Antipsychotic effects of bretazenil, a partial benzodiazepine agonist in acute schizophrenia—A study group report

Delini‐Stula, A.; Berdah-Tordjman, D

doi:10.1016/0022-3956(96)00003-9

Cited by 33 publications

(13 citation statements)

References 13 publications

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“…Moreover, the nonselective partial agonist bretazenil was efficacious as monotherapy in 40% of neuroleptic-free patients (42). In line with these clinical results, the ␣3-containing GABA A -receptor subtype would qualify as a promising target for the development of selective antipsychotics.…”

Section: Discussionmentioning

confidence: 75%

A schizophrenia-related sensorimotor deficit links α3-containing GABA _A receptors to a dopamine hyperfunction

Yee

Keist

Boehmer

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

181

148

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Overactivity of the dopaminergic system in the brain is considered to be a contributing factor to the development and symptomatology of schizophrenia. Therefore, the GABAergic control of dopamine functions was assessed by disrupting the gene encoding the ␣3 subunit of the GABAA receptor. ␣3 knockout (␣3KO) mice exhibited neither an obvious developmental defect nor apparent morphological brain abnormalities, and there was no evidence for compensatory up-regulation of other major GABA A-receptor subunits. Anxiety-related behavior in the elevated-plus-maze test was undisturbed, and the anxiolytic-like effect of diazepam, which is mediated by ␣2-containing GABAA receptors, was preserved. As a result of the loss of ␣3 GABAA receptors, the GABA-induced whole-cell current recorded from midbrain dopamine neurons was significantly reduced. Spontaneous locomotor activity was slightly elevated in ␣3KO mice. Most notably, prepulse inhibition of the acoustic startle reflex was markedly attenuated in the ␣3KO mice, pointing to a deficit in sensorimotor information processing. This deficit was completely normalized by treatment with the antipsychotic D2-receptor antagonist haloperidol. The amphetamineinduced hyperlocomotion was not altered in ␣3KO mice compared with WT mice. These results suggest that the absence of ␣3-subunit-containing GABAA receptors induces a hyperdopaminergic phenotype, including a severe deficit in sensorimotor gating, a common feature among psychiatric conditions, including schizophrenia. Hence, agonists acting at ␣3-containing GABAA receptors may constitute an avenue for an effective treatment of sensorimotor-gating deficits in various psychiatric conditions. haloperidol ͉ sensorimotor gating

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Section: Discussionmentioning

confidence: 75%

A schizophrenia-related sensorimotor deficit links α3-containing GABA _A receptors to a dopamine hyperfunction

Yee

Keist

Boehmer

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

181

148

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“…Evidence that dysfunction of GABAergic neurotransmission is associated with ASD is increasing. For example, loss of MeCP2 from a subset of GABAergic neurons in the forebrain results in a reduced inhibitory quantal size and in the recapitulation of many features of Rett syndrome, indicating that subtle dysfunction of GABAergic neurons potentially contributes to ASD ( 153 ). Furthermore, in Scn1a (Na v 1.1) heterozygous knockout mice (i.e., haploinsufficient mice)---which are a model of Dravet's syndrome, also a syndromic form of ASD---GABAergic neurotransmission is decreased, and mice exhibit hyperactivity, stereotypies, social interaction deficits, and impaired context-dependent spatial memory ( 154 ).…”

Section: Autismmentioning

confidence: 99%

GABA_AReceptor Subtypes: Therapeutic Potential in Down Syndrome, Affective Disorders, Schizophrenia, and Autism

Rudolph

Möhler

2014

Annu. Rev. Pharmacol. Toxicol.

281

245

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The γ-aminobutyric acid (GABA) system plays a pivotal role in orchestrating the synchronicity of local networks and the functional coupling of different brain regions. Here we review the impact of the GABAA receptor subtypes on cognitive and emotional behavior, paying particular attention to five disease states: cognitive dysfunction and Down syndrome, anxiety disorders, depression, schizophrenia, and autism. Through the bidirectional modulation of tonic inhibition, α5-subunit-containing GABAA receptors permit the bidirectional modulation of cognitive processes, and a partial inverse agonist acting at the α5-subunit-containing GABAA receptor is in a clinical trial in individuals with Down syndrome. With regard to anxiety disorders, the viability of nonsedative anxiolytics based on the modulation of α2- and α3-subunit-containing GABAA receptors has been established in clinical proof-of-concept trials. Regarding the remaining three disease states, the GABA hypothesis of depression offers new options for antidepressant drug development, cognitive symptoms in schizophrenia are attributed to a cortical GABAergic deficit, and dysfunctional GABAergic inhibition is increasingly understood to contribute to the pathophysiology of autism spectrum disorders.

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“…Like barbiturates, modulation by pregnane steroids, such as AP, require minimal GABA A structure to produce stimulation but they differ in other The reviewers relied here on the summary and reference provided by Delini-Stula and BerdahTordjman. 240 The study itself could not be located using the reference provided. Improvement was unrelated to the anxiolytic-sedative effects.…”

Section: Neuroactive Steroidsmentioning

confidence: 99%

GABA and Schizophrenia: A Review of Basic Science and Clinical Studies

Wassef¹,

Baker

Kochan

2003

Journal of Clinical Psychopharmacology

224

148

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Alterations in the GABA neurotransmitter system are found in clinical and basic neuroscience schizophrenia studies as well as animal models and may be involved in the pathophysiology of schizophrenia. The interaction of GABA with other well-characterized neurotransmitter abnormalities remains to be understood. Future studies should elucidate the potential therapeutic role for GABA ligands in schizophrenia treatment.

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Antipsychotic effects of bretazenil, a partial benzodiazepine agonist in acute schizophrenia—A study group report

Cited by 33 publications

References 13 publications

A schizophrenia-related sensorimotor deficit links α3-containing GABA _A receptors to a dopamine hyperfunction

A schizophrenia-related sensorimotor deficit links α3-containing GABA _A receptors to a dopamine hyperfunction

GABA_AReceptor Subtypes: Therapeutic Potential in Down Syndrome, Affective Disorders, Schizophrenia, and Autism

GABA and Schizophrenia: A Review of Basic Science and Clinical Studies

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Antipsychotic effects of bretazenil, a partial benzodiazepine agonist in acute schizophrenia—A study group report

Cited by 33 publications

References 13 publications

A schizophrenia-related sensorimotor deficit links α3-containing GABA A receptors to a dopamine hyperfunction

A schizophrenia-related sensorimotor deficit links α3-containing GABA A receptors to a dopamine hyperfunction

GABAAReceptor Subtypes: Therapeutic Potential in Down Syndrome, Affective Disorders, Schizophrenia, and Autism

GABA and Schizophrenia: A Review of Basic Science and Clinical Studies

Contact Info

Product

Resources

About

A schizophrenia-related sensorimotor deficit links α3-containing GABA _A receptors to a dopamine hyperfunction

A schizophrenia-related sensorimotor deficit links α3-containing GABA _A receptors to a dopamine hyperfunction

GABA_AReceptor Subtypes: Therapeutic Potential in Down Syndrome, Affective Disorders, Schizophrenia, and Autism