Partial Benzodiazepine Agonists in Schizophrenia: Expectations and Present Clinical Findings

Delini‐Stula, A.; Berdah-Tordjman, D; Neumann, N.-U.

doi:10.1097/00002826-199201001-00211

Cited by 17 publications

(9 citation statements)

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“…Bretazenil (Table 3), a partial positive allosteric modulator of the action of GABA at several GABA A receptors, is virtually devoid of sedative action, tolerance, and dependence liabilities when administered for short time periods to rodents (Auta et al 1994) or humans (Busto et al 1994). It has been reported that this drug produces antipsychotic activity of the magnitude seen with traditional neuroleptics in month-long open trials (Delini-Stula et al 1992). However, the bretazenil t-1/2 is short lasting due to its rapid metabolism, and in rodents, prolonged administration of high doses of this drug elicits sedation and amnesia, presumably due to the formation of bretazenil metabolites that may be endowed with full agonist activity.…”

Section: Gaba a Receptor Agonistsmentioning

confidence: 99%

GABAergic dysfunction in schizophrenia: new treatment strategies on the horizon

et al. 2005

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BZs, such as diazepam, although they are efficient in equilibrating GABA(A) receptor signal transduction in a manner beneficial in the treatment of positive and negative symptoms of SZ, may not be ideal drugs, because by mediating a full positive allosteric modulation of GABA(A) receptors containing the alpha(1) subunit, they contribute to sedation and to the development of tolerance after even a brief period of treatment. In contrast, other BZ-binding site ligands, such as 6-(2bromophenyl)-8-fluoro-4H-imidazo [1,5-a][1,4] benzodiazepine-3-carboxamide (imidazenil), which fail to allosterically and positively modulate the action of GABA at GABA(A) receptors with alpha(1) subunits but that selectively allosterically modulate cortical GABA(A) receptors containing alpha(5) subunits, contribute to the anxiolytic, antipanic, and anticonvulsant actions of these ligands without producing sedation, amnesia, or tolerance. Strong support for the use of imidazenil in psychosis emerges from experiments with reeler mice or with methionine-treated mice, which express a pronounced reelin and GAD(67) downregulation that is also operative in SZ and BP disorders. In mice that model SZ symptoms, imidazenil increases signal transduction at GABA(A) receptors containing alpha(5) subunits and contributes to the reduction of behavioral deficits without producing sedation or tolerance liability. Hence, we suggest that imidazenil may be considered a prototype for a new generation of positive allosteric modulators of GABA(A) receptors, which, either alone or in combination with neuroleptics, should be evaluated in GABAergic dysfunction operative in the treatment of SZ and BP disorders with psychosis.

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Section: Gaba a Receptor Agonistsmentioning

confidence: 99%

GABAergic dysfunction in schizophrenia: new treatment strategies on the horizon

et al. 2005

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“…Thus, the PBAs' direction of action (GABA A stimulation or antagonism) depends on the receptor density in the particular target structure. 231 Compounds with low intrinsic efficacy produce less physical dependence. 12 Chronic 232 and subchronic 233 exposure to bretazenil (Ro 16-6028), a PBA, produced no withdrawal signs or benzodiazepine receptor down-regulation.…”

Section: Partial Benzodiazepine Agonists (Pba)mentioning

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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“…One early study investigated bretazenil (Ro 16-6028), a short-acting partial benzodiazepine agonist, on clinical outcome measures predictive of antipsychotic efficacy in schizophrenic patients (Delini-Stula and Berdah-Tordjman, 1996; Delini-Stula et al, 1992). Using semi-quantitative measures of psychosis, results of these studies indicated that approximately half of the subjects responded favorably to treatment compared to placebo control.…”

Section: Gabaar As a Therapeutic Target For Schizophreniamentioning

confidence: 99%

GABAA receptors and their associated proteins: Implications in the etiology and treatment of schizophrenia and related disorders

et al. 2009

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Abstractγ-amino butyric acid type A (GABA A ) receptors play an important role in mediating fast synaptic inhibition in the brain. They are ubiquitously expressed in the CNS and also represent a major site of action for clinically relevant drugs. Recent technological advances have greatly clarified the molecular and cellular roles played by distinct GABA A receptor subunit classes and isoforms in normal brain function. At the same time, postmortem and genetic studies have linked neuropsychiatric disorders including schizophrenia and bipolar disorder with GABAergic neurotransmission and various specific GABA A receptor subunits, while evidence implicating GABA A R-associated proteins is beginning to emerge. In this review we discuss the mounting genetic, molecular, and cellular evidence pointing toward a role for GABA A receptor heterogeneity in both schizophrenia etiology and therapeutic development. Finally, we speculate on the relationship between schizophrenia-related disorders and selected GABA A receptor associated proteins, key regulators of GABA A receptor trafficking, targeting, clustering, and anchoring that often carry out these functions in a subtype-specific manner.

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Partial Benzodiazepine Agonists in Schizophrenia: Expectations and Present Clinical Findings

Cited by 17 publications

References 0 publications

GABAergic dysfunction in schizophrenia: new treatment strategies on the horizon

GABAergic dysfunction in schizophrenia: new treatment strategies on the horizon

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

GABAA receptors and their associated proteins: Implications in the etiology and treatment of schizophrenia and related disorders

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