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M K Ticku

Publications and source records attributed to M K Ticku.

At least 37 records · Page 2Linked to original sources
PubMed1996

Postnatal phencyclidine treatment differentially regulates N-methyl-D-aspartate receptor subunit mRNA expression in developing rat cerebral cortex.

The present study was designed to determine the effects of chronic neonatal exposure to the NMDA receptor antagonist phencyclidine (PCP) on [3H]MK-801 binding and on gene expression of NMDA receptor subunits in juvenile male rats. Rat pups were injected daily with PCP from day 5 to 15 and killed on day 21. [3H]MK-801 binding was measured by quantitative autoradiography. A sensitive RNase protection assay was employed to determine simultaneously the mRNA levels of NR1 subunit (comprising all different splice variants) and three NR2 subunits (NR2A-NR2C). The relative distribution profile of NMDA receptor subunits in the cerebral cortex was NR2B > NR1 > NR2A > NR2C and in the cerebellum NR2C = NR1 > NR2A = NR2B. Chronic PCP administration in postnatal rats produced significant reduction in both [3H]MK-801 binding and mRNA level of the NR2B subunit in the cerebral cortex. Expression of the other NMDA receptor subunits in the cerebral cortex did not change following the drug treatment. In the cerebellum, neither [3H]MK-801 binding nor any of the NMDA receptor subunit expression levels showed any alteration. Together, these data provide a molecular correlate for chronic postnatal PCP-induced down-regulation of [3H]MK-801 binding in rat cerebral cortex and suggest that the NR2B subunit plays an important role in developmental plasticity.

Animals↗
PubMed1996

Chronic ethanol-mediated up-regulation of the N-methyl-D-aspartate receptor polypeptide subunits in mouse cortical neurons in culture.

The goal of this study was to determine whether chronic ethanol-mediated up-regulation of the N-methyl-D-aspartate receptors (NMDAR) was associated with an augmentation of the NMDAR polypeptide subunits in the mammalian cortical neurons. The results show that chronic ethanol treatment produced an increase in the R1 and R2B polypeptide subunits. The R2A subunit was not expressed in these neurons. Chronic NMDAR antagonist ((+)-3-2-(carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP)) treatment also increased the R1 and R2B polypeptide subunits. A similar increase was observed when ethanol and CPP were used in combination. Binding studies using [3H]MK-801 ((+)-5-methyl-10, 11-dihydro-5H-dibenzo[a,d]cyclophenptan-5,10-imine maleate), a noncompetitive NMDAR antagonist, confirmed that concomitant exposure of ethanol and CPP up-regulated the NMDAR. Our results demonstrate for the first time that chronic ethanol treatment increased the NMDA receptor polypeptide subunit synthesis and that it was associated with an increase in [3H]MK-801 binding sites.

Animals↗
PubMed1996

NMDA receptor upregulation: molecular studies in cultured mouse cortical neurons after chronic antagonist exposure.

We examined the possibility of changes in gene expression of the NMDA receptor subunits after chronic antagonist treatment. Exposure of neurons to the NMDA antagonist D(-)-2-amino-5-phosphonopentanoic acid (AP-5) produced an increase in the levels of the R2B mRNA subunit. Concomitant exposure of neurons to AP-5 and NMDA reversed the upregulation. Chronic AP-5 treatment increased the R1 polypeptide, whereas no change was observed in the levels of mRNA encoding the R1 subunit. A more pronounced increase was observed in the R2A/B polypeptides. These data demonstrate that chronic treatment with NMDA antagonists selectively upregulates the NMDA receptor mRNAs and polypeptides. Furthermore, antagonist treatment produced a differential regulation of the R1, R2A, and R2B subunits in cortical neurons.

2-Amino-5-phosphonovalerate↗
PubMed1996

Chronic neurosteroid treatment attenuates single cell GABAA response and its potentiation by modulators in cortical neurons.

