Chronic Benzodiazepine Administration XI Concurrent Administration of PK11195 Attenuates Lorazepam Discontinuation Effects

Byrnes, John; Miller, Lawrence G.; Perkins, Karen; Greenblatt, David J.; Shader, Richard I.

doi:10.1038/npp.1993.30

Cited by 14 publications

(3 citation statements)

References 9 publications

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“…The competitive ligand Ro 5-4864, at 10 mgkg per day, blocks the effect of PK 11195 on lorazepam discontinuation. This effect is attenuated in the hippocampus but not in the cortex by concurrent administration of PK 11195 (Byrnes et al, 1993). These results indicate that concurrent administration of PK 11195 may attenuate discontinuation effects of lorazepam.…”

Section: Homologous and Heterologous Uncouplingmentioning

confidence: 65%

From ion currents to genomic analysis: Recent advances in GABA_A receptor research

Rabow

Russek

Farb

1995

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474

359

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The gamma-aminobutyric acid type A (GABAA) receptor represents an elementary switching mechanism integral to the functioning of the central nervous system and a locus for the action of many mood- and emotion-altering agents such as benzodiazepines, barbiturates, steroids, and alcohol. Anxiety, sleep disorders, and convulsive disorders have been effectively treated with therapeutic agents that enhance the action of GABA at the GABAA receptor or increase the concentration of GABA in nervous tissue. The GABAA receptor is a multimeric membrane-spanning ligand-gated ion channel that admits chloride upon binding of the neurotransmitter GABA and is modulated by many endogenous and therapeutically important agents. Since GABA is the major inhibitory neurotransmitter in the CNS, modulation of its response has profound implications for brain functioning. The GABAA receptor is virtually the only site of action for the centrally acting benzodiazepines, the most widely prescribed of the anti-anxiety medications. Increasing evidence points to an important role for GABA in epilepsy and various neuropsychiatric disorders. Recent advances in molecular biology and complementary information derived from pharmacology, biochemistry, electrophysiology, anatomy and cell biology, and behavior have led to a phenomenal growth in our understanding of the structure, function, regulation, and evolution of the GABAA receptor. Benzodiazepines, barbiturates, steroids, polyvalent cations, and ethanol act as positive or negative modulators of receptor function. The description of a receptor gene superfamily comprising the subunits of the GABAA, nicotinic acetylcholine, and glycine receptors has led to a new way of thinking about gene expression and receptor assembly in the nervous system. Seventeen genetically distinct subunit subtypes (alpha 1-alpha 6, beta 1-beta 4, gamma 1-gamma 4, delta, p1-p2) and alternatively spliced variants contribute to the molecular architecture of the GABAA receptor. Mysteriously, certain preferred combinations of subunits, most notably the alpha 1 beta 2 gamma 2 arrangement, are widely codistributed, while the expression of other subunits, such as beta 1 or alpha 6, is severely restricted to specific neurons in the hippocampal formation or cerebellar cortex. Nervous tissue has the capacity to exert control over receptor number, allosteric uncoupling, subunit mRNA levels, and posttranslational modifications through cellular signal transduction mechanisms under active investigation. The genomic organization of the GABAA receptor genes suggests that the present abundance of subtypes arose during evolution through the duplication and translocations of a primordial alpha-beta-gamma gene cluster. This review describes these varied aspects of GABAA receptor research with special emphasis on contemporary cellular and molecular discoveries.

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Section: Homologous and Heterologous Uncouplingmentioning

confidence: 65%

From ion currents to genomic analysis: Recent advances in GABA_A receptor research

Rabow

Russek

Farb

1995

Synapse

474

359

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“…In fact, neurochemical studies have showed that partial and receptor subtype l-selective agonists induce a less severe GABAergic transmission dysfunction (Schoch et al, 1993) than full, non-selective agonists. h i m a l studies have also shown that concurrent administration of PK 11195, a peripheral site benzodiazepine antagonist, attenuates discontinuation effects of BZs, suggesting a common role of the central and peripheral benzodiazepine receptor during withdrawal (Bymes et al, 1993;Martinez et al, 1992).…”

