Benzodiazepine tolerance at GABAergic synapses on hippocampal CA1 pyramidal cells. Regional differences in the inhibition of mouse in vivo [3H]Ro 15-1788 binding reflect selectivity for alpha 1 versus alpha 2 and alpha 3 subunit-containing GABAA receptors. Functional GABAA receptor heterogeneity of acutely dissociated hippocampal CA1 pyramidal cells. Ambien online references

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PURPOSE: Identification of changes in neurotransmitter function in animal models of epilepsy provides a basis for rational drug development and an understanding of the mechanisms underlying epileptogenesis. We investigated changes in the efficacy of the benzodiazepine type I agonist zolpidem and the polyamine site N-methyl-D-aspartate receptor antagonist ifenprodil in a rat model of microgyria. METHODS: Neonatal freeze lesions were used to produce a microsulcus in the normally lissencephalic rat neocortex with anatomical similarities to human polymicrogyria. Whole-cell voltage-clamp recordings were made from visually identified layer 2/3 pyramidal cells in acutely prepared brain slices from nonlesioned and lesioned rats. RESULTS: The effect of 20 nmol/L zolpidem on the decay time constant of inhibitory postsynaptic currents was significantly less in neurons from brain slices containing the freeze lesion. A higher concentration (100 nmol/L) of zolpidem was equally efficacious in lesioned and nonlesioned cortex. In lesioned cortex, the threshold for evoking epileptiform discharges was significantly increased in the presence of 10 micromol/L ifenprodil. This effect was significant in both intrinsic hyperexcitability and partial disinhibition with 2 micromol/L bicuculline in lesioned cortex. Ifenprodil had significantly less effect on the threshold of discharges evoked in control cortex in the partial disinhibition model. CONCLUSIONS: The decreased sensitivity of gamma-aminobutyric acid A receptors to 20 nmol/L zolpidem in the freeze-lesion model is consistent with a delayed or arrested maturation in this animal model. These data support a delay in the developmental switch from alpha2 to alpha1 subunits in gamma-aminobutyric acid A receptors of neocortical pyramidal cells in lesioned cortex. The increased ifenprodil sensitivity of the threshold for evoking epileptiform discharges in both control and disinhibited slices containing the microsulcus is explained by a delay in the expression of the 2A (NR2A) N-methyl-D-aspartate receptor subunit. Delayed development may be a hallmark of this type of cortical dysplasia.

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Synapse. 1999 Mar 15;31(4):263-77.
Benzodiazepine tolerance at GABAergic synapses on hippocampal CA1 pyramidal cells.

Zeng XJ, Tietz EI.

Department of Pharmacology, Medical College of Ohio, Toledo 43614-5804, USA.

Modulation of GABA function following 1 week oral administration of flurazepam (FZP) was investigated in chloride-loaded, rat hippocampal CA1 pyramidal neurons. Rats were sacrificed 2 or 7 days after ending drug treatment, when anticonvulsant tolerance was present or absent in vivo, respectively. Spontaneous (s)IPSCs and miniature (m)IPSCs were recorded using whole-cell voltage-clamp techniques. s/mIPSCs were bicuculline-sensitive, voltage-dependent, and reversed their polarity at 0 mV, the predicted E(Cl-). Comparisons of s/mIPSCs between FZP-treated and control groups were made at Vh = -90, -70, and -50 mV. The frequency of sIPSCs, but not mIPSCs, was significantly decreased in FZP-treated neurons 2 days, but not 7 days, after FZP treatment, suggesting a decrease in interneuron activity. These conclusions were supported by the negative findings of additional studies of [3H]GABA release from hippocampal slices and [3H]GABA uptake from hippocampal synaptosomes. The lack of change in the paired-pulse depression of GABA(B)-mediated IPSPs suggested that autoreceptor function was also not impaired following chronic FZP treatment. A large reduction in both sIPSC and mIPSC amplitude (60%) in FZP-treated neurons, the absence of mIPSCs in one-third of FZP-treated cells, and a measurable reduction in synaptic and unitary conductance confirmed that postsynaptic GABA(A) receptor function was profoundly impaired in FZP-treated CA1 neurons. Zolpidem, an alpha1-selective benzodiazepine receptor ligand, enhanced mIPSC amplitude and decay, but its ability to prolong mIPSC decay was reduced in FZP-treated neurons. Several pre- and postsynaptic changes at GABAergic synapses on CA1 pyramidal cells might be related to the decreased tonic GABA inhibition in FZP-treated CA1 neurons associated with the expression of benzodiazepine anticonvulsant tolerance.

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Neuropsychopharmacology. 1999 Mar;20(3):255-62.
Regional differences in the inhibition of mouse in vivo [3H]Ro 15-1788 binding reflect selectivity for alpha 1 versus alpha 2 and alpha 3 subunit-containing GABAA receptors.