In previous studies we have observed that chronic neurosteroid 5 alpha-pregnan-3 alpha-ol-20-one (5 alpha 3 alpha) treatment produced downregulation of the GABAA receptors, heterologous uncoupling, and decreased heterologous efficacy at the GABAA receptor complex in cultured mammalian cortical neurons. In this study, using whole cell recording, we examined the consequence of chronic 5 alpha 3 alpha (1 microM; 5 days) treatment on GABA-induced currents in isolated cortical neurons. We observed that the GABA current was decreased by 78% after 5 days treatment of cortical cells with 1 microM 5 alpha 3 alpha. We also observed decreased pentobarbital, and 5 alpha 3 alpha potentiation of GABA currents after chronic 5 alpha 3 alpha treatment. These findings support the notion that GABA response, and its potentiation by pentobarbital, and neurosteroid, 5 alpha 3 alpha, are attenuated after chronic 5 alpha 3 alpha treatment.

Animals↗
PubMed1996

Chronic ethanol treatment produces a selective upregulation of the NMDA receptor subunit gene expression in mammalian cultured cortical neurons.

Our previous work has shown that chronic ethanol treatment upregulated NMDA receptor function and binding in mammalian cortical neurons. However, the potential molecular mechanisms involved in these phenomenon have yet to be elucidated. In the present study, using RNase protection assay, we investigated the effect of chronic ethanol treatment on the NMDA receptor subunits R1, R2A, and R2B mRNA levels in cultured cortical neurons. We found that chronic ethanol (50 mM, 5 days) exposure did not change the NMDA receptor R1 and R2A subunits mRNA levels. In contrast, the NMDA receptor R2B subunit mRNA level was increased by approximately 40% with respect to the control values. The levels of the R2B subunit mRNA returned to the control values following the removal of ethanol for 72 h. In order to determine the involvement of the NMDA receptors in the action of chronic ethanol exposure, we further investigated the effect of the NMDA receptor antagonists on the upregulation induced by chronic ethanol exposure. The results indicate that the increased R2B subunit level was reversed by concomitant chronic exposure of the cortical neurons to the NMDA receptor competitive (10 microM; CPP), and non-competitive (1 microM; MK-801) antagonists, but not by the non-NMDA receptor antagonist, CNQX (10 microM), or the L-type calcium channel blocker, nitrendipine (10 microM). Taken together, these results suggested that chronic ethanol exposure selectively upregulated the NMDA receptor subunit R2B mRNA level in cortical neurons, and this increased NMDA receptor gene expression appears to be a NMDA receptor mediated process. The altered NMDA receptor gene expression may be responsible for the observed upregulation of the NMDA receptor binding and function in the cortical neurons following chronic ethanol exposure.

Animals↗
PubMed1995

Chronic ethanol treatment differentially regulates NMDA receptor subunit mRNA expression in rat brain.

Previous studies have implicated the N-methyl-D-aspartate receptor (NMDAR) complex in the physical dependence and withdrawal effects of chronic ethanol administration. In this study, we examined the effect of chronic ethanol administration and ethanol withdrawal on the NMDAR subunit R1, R2A, R2B, and R2C mRNA levels in rat hippocampus, cerebral cortex, and cerebellum. Using the RNase protection assay, we compared the levels of the NMDAR subunits mRNAs in ethanol-treated and control rats. Our results indicate that chronic ethanol administration and ethanol withdrawal do not change the NMDAR R1 subunit mRNA levels in cerebral cortex, hippocampus, or cerebellum at any time point. In contrast, 9 h after the last ethanol administration the R2A and R2B mRNA subunits were elevated by approximately 40% in cerebral cortex, and approximately 30% in hippocampus with respect to the levels in control animals. At 48 h the mRNA levels returned to the control levels. The chronic ethanol treatment did not alter R1, R2A, and R2C subunit mRNA levels in cerebellum. Our results demonstrate that chronic ethanol administration produces a differential regulation of the genes encoding the various subunits of the NMDAR.

Animals↗
PubMed1995

Chronic ethanol treatment upregulates the NMDA receptor function and binding in mammalian cortical neurons.

