA) as well as later recirculation times (2 h = 111.3 +/- 30.9 and 20.9 +/- 3.6, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2001

Early postnatal ethanol intubation blunts GABA(A) receptor up-regulation and modifies 3alpha-hydroxy-5alpha-pregnan-20-one sensitivity in rat MS/DB neurons.

Previously we found postnatal binge-like ethanol exposure using an artificial-rearing method in the rat delayed developmental up-regulation of GABA(A) receptors (GABA(A)Rs) in both medial septum/diagonal band (MS/DB) and cerebellar Purkinje neurons. In the present study, the impact of ethanol on developing GABA(A)Rs in MS/DB neurons was further tested under conditions not requiring anesthesia or maternal deprivation. Nursing rat pups received ethanol (4.5-5.25 g/kg/day) on postnatal days (PD) 4-9, which was administrated manually by oral intragastric intubation. This treatment caused dose-dependent blunting of peak GABA(A) receptor whole cell currents in acutely dissociated MS/DB cells on PD 12-15. The threshold with oral intubation was slightly higher than previously observed for artificial-rearing (4.9 vs. 4.5 g/kg/day). The previously observed reduced sensitivity of GABA(A)Rs to Zn(2+)-inhibition after ethanol was not found with the intubation model. In studies only carried out using the intubation method, 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha-OH-DHP) caused an allosteric concentration-dependent potentiation of currents activated by non-saturated concentrations of GABA. A bicuculline sensitive direct activation of GABA(A)Rs also occurred with higher concentrations of 3alpha-OH-DHP alone. Ethanol intubation up-regulated allosteric neurosteroid potentiation with low concentrations of GABA, but did not change direct agonist actions of 3alpha-OH-DHP. Finally, 3alpha-OH-DHP did not prime ethanol insensitive GABA(A)Rs to become sensitivity to acute ethanol potentiation. These results indicate ethanol consistently blunts postnatal GABA(A) receptor up-regulation across early postnatal binge-type ethanol exposure models and may increase positive modulation of GABA(A) receptors by endogenous neurosteroids.

Age Factors↗
PubMed2003

Dynorphinergic GABA neurons are a target of both typical and atypical antipsychotic drugs in the nucleus accumbens shell, central amygdaloid nucleus and thalamic central medial nucleus.

Administration of typical and atypical antipsychotic drugs leads to activation of cells in the nucleus accumbens shell, central amygdaloid nucleus, and midline thalamic central medial nucleus, implicating important shared effects of these drugs. However, the exact cell types responding to antipsychotic drugs in the nucleus accumbens shell, central amygdaloid nucleus, and midline thalamic central medial nucleus are unclear. We report here that, in a rat model, the results of studies using double immunofluorescence labeling with antibodies directed against markers specific to candidate cell types suggest that the cells responding to haloperidol and clozapine in all three sites are: 1) neurons, rather than astrocytes; 2) inhibitory GABA neurons, but not acetylcholinergic neurons; and 3) dynorphin-containing GABA neurons, but not M-enkephalin-containing GABA neurons. The present study provides pharmacological evidence, at the cellular level in vivo, that the shared effects of antipsychotic drugs, whether typical and atypical, is activation of dynorphinergic GABA neurons in the nucleus accumbens shell, central amygdaloid nucleus, and midline thalamic central medial nucleus. Alternative ways to modulate dynorphinergic GABA neuronal activity or its target receptors might present an important new avenue for the treatment of schizophrenia and other psychotic disorders.

Acetylcholine↗