Effects of benzodiazepine treatment on cortical GABA(A) and muscarinic receptors: studies in schizophrenia and rats.

Changes in cortical γ-aminobutyric acid A (GABA(A)) receptors and muscarinic receptors have been reported in schizophrenia, a disorder treated with antipsychotic drugs and benzodiazepines. As there is a reported functional relationship between the GABAergic and cholinergic systems in the human central nervous system we have investigated whether there are changes in the GABA(A) and muscarinic receptors in the cortex of subjects from APD-treated subjects with schizophrenia and whether changes were different in subjects who had also received benzodiazepine treatment. We failed to show any strong correlations between changes in GABA(A) and muscarinic receptors in the CNS of subjects with schizophrenia. We showed that subjects with schizophrenia treated with benzodiazepines had lower levels of muscarinic receptors; which was not the case in rats treated with APDs, benzodiazepines or a combination of both drugs. Further, the benzodiazepine binding site, but not the muscimol binding site, was decreased in the parietal cortex of subjects with schizophrenia independent of benzodiazepine status at death. These data would therefore support our previously stated hypotheses that changes in the cortical cholinergic and GABAergic systems are involved in the pathophysiology of schizophrenia.

An integrated approach to addressing addiction and depression in college students.

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Treatment with haloperidol and diazepam alters GABA(A) receptor density in the rat brain.

A significant body of data suggests that GABA(A) receptors are altered in the CNS of subjects with schizophrenia. However, subjects with schizophrenia are treated with antipsychotic drugs and, in some cases, antipsychotic drugs and benzodiazepines. It has therefore been suggested that the changes in GABA(A) receptors in the CNS of subjects with schizophrenia are due to such drug treatments. Surprisingly, there appear to be no studies to determine the effect of a combined antipsychotic-benzodiazepine treatment on GABA(A) receptors. We therefore measured both the GABA binding site ([3H]muscimol) and the benzodiazepine binding site ([3H]flumazenil) in the CNS of rats treated with either haloperidol, diazepam or a combination of the two drugs. The main findings of our study are that treatment with diazepam or the combination of diazepam and haloperidol results in regionally selective increases GABA binding sites but treatment with haloperidol alone decreases the GABA binding site in the thalamus but increases these sites in the hypothalamus. By contrast, treatment with diazepam, haloperidol and a combination of the two drugs resulted in widespread decreases in the number of benzodiazepine binding sites in the rat CNS. The notable exception to this outcome was increased numbers of benzodiazepine binding sites in the frontal cortex of rats that had received diazepam. Our data suggests that there are complex changes in the GABA(A) receptor following treatment with haloperidol, diazepam or a combination of these drugs. This outcome may be relevant to the therapeutic benefits of using both drugs in conjunction early in the treatment of a psychotic episode.

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.

The heterogeneity of central benzodiazepine receptor subtypes in the human hippocampal formation, frontal cortex and cerebellum using [3H]flumazenil and zolpidem.

The ability of clonazepam and zolpidem to displace [3H]flumazenil binding was measured in the human hippocampal formation, frontal cortex (BA9) and the cerebellum using in situ radioligand binding and autoradiography. The use of high resolution phosphorimaging in all regions indicated the displacement of [3H]flumazenil by clonazepam was monophasic with K(i) values ranging from 2.73+/-0.17 to 6.49+/-0.21 nM. [3H]flumazenil binding that was not displaced by clonazepam ranged from 3.39+/-0.86 to 7.15+/-1.11%. The ability of zolpidem to displace [3H]flumazenil was also monophasic in the frontal cortex and cerebellum with K(i) values of 37.53+/-1.79 and 31.80+/-1.68 nM, respectively. In contrast, within all hippocampal regions, zolpidem displacement of [3H]flumazenil was biphasic, with K(i) values for the high affinity site ranging from 0.13+/-0.04 to 0.54+/-0.03 nM, whereas the low affinity site was between 84.98+/-1.58 and 98.84+/-1.89 nM. In addition, zolpidem insensitive [3H]flumazenil binding was observed to vary markedly between brain regions, ranging between 37.85+/-1.60 and 6.13+/-0.83%. In conclusion, the present results indicate that in situ radioligand binding and high-resolution phosphorimaging techniques can be utilized to measure the differential displacement of [3H]flumazenil by zolpidem and clonazepam. Moreover, our data suggests that the differential distribution of the zolpidem insensitive component of [3H]flumazenil binding is an indicator of GABA/BZ receptors assembled by different subunits within the human brain.

[(3)H]Flumazenil binding in the human hippocampal formation, frontal cortex and cerebellum detected by high-resolution phosphorimaging.

The pharmacological characterisation of the benzodiazepine binding site associated with the gamma-aminobutyric acid (GABA(A)) receptor in human brain has been demonstrated using in situ radioligand binding and autoradiography. The use of high-resolution phosphorimaging has allowed both the affinity (K(d)) and density (B(max)) of [(3)H]flumazenil binding to be measured within regions of the hippocampal formation as well as the cerebellum and frontal cortex. The Scatchard plots of data from all brain regions were linear with Hill coefficients close to unity consistent with the presence of a single binding site for [(3)H]flumazenil. The affinities of [(3)H]flumazenil binding within all the brain regions were similar (K(d) 1.57+/-0.20-3.08+/-0.01 nM), while the density of [(3)H]flumazenil binding varied significantly between the brain regions analysed (B(max) 182.7+/-7.3-596.7+/-34.0 fmol/mg ETE; P<0.0001). In conclusion, the present results indicate that in situ radioligand binding and high-resolution phosphorimaging techniques can be utilized to measure the distribution, density and affinity of [(3)H]flumazenil to the GABA(A) receptor within the human frontal cortex, cerebellum and hippocampal formation.