In the present study, we investigated the effects of chronic ethanol exposure on NMDA-mediated increase in intracellular calcium concentration ([Ca2+]i) by means of fluorescent measurement of [Ca2+]i with Fura-2AM in mammalian cortical cultured neurons, and the radioligand [3H]MK-801 binding to cortical neuronal membranes. Chronic exposure of the cortical neurons to ethanol (50 mM, 5 days) did not produce any change in the cell protein, morphological appearance, and the resting [Ca2+]i; however, it significantly enhanced the NMDA-mediated increase in [Ca2+]i. The EC50 value of NMDA was not significantly altered following chronic ethanol exposure, however, its Emax value was increased by approximately 45%. Furthermore, chronic ethanol exposure increased the specific [3H]MK-801 binding in cortical neuronal membrane preparation by approximately 30%. The enhancement of the NMDA-mediated increase in [Ca2+]i and the increase in [3H]MK-801 specific binding were reversed following 48 h ethanol withdrawal. Additionally, this enhanced NMDA response and the increased [3H]MK-801 specific binding were susceptible to blockade by the concomitant chronic exposure of the cortical neurons to the NMDA receptor competitive (20 microM CPP), and non-competitive (1 microM MK-801) antagonists, but not by the non-NMDA receptor antagonist, CNQX (10 microM), and the L-type calcium channel blocker, nitrendipine (10 microM). Taken together, these results suggest that chronic ethanol exposure upregulated the NMDA receptor function and binding in cortical cultured neurons, and this increased NMDA receptor function is a NMDA receptor-mediated process. This altered NMDA receptor function may be responsible for the chronic ethanol-induced behavioral consequences and withdrawal syndrome associated with chronic ethanol exposure.

Animals↗
PubMed1995

Effects of the anticonvulsant losigamone and its isomers on the GABAA receptor system.

We conducted in vitro studies to clarify the possible involvement of GABAA receptor-mediated processes in the anticonvulsant effects of losigamone and its optical isomers AO-242 (+ losigamone) and AO-294 (- losigamone). In binding experiments with cortical and cerebellar membrane preparations of rat brain, < or = 100 microM losigamone did not affect the specific binding of [3H]GABA, [3H]flunitrazepam, or [35S]t-butyl-bicyclophosphorothionate (TBPS) to their receptors. Losigamone, however, in concentrations of 10(-8)-10(-5) M, stimulated 36Cl influx into spinal cord neurons in the absence of exogenous GABA. This effect was inhibited by the GABA antagonists bicuculline (BIC) and picrotoxin (PIC). Losigamone 10(-5) M potentiated the effect of a suboptimal concentration of exogenous GABA 10(-5) M on 36 Cl influx. Both isomers of losigamone likewise stimulated 36Cl influx into spinal cord neurons, and these effects were similarly antagonized by BIC and PIC. Losigamone and its optical isomers AO-294 and AO-242 antagonized potassium-induced hyperexcitability in rat hippocampal slices concentration dependently. There were no clear differences in the potencies of losigamone, AO-242, or AO-294. However, AO-294 and AO-242 differed significantly in their ability to suppress TBPS-induced hyperexcitability of hippocampal slices. Such observations demonstrate that although losigamone does not bind to GABA, benzodiazepine (BZD) or PIC binding sites of the neuronal chloride channel, it is capable of stimulating 36Cl influx in the spinal cord neurons by a GABA-sensitive mechanism and at a side distant from the GABA channel.

Animals↗
PubMed1995

Chronic neurosteroid treatment decreases the efficacy of benzodiazepine ligands and neurosteroids at the gamma-aminobutyric acidA receptor complex in mammalian cortical neurons.

The effect of chronic 5 alpha-pregnane-3 alpha-ol-20-one (5 alpha 3 alpha; neurosteroid) treatment was investigated on the gamma-aminobutyric acid (GABA), 5 alpha 3 alpha, and ligands that bind to the benzodiazepine (BZ) site on GABA-induced [36Cl-]influx in intact cultured mammalian cortical neurons. Chronic 5 alpha 3 alpha treatment (1 microM; 5 days) decreased the efficacy of GABA, because its Emax (maximal response) value was decreased, whereas the EC50 (potency) value was not altered. Chronic 5 alpha 3 alpha treatment also decreased the Emax value of BZ agonists like diazepam to potentiate GABA-induced [36Cl-] influx, and decreased the -Emax (maximal inhibitory response) value of inverse agonists like methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3'-carboxylate to inhibit GABA-induced [36Cl-] influx, whereas not altering their EC50/IC50 values. Furthermore, chronic 5 alpha 3 alpha treatment decreased the Emax value of 5 alpha 3 alpha to potentiate GABA-induced [36Cl-] influx, without altering its EC50 value. The decreased efficacy of GABA and 5 alpha 3 alpha were reversed by concomitant exposure of the neurons to R 5135 (3 alpha-hydroxy-16-imino-5 beta-17-androstan-11-one; a competitive GABA antagonist). Taken together, these findings suggest that chronic 5 alpha 3 alpha treatment produces decreased efficacy of GABA, ligands that bind to the BZ site, and neurosteroids at the GABAA-BZ receptor complex. The decreased efficacy is heterologous in nature and involves mediation via the GABAA receptor site.