Section: Biological Basts Of the Bz Withdrawal Syndromementioning

confidence: 99%

Long-Term use of Benzodiazepines: Tolerance, Dependence and Clinical Problems in Anxiety and Mood Disorders

Michelini

Cassano²,

Frare³

et al. 2007

Pharmacopsychiatry

117

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This paper reviews the literature on the epidemiological, biological and clinical features of benzodiazepine dependence and withdrawal syndrome, focusing on clinical problems associated with the long-term use of benzodiazepine (BZs) in mood and anxiety disorders. These conditions represent the most frequent mental disorders for which BZs are overprescribed. In addition to dependence and withdrawal phenomena, the presence of chronic subtle toxicity and the interference with the underlying psychopathology observed with BZ use suggests a need for a more careful evaluation of the risk-benefit ratio in the long-term administration of BZs.

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“…The usefulness of BDZ is therefore limited, although most have primarily satisfactory antiepileptic efficacies.Many studies have focused on the mechanisms of tolerance and dependence. Changes of binding capacity, gene expression and metabolism in neural receptors, including GABA A receptors [1] , glutamatergic receptors [2] and peripheral BDZ receptors [3] , were studied in the presence of tolerance and/or dependence. Other factors, such as nitric oxide [4] , calcium-channel blockers [5] , protein kinases [6] and bicarbonate radicals [7] were also studied.…”

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confidence: 99%

Changes of brain neuropeptide Y and its receptors in rats with flurazepam tolerance and dependence1

Zhang

Wang

2005

Acta Pharmacologica Sinica

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Aim: Anticonvulsant tolerance and dependence are two obstacles that restrict the clinical use of benzodiazepines (BDZ). In order to explore the mechanism of these two adverse reactions, changes of neuropeptide Y (NPY) and its receptors in the hippocampus of rat models, in relation to flurazepam (FZP, a member of BDZ) tolerance and dependence, were investigated. Methods: The mRNA of preproNPY and its receptors (Y1, Y2, and Y5) in the hippocampus were determined by competitive RT‐PCR, and the distribution of NPY in the hippocampus was examined by immunohistochemistry. Results: A decrease of preproNPY mRNA in the hippocampus was found in tolerant and dependent rats. The level of preproNPY mRNA in the hippocampus was reversely correlated with the degree of tolerance and dependence, measured by the threshold of pentylenetetrazol‐induced seizures. Immunohistochemistry indicated a decrease of NPY‐immunoreactive material in neurons of the CA1, CA3, and dentate gyrus regions of both tolerant and dependent rats. The mRNA of NPY receptors Y1 and Y5 decreased in tolerant rats but did not change in dependent rats. The mRNA of NPY receptor Y2 increased in tolerant rats but decreased in dependent rats. Conclusion: A decrease of NPY in the hippocampus might be involved in anticonvulsant tolerance and dependence following long‐term treatment with FZP. Y1 Y2, and Y5 mRNA were also altered in FZP tolerance and dependence.

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Chronic Benzodiazepine Administration XI Concurrent Administration of PK11195 Attenuates Lorazepam Discontinuation Effects

Cited by 14 publications

References 9 publications

From ion currents to genomic analysis: Recent advances in GABA_A receptor research

From ion currents to genomic analysis: Recent advances in GABA_A receptor research

Long-Term use of Benzodiazepines: Tolerance, Dependence and Clinical Problems in Anxiety and Mood Disorders

Changes of brain neuropeptide Y and its receptors in rats with flurazepam tolerance and dependence1

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Chronic Benzodiazepine Administration XI Concurrent Administration of PK11195 Attenuates Lorazepam Discontinuation Effects

Cited by 14 publications

References 9 publications

From ion currents to genomic analysis: Recent advances in GABAA receptor research

From ion currents to genomic analysis: Recent advances in GABAA receptor research

Long-Term use of Benzodiazepines: Tolerance, Dependence and Clinical Problems in Anxiety and Mood Disorders

Changes of brain neuropeptide Y and its receptors in rats with flurazepam tolerance and dependence1

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From ion currents to genomic analysis: Recent advances in GABA_A receptor research

From ion currents to genomic analysis: Recent advances in GABA_A receptor research