Atack JR, Smith AJ, Emms F, McKernan RM.

Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Essex, UK.

The benzodiazepines flunitrazepam, diazepam, and Ro 15-1788 and the beta-carboline DMCM bind with equivalent affinity to the benzodiazepine binding site of GABAA receptors containing different alpha subunits (i.e., alpha 1, alpha 2, alpha 3, or alpha 5); whereas, the triazolopyridazine CL 218,872 and imidazopyridine zolpidem have higher affinity for alpha 1 subunit-containing GABAA receptors. In the present study, the in vivo binding of [3H]Ro 15-1788 in mouse cerebellum and spinal cord was used to establish the occupancy of the benzodiazepine binding site of GABAA receptors containing primarily alpha 1 and alpha 2/alpha 3 subunits, respectively. Thus, the nonselective compounds flunitrazepam, diazepam, and DMCM all produced a similar inhibition of binding in cerebellum and spinal cord (respective ID50 values of 0.2 to 0.3 mg/kg, 2 mg/kg, and 10 mg/kg i.p.); whereas, the alpha 1 selective compounds CL 218,872 and zolpidem were more potent at inhibiting [3H]Ro 15-1788 binding in the cerebellum (ID50 values 4.5 mg/kg and 10 mg/kg i.p.) compared to the spinal cord (ID50 values 12 mg/kg and > 30 mg/kg i.p.). Thus, the reduction of in vivo f[3H]Ro 15-1788 binding in tissues containing alpha 1 and alpha 2/alpha 3 receptor populations reflects the in vitro affinities of subtype selective compounds and should help to interpret the behavioral profile of such compounds.

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J Neurophysiol. 1999 Apr;81(4):1575-86.
Functional GABAA receptor heterogeneity of acutely dissociated hippocampal CA1 pyramidal cells.

Tietz EI, Kapur J, Macdonald RL.

Department of Pharmacology, Medical College of Ohio, Toledo, Ohio 43614-5804, USA.

CA1 pyramidal cells were voltage clamped, and GABA was applied to individual cells with a modified U-tube, rapid drug application system. With Vh = -50 mV, inward currents elicited by 10 microM GABA were inhibited by GABAA receptor (GABAR) antagonists and were baclofen insensitive, suggesting that GABA actions on isolated CA1 pyramidal cells were GABAR mediated. GABA concentration-response curves averaged from all cells were fitted best with a two-site equation, indicating the presence of at least two GABA binding sites, a higher-affinity site (EC50-1 = 11.0 microM) and a lower-affinity site (EC50-2 = 334.2 microM), on two or more populations of cells. The effects of GABAR allosteric modulators on peak concentration-dependent GABAR currents were complex and included monophasic (loreclezole) or multiphasic (diazepam) enhancement, mixed enhancement/inhibition (DMCM, zolpidem) or multiphasic inhibition (zinc). Monophasic (70% of cells) or biphasic (30% of cells) enhancement of GABAR currents by diazepam suggested three different sites on GABARs (EC50-1 =1.8 nM; EC50-2 = 75.8 nM; EC50-3 = 275.9 nM) revealing GABAR heterogeneity. The imidazopyridine zolpidem enhanced GABAR currents in 70% of cells with an EC50 = 222.5 nM, suggesting a predominance of moderate affinity alpha2 (or alpha3-) subtype-containing BZ Type IIA receptors. A small fraction of cells (10%) had a high affinity for zolpidem, something that is suggestive of alpha1 subtype-containing BZ Type I receptors. The remaining 30% of cells were insensitive to or inhibited by zolpidem, suggesting the presence of alpha5 subtype-containing BZ Type IIB receptors. Whether BZ Type I and Type II receptors coexist could not be determined. The beta-carboline methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) inhibited GABAR currents in all cells at midnanomolar concentrations, but in addition, potentiated GABAR currents in some cells at low nanomolar concentrations, characterizing two groups of cells, the latter likely due to functional assembly of alpha5betaxgamma2GABARs. In all cells, GABAR currents were moderately sensitive (EC50 = 9 microM) to loreclezole, consistent with a relatively greater beta3 subtype, than beta1 subtype, subunit mRNA expression. Two populations of cells were identified based on their sensitivities to zinc(IC50 = 28 and 182 microM), suggesting the presence of at least two GABAR isoforms including alpha5beta3gamma2 GABARs. Consistent with the heterogeneity of expression of GABAR subunit mRNA and protein in the hippocampus and based on their differential responses to GABA and to allosteric modulators, distinct populations of CA1 pyramidal cells likely express multiple, functional GABAR isoforms.

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