Animals↗
PubMed1995

Chronic neurosteroid treatment produces functional heterologous uncoupling at the gamma-aminobutyric acid type A/benzodiazepine receptor complex in mammalian cortical neurons.

We have investigated the effects of chronic treatment with the neurosteroid 5 alpha-pregnan-3 alpha-ol-20-one (5 alpha 3 alpha) on the gamma-aminobutyric acid (GABA)A receptor complex in cultured mammalian cortical neurons. Chronic 5 alpha 3 alpha treatment (up to 2 microM, 5 days) did not produce any changes in the morphological appearance or the cell protein content of cortical neurons. The basal binding of [3H]flunitrazepam, [3H]Ro15-1788, and [3H]Ro15-4513 was not altered after the chronic treatment. Chronic 5 alpha 3 alpha treatment did not alter the Kd or Bmax values of [3H]flunitrazepam binding to intact cortical neurons. However, chronic 5 alpha 3 alpha treatment produced uncoupling between GABA, barbiturate, and neurosteroid sites and the benzodiazepine site. The EC50 values of these ligands were not significantly altered; however, their Emax values were decreased after chronic 5 alpha 3 alpha treatment. The 5 alpha 3 alpha-induced uncoupling was time and concentration dependent. The binding of [3H]GABA and t-[35S]butylbicyclophosphorothionate was also decreased after chronic 5 alpha 3 alpha treatment. Chronic 5 alpha 3 alpha treatment decreased the Bmax of the low affinity GABAA receptor sites, without affecting the high affinity sites, and decreased the Bmax of t-butylbicyclophosphorothionate binding sites. The EC50 value for GABA-induced 36Cl- influx was not altered, whereas the Emax value was decreased after chronic 5 alpha 3 alpha treatment. Furthermore, the 5 alpha 3 alpha-induced uncoupling was reversed by concomitant exposure of the cortical neurons to 5 alpha-pregnan-3 beta-ol-20-one or R5135, suggesting an involvement of the neurosteroid and GABA recognition sites in the observed uncoupling. Taken together, these results suggest that chronic 5 alpha 3 alpha treatment produces heterologous uncoupling at the GABAA receptor complex.

Androstanes↗
PubMed1995

Effects of chronic pentobarbital treatment on the GABAA receptor complex in mammalian cortical neurons.

In this study we examined the binding characteristics of the gamma-aminobutyric acid (GABAA) receptor complex after chronic pentobarbital sodium treatment in cultured mammalian cortical neurons. Chronic pentobarbital sodium treatment (200 microM, 5 days) did not alter the basal binding of ligands like [3H]flunitrazepam, [3H]ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5 alpha][1,4]-BZ-3-carboxylate and [3H]ethyl-8-azido-5,6-dihydro- 5-methyl-6-oxo-4H-imidazo [1,5 alpha][1,4]BZ-3-carboxylate that bind to the benzodiazepine (BZ) recognition site of the GABAA receptor complex. Similarly, chronic pentobarbital sodium treatment did not alter the basal binding of [3H]GABA and t-butylbicyclophosphoro[35S]thionate. However, chronic pentobarbital sodium treatment produced uncoupling between GABA, barbiturate and neurosteroid sites with the BZ site. The efficacy (Emax) values of GABA, pentobarbital and neurosteroid, 5 alpha-pregnan-3 alpha-ol-20-one, on [3H]flunitrazepam binding were significantly decreased, whereas their potency (EC50) values were not altered after chronic pentobarbital sodium treatment. Taken together, these results suggest that chronic pentobarbital sodium treatment produces heterologous uncoupling of the GABA-BZ receptor ionophore complex.

Animals↗
PubMed1994

Development pattern of the GABAA-benzodiazepine receptor ionophore complex in primary cultures of cortical neurons.

