Uncoupling of GABAA and benzodiazepine receptor binding activity in the hippocampal formation of schizophrenic brain

Beneš, Francine M.; Wickramasinghe, Rohan H.; Vincent, Stephen L.; Khan, Yusuf S.; Todtenkopf, Mark S.

doi:10.1016/s0006-8993(97)00113-3

Cited by 81 publications

(46 citation statements)

References 21 publications

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“…Our results are also consistent with the observation that mRNA expression of the main subunits of the adult GABA A րBDZ receptor complex is unaltered in prefrontal cortex in schizophrenia (Akbarian et al 1995a). Obviously, these investigations cannot rule out potential alterations limited to specific layers of the cortex or subfields of the hippocampus, such as recently described (Benes et al 1997).…”

Section: Discussionmentioning

confidence: 94%

“…Benzodiazepine receptors have been reported to be unchanged in the hippocampus and prefrontal cortex (Reynolds and Stroud 1993;Benes et al 1997;Pandey et al 1997), decreased in hippocampus, anterior cingulate cortex, somatomotor cortex, cerebellum, globus pallidus (Squires et al 1993), and increased in frontal, temporal and putamen (Kiuchi et al 1989). The increase in [ 3 H]muscimol binding to the GABA binding site of the GABA A ր BDZ receptor complex, in the face of unchanged BDZ receptor binding in some regions of schizophrenic brains, has been interpreted as indicating an uncoupling of GABA A and BDZ receptors in schizophrenia (Benes et al 1997). Thus, the overall picture is suggestive of a functional and ր or structural decrease in GABAergic activity, possibly associated with a compensatory regulation of postsynaptic receptors.…”

Section: I]iomazenil; Spectmentioning

confidence: 99%

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No Evidence of Altered In Vivo Benzodiazepine Receptor Binding in Schizophrenia

Abi‐Dargham

Laruelle

Krystal

et al. 1999

Neuropsychopharmacology

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Section: Discussionmentioning

confidence: 94%

Section: I]iomazenil; Spectmentioning

confidence: 99%

No Evidence of Altered In Vivo Benzodiazepine Receptor Binding in Schizophrenia

Abi‐Dargham

Laruelle

Krystal

et al. 1999

Neuropsychopharmacology

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“…It should be noted that GABA A signalling was increased in various brain regions in schizophrenia subjects in post-mortem studies (Benes et al, 1992, Benes et al, 1997, Dean et al, 1999, Deng and Huang, 2006, Hanada et al, 1987, Ishikawa et al, 2004, Woo et al, 2004) (although conflicting data existed (Pandey et al, 1997, Squires et al, 1993). However, our study exhibited increasing effects of antipsychotics on GABA A signalling in the NAc, which was also reported by Zink et al, (2004).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies reported abnormal GABA A receptor density in various brain regions of schizophrenia subjects, including the prefrontal cortex (PFC) (Dean et al, 1999, Ishikawa et al, 2004, cingulate cortex (Benes et al, 1992), superior temporal gyrus (Deng and Huang, 2006) and hippocampus (Benes et al, 1997). Antipsychotic drug administration also affects GABA A receptors.…”

Section: Introductionmentioning

confidence: 99%

Aripiprazole Increases the PKA Signalling and Expression of the GABAA Receptor and CREB1 in the Nucleus Accumbens of Rats

et al. 2016

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The GABAA receptor is implicated in the pathophysiology of schizophrenia and regulated by PKA signalling. Current antipsychotics bind with D2-like receptors, but not the GABAA receptor. The cAMP-responsive element-binding protein 1 (CREB1) is also associated with PKA signalling and may be related to the positive symptoms of schizophrenia. This study investigated the effects of antipsychotics in modulating D2-mediated PKA signalling and its downstream GABAA receptors and CREB1. Rats were treated orally with aripiprazole (0.75 mg/kg, ter in die (t.i.d.)), bifeprunox (0.8 mg/kg, t.i.d.), haloperidol (0.1 mg/kg, t.i.d.) or vehicle for 1 week. The levels of PKA-Cα and p-PKA in the prefrontal cortex (PFC), nucleus accumbens (NAc) and caudate putamen (CPu) were detected by Western blots. The mRNA levels of Gabrb1, Gabrb2, Gabrb3 and Creb1, and their protein expression were measured by qRT-PCR and Western blots, respectively. Aripiprazole elevated the levels of p-PKA and the ratio of p-PKA/PKA in the NAc, but not the PFC and CPu. Correlated with this elevated PKA signalling, aripiprazole elevated the mRNA and protein expression of the GABAA (β-1) receptor and CREB1 in the NAc. While haloperidol elevated the levels of p-PKA and the ratio of p-PKA/PKA in both NAc and CPu, it only tended to increase the expression of the GABAA (β-1) receptor and CREB1 in the NAc, but not the CPu. Bifeprunox had no effects on PKA signalling in these brain regions. These results suggest that aripiprazole has selective effects on upregulating the GABAA (β-1) receptor and CREB1 in the NAc, probably via activating PKA signalling.

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“…Quantitative autoradiography. The autoradiographic method used for [ 3 H]flunitrazepam binding was a modification of that reported by Benes et al [5]. At the time of assay, tissue sections were first thawed at 4°C for 1 h and then incubated with 1 nM in the presence (non-specific binding, in duplicate) or absence (total binding, in duplicate) of 1 μM diazepam (Sigma Chemical Co., St. Louis, MO).…”

Section: Immunohistochemical Stainingmentioning

confidence: 99%

Normal [3H]flunitrazepam binding to GABAA receptors in the locus coeruleus in major depression and suicide

Zhu¹,

Karolewicz²,

Nail³

et al. 2006

Brain Research

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Major depression and suicide are associated with altered concentrations of specific noradrenergic proteins in the human locus coeruleus (LC). Based on experimental studies that can reproduce these LC abnormalities in laboratory animals, we hypothesized that noradrenergic pathobiology in depression is a result of over-activity of the LC. LC activity is under the control of both excitatory and inhibitory inputs. A major inhibitory input to the LC is GABAergic, arising from the nucleus prepositus hypoglossi. Numerous studies demonstrating low levels of GABA in the CSF and plasma of subjects with major depressive disorder (MDD) raise the possibility that LC over-activity in depression may be secondary to reduced GABAergic input to the LC. Here, GABAergic input to the LC in depression was evaluated by studying the binding of [ 3 H]flunitrazepam to GABA A receptors at three anatomically-defined levels of the human postmortem LC. LC tissues were collected from subjects with MDD, subjects with depressive disorders including MDD that died as a result of suicide, and psychiatrically normal control subjects. A modest rostral-caudal gradient of GABA A receptor binding density was observed amongst all subjects. No significant differences in the amount of binding to GABA A receptors were observed between control subjects (n=21) and MDD subjects (n=9) or depressed suicide victims (n=17). These results demonstrate that GABA A receptor binding in the LC measured with [ 3 H]flunitrazepam is not altered in subjects with depressive illnesses.

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Uncoupling of GABAA and benzodiazepine receptor binding activity in the hippocampal formation of schizophrenic brain

Cited by 81 publications

References 21 publications

No Evidence of Altered In Vivo Benzodiazepine Receptor Binding in Schizophrenia

No Evidence of Altered In Vivo Benzodiazepine Receptor Binding in Schizophrenia

Aripiprazole Increases the PKA Signalling and Expression of the GABAA Receptor and CREB1 in the Nucleus Accumbens of Rats

Normal [3H]flunitrazepam binding to GABAA receptors in the locus coeruleus in major depression and suicide

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