Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective Receptor Modulators?

Vinkers, Christiaan H.; Olivier, Berend

doi:10.1155/2012/416864

Cited by 144 publications

(159 citation statements)

References 146 publications

(172 reference statements)

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“…However, studies also suggest that long-term application of benzodiazepine increases risk of AD 72 or mild cognitive impairment with GABAA inhibition. 73,74 It seems that short-term treatment of midazolam improves anxiety by enhancing GABA transmission, whereas long-term application of the drug may impair the cognitive functions by desensitizing GABA receptors. Therefore, more efficient GABA agonists are needed.…”

Section: Discussionmentioning

confidence: 99%

Correcting miR92a-vGAT-Mediated GABAergic Dysfunctions Rescues Human Tau-Induced Anxiety in Mice

Wang

Tan

et al. 2017

Molecular Therapy

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Patients with Alzheimer's disease (AD) commonly show anxiety behaviors, but the molecular mechanisms are not clear and no efficient intervention exists. Here, we found that overexpression of human wild-type, full-length tau (termed htau) in hippocampus significantly decreased the extracellular g-aminobutyric acid (GABA) level with inhibition of g oscillation and the evoked inhibitory postsynaptic potential (eIPSP). With tau accumulation, the mice show age-dependent anxiety behaviors. Among the factors responsible for GABA synthesis, release, uptake, and transport, we found that accumulation of htau selectively suppressed expression of the intracellular vesicular GABA transporter (vGAT). Tau accumulation increased miR92a, which targeted vGAT mRNA 3 0 UTR and inhibited vGAT translation. Importantly, we found that upregulating GABA tones by intraperitoneal injection of midazolam (a GABA agonist), ChR2-mediated photostimulating and overexpressing vGAT, or blocking miR92a by using specific antagomir or inhibitor efficiently rescued the htau-induced GABAergic dysfunctions with attenuation of anxiety. Finally, we also demonstrated that vGAT level decreased while the miR92a increased in the AD brains. These findings demonstrate that the AD-like tau accumulation induces anxiety through disrupting miR92a-vGAT-GABA signaling, which reveals molecular mechanisms underlying the anxiety behavior in AD patients and potentially leads to the development of new therapeutics for tauopathies.

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Section: Discussionmentioning

confidence: 99%

Correcting miR92a-vGAT-Mediated GABAergic Dysfunctions Rescues Human Tau-Induced Anxiety in Mice

Wang

Tan

et al. 2017

Molecular Therapy

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“…However, some studies suggest that olanzapine and haloperidol progressively lose their behavioural effects in animals, which is reflected in adaptations of the dopamine system (Samaha, Seeman, Stewart, Rajabi & Kapur, 2007). Tolerance to benzodiazepine effects is also recognised, although the precise mechanisms is not known (Vinkers & Olivier, 2012).…”

Section: Long-term Changesmentioning

confidence: 99%

Research on a ‘drug-centred’ approach to psychiatric drug treatment: assessing the impact of mental and behavioural alterations produced by psychiatric drugs

Moncrieff

2017

Epidemiol Psychiatr Sci

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Aims:This article explores an alternative understanding of how psychiatric drugs works that is referred to as the drug-centred model of drug action. Unlike the current diseasecentred model, which suggests that psychiatric drugs work by correcting an underlying brain abnormality, the drug-centred model emphasises how psychiatric drugs affect mental states and behaviour by modifying normal brain processes. The alterations produced may impact on the emotional and behavioural problems that constitute the symptoms of mental disorders. Methods:Arguments are put forward that justify the consideration of the drug-centred model.The research necessary to support the prescription of drugs according to such a model is explored. Results:Evidence from neurochemistry and comparative drug trials do not confirm the disease-centred model of drug action. Since psychiatric drugs are recognised to have mind and behaviour-altering properties, the drug-centred model constitutes a plausible alternative. The drug-centred model suggests research is needed to identify all the alterations produced by various sorts of drugs, both acute and long-term, and how these might interact with the symptoms and problems associated with different mental disorders. This requires detailed animal and volunteer studies and data from patients prescribed drug treatment long-term, along with placebo-controlled and comparative 3 trials that look at the overall impact of drug-induced alterations on well-being and functioning as well as symptoms. Research is also needed on alternative ways of fulfilling the function of drug treatment. The moral aspect of using drugs to modify behaviour rather than treat disease needs honest and transparent consideration. Conclusions:It is hoped this discussion will encourage the psychiatric and pharmaceutical research community to provide more of the information that is required to use psychiatric drugs safely and effectively.

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“…These drug interactions, together with structural diversity of GABAA receptors, shape the complex nature of GABAA receptor pharmacology, although simultaneously offer a great opportunity for the design of novel and more selective compounds for improved therapeutic applications [7]. Unfortunately, severe problems are related to the long-term use of drugs acting at GABAA receptors, including loss of efficacy, and development of tolerance and dependence that largely limit the time window of their desirable therapeutic benefits [4,[8][9][10][11].…”

Section: Introduction To Gaba Receptor Diversity and Pharmacologicalmentioning

confidence: 99%

GABA Receptors: Pharmacological Potential and Pitfalls

Jembrek¹,

Vlainić

2015

CPD

116

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Gamma-amino butyric acid (GABA), the major inhibitory neurotransmitter in the mammalian central nervous system, plays a key role in the regulation of neuronal transmission throughout the brain, affecting numerous physiological and psychological processes. Changes in GABA levels provoke disbalance between excitatory and inhibitory signals, and are involved in the development of numerous neuropsychiatric disorders. GABA exerts its effects via ionotropic (GABAA) and metabotropic (GABAB) receptors. Both types of receptors are targeted by many clinically important drugs that affect GABAergic function and are widely used in the treatment of anxiety disorder, epilepsy, insomnia, spasticity, aggressive behaviour, and other pathophysiological conditions and diseases. Of particular importance are drugs that modulate GABAA receptor complex, such as benzodiazepines, barbiturates, neuroactive steroids, intravenous and inhalational anesthetics, and ethanol. Molecular interactions and subsequent pharmacological effects induced by drugs acting at GABAA receptors are extremely complex due to structural heterogeneity of GABAA receptors and existence of numerous allosterically interconnected binding sites and various chemically distinct ligands that are able to bound to them. There is a growing interest in the development and application of subtype-selective drugs that will achieve specific therapeutic benefits without undesirable side effects. The aim of this review is to briefly summarize the key pharmacological properties of GABA receptors, and to present selected novel findings with the potential to open new perspectives in the development of more effective therapeutic strategies.

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Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective Receptor Modulators?

Cited by 144 publications

References 146 publications

Correcting miR92a-vGAT-Mediated GABAergic Dysfunctions Rescues Human Tau-Induced Anxiety in Mice

Correcting miR92a-vGAT-Mediated GABAergic Dysfunctions Rescues Human Tau-Induced Anxiety in Mice

Research on a ‘drug-centred’ approach to psychiatric drug treatment: assessing the impact of mental and behavioural alterations produced by psychiatric drugs

GABA Receptors: Pharmacological Potential and Pitfalls

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