The development pattern of the GABAA/benzodiazepine (BZ) receptor ionophore complex was characterized in mammalian cortical cultured neurons utilizing radioligand binding and GABA-induced 36Cl-influx. The specific binding of [3H]flunitrazepam, [3H]Ro15-1788 and [3H]Ro15-4513 increased with time from day 3 to day 21. The EC50 value and Emax of the GABA, muscimol and pentobarbital to enhance [3H]-flunitrazepam binding did not change during the development. Furthermore, GABA-induced 36Cl- influx also did not change during development from day 3 to day 21. However, the potency of ligands that bind to type-1 BZ receptors (alprazolam, zolpidem and C1218,872) to inhibit [3H]flunitrazepam binding increased from day 7 to day 21. Taken together, these data suggest the presence of type-II BZ receptors in early stages of the development which appears to change to type-I BZ receptors with age in the cortical neurons in culture.

Affinity Labels↗
PubMed1994

Ethanol enhancement of GABA-induced 36Cl- influx does not involve changes in Ca2+.

The effect of changes in intracellular Ca2+ on ethanol enhancement of GABA-mediated 36Cl- influx was investigated in mammalian cortical neurons in culture. Ethanol potentiated the effect of submaximal concentrations of GABA on the 36Cl- influx, and at 50 mM ethanol directly activated 36Cl- influx in these neurons. Pretreatment of the neurons with dantrolene (an agent that depletes intracellular Ca2+) and the Ca2+ ionophore, A 23187, did not alter the effect of GABA or ethanol enhancement of GABA-mediated 36Cl- influx. Together, these results suggest that changes in intracellular Ca2+ are not involved in ethanol modulation of GABAAergic responses in cortical neurons.

Animals↗
PubMed1994

Chronic GABA treatment downregulates the GABAA receptor alpha 2 and alpha 3 subunit mRNAS as well as polypeptide expression in primary cultured cerebral cortical neurons.

Chronic GABA exposure of mammalian primary cultured cortical neurons results in a downregulation of the GABA-benzodiazepine receptor complex. In the present study, the mRNA levels, as well as polypeptide expression, for the GABAA receptor alpha 2 and alpha 3 subunits in cultured embryonic mouse cerebral cortical neurons (7 day old) were examined using northern analysis and immunoblotting techniques following chronic GABA treatment. The alpha 1 subunit mRNA or polypeptide could not be detected in these neurons. The steady state levels of mRNA for the GABAA receptor alpha 2 and alpha 3 subunits showed a decrease in comparison with untreated neurons. There was no change in the level of the beta actin or poly(A)+ RNA under the same experimental conditions. This agonist-induced reduction in the GABAA receptor alpha 2 and alpha 3 subunit mRNA was blocked by the concomitant exposure of neurons to R 5135, an antagonist of GABAA receptor. The polypeptide expression for the GABAA receptor alpha 2 and alpha 3 subunits in chronically GABA-treated neurons also showed a decline and this change was also blocked by the concomitant exposure of cells to GABA and R 5135. These results indicate that the chronic exposure of the GABAA receptor complex to agonist downregulates the expression of the alpha subunits of the receptor complex, which may be related to an observed decreases in the number of binding sites and GABA-induced 36Cl-influx in the cortical neurons.

Amino Acid Sequence↗
PubMed1994

Chronic ethanol treatment upregulates the GABA receptor beta subunit expression.

The molecular mechanisms associated with ethanol-induced tolerance and physical dependence have yet to be elucidated. In previous studies we have demonstrated that chronic ethanol administration produced a decrease in the GABAA receptor mRNA level of alpha 1, alpha 2, alpha 5 subunits, and a decrease in the polypeptide (alpha 1, alpha 2, and alpha 3) expression in the rat cerebral cortex. In this study we examined the effect of chronic ethanol treatment on the mRNA levels and the expressions of the beta-subunits of the GABAA receptors in rat cerebral cortex. The results indicate that chronic ethanol administration produced an upregulation of the beta 1 subunit mRNA (12 kb) by 29 +/- 10%, beta 2 mRNA (8 kb) by 55 +/- 6% and the beta 3-subunit (6 kb) mRNA by 72 +/- 9% in cerebral cortex. The levels of the beta 2 and beta 3 subunit mRNAs remains elevated at 24 hr withdrawal. We also investigated the effect of chronic ethanol administration on the beta-subunit polypeptide expression using monoclonal antibody BD17, which recognizes the beta 2 (P56) and beta 3 (P58) polypeptides. Chronic ethanol treatment increased the levels of both of these polypeptides in cerebral cortex. Taken together, chronic ethanol administration produced an upregulation of the beta-subunit mRNA and the polypeptide expression of these subunits in rat cerebral cortex. In contrast, chronic ethanol treatment decreased the expression of various alpha-subunits in the cerebral cortex.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcoholism↗
PubMed1994

Chronic flurazepam treatment produces decreased efficacy of the benzodiazepine ligands and pentobarbital with gamma-aminobutyric acidA receptors in cortical neurons.

The present study was designed to determine whether chronic benzodiazepine (BZ) agonist treatment alters the "set point" of the BZ pharmacological profile. This was achieved by investigating the modulation of gamma-aminobutyric acid (GABA)-mediated [36Cl-] influx by BZ ligands, as well as pentobarbital after chronic flurazepam treatment, in well characterized mammalian cortical neurons. Chronic flurazepam treatment (5 microM, 10 days) produced decreased efficacy of BZ agonists (diazepam and flunitrazepam) and inverse agonists (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3'-carboxylate and ethyl-beta-carboline-3-carboxylate), as measured by GABA-induced [36Cl-] influx. The chronic flurazepam treatment, although not altering their EC50/IC50 values, decreased the Emax/-Emax values. Furthermore, the decreased efficacy was reversed after a 72-hr withdrawal, and by concomitant exposure of the neurons to Ro15-1788 (ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5 alpha][1,4]- BZ-3-carboxylate), a BZ receptor antagonist, but not by R 5135 (3 alpha-hydroxy-16-imino-5 beta-17-androstan-11-one; a GABA receptor antagonist) and pircrotoxin (a channel blocker). The chronic flurazepam treatment also produced uncoupling between pentobarbital and BZ receptor sites, and decreased the efficacy of pentobarbital to enhance GABA-mediated [36Cl-] influx, events also reversed at 72-hr withdrawal and concomitant exposure to Ro15-1788. Chronic flurazepam treatment-induced uncoupling and decreased efficacy of BZ agonists was not reversed by the GABAA receptor antagonist, R 5135, or channel blocker, picrotoxin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Chronic benzodiazepine agonist treatment produces functional uncoupling of the gamma-aminobutyric acid-benzodiazepine receptor ionophore complex in cortical neurons.

We have investigated the effect of chronic flurazepam HCl treatment on the gamma-aminobutyric acid (GABA)A receptor complex in cultured mammalian cortical neurons. Chronic flurazepam (1-5 microM, for 1-10 days) treatment did not produce any changes in the morphological appearance or the cell protein content of cortical neurons. The basal binding of [3H]flunitrazepam, [3H] Ro15-1788, and [3H]Ro15-4513 was also not altered after the chronic treatment. However, chronic flurazepam treatment produced uncoupling between GABA and pentobarbital sites and the [3H]flunitrazepam binding site. The EC50 values of GABA and pentobarbital were not significantly altered after chronic flurazepam treatment; however, their Emax values were decreased by approximately 50%. The effect of chronic flurazepam treatment on the observed uncoupling was both time and concentration dependent. Furthermore, the binding of [3H]GABA and t-butylbicyclophosphoro[35S]thionate was also not altered by chronic flurazepam treatment. The effect of GABA on 36Cl influx was not altered after chronic flurazepam treatment; however, treatment significantly attenuated the ability of diazepam to enhance GABA-induced 36Cl influx. Chronic flurazepam-induced uncoupling and decreased diazepam efficacy were reversed by the concomitant presence of the benzodiazepine antagonist Ro15-1788, suggesting that these events are mediated via the benzodiazepine receptor site. Taken together, these results suggest that chronic benzodiazepine treatment produces uncoupling of GABA and pentobarbital sites from the benzodiazepine site and decreased coupling between the benzodiazepine site and GABA receptor-gated Cl- channels. The uncoupling and decreased efficacy may be due to an alteration in the levels of various alpha subunits and may be responsible for the tolerance associated with chronic benzodiazepine agonist treatment.

Animals↗