The behavioral pharmacology of zolpidem: evidence for the functional significance of α1-containing GABAA receptors

Fitzgerald, Amanda C.; Wright, Brittany T.; Heldt, Scott A.

doi:10.1007/s00213-014-3457-x

Cited by 34 publications

(31 citation statements)

References 250 publications

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“…Zolpidem is a short-acting nonbenzodiazepine hypnotic that potentiates GABA transmission by acting on GABA A receptors (reviewed in [8] – [10] ). Because GABA A receptors are widespread in the brain, Zolpidem was proposed for use as a therapeutic agent in a wide variety of CNS disorders such as epilepsy [11] , [12] , anxiety [13] – [17] , pain management [18] – [20] , deep coma and disorders of consciousness [21] – [27] and many more (reviewed in [28] ). It is also one of the most commonly prescribed medications for the treatment of insomnia in the world: in the US alone it accounts for more than 30 million of yearly prescriptions [8] .…”

Section: Introductionmentioning

confidence: 99%

Zolpidem Reduces Hippocampal Neuronal Activity in Freely Behaving Mice: A Large Scale Calcium Imaging Study with Miniaturized Fluorescence Microscope

et al. 2014

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Therapeutic drugs for cognitive and psychiatric disorders are often characterized by their molecular mechanism of action. Here we demonstrate a new approach to elucidate drug action on large-scale neuronal activity by tracking somatic calcium dynamics in hundreds of CA1 hippocampal neurons of pharmacologically manipulated behaving mice. We used an adeno-associated viral vector to express the calcium sensor GCaMP3 in CA1 pyramidal cells under control of the CaMKII promoter and a miniaturized microscope to observe cellular dynamics. We visualized these dynamics with and without a systemic administration of Zolpidem, a GABAA agonist that is the most commonly prescribed drug for the treatment of insomnia in the United States. Despite growing concerns about the potential adverse effects of Zolpidem on memory and cognition, it remained unclear whether Zolpidem alters neuronal activity in the hippocampus, a brain area critical for cognition and memory. Zolpidem, when delivered at a dose known to induce and prolong sleep, strongly suppressed CA1 calcium signaling. The rate of calcium transients after Zolpidem administration was significantly lower compared to vehicle treatment. To factor out the contribution of changes in locomotor or physiological conditions following Zolpidem treatment, we compared the cellular activity across comparable epochs matched by locomotor and physiological assessments. This analysis revealed significantly depressive effects of Zolpidem regardless of the animal’s state. Individual hippocampal CA1 pyramidal cells differed in their responses to Zolpidem with the majority (∼65%) significantly decreasing the rate of calcium transients, and a small subset (3%) showing an unexpected and significant increase. By linking molecular mechanisms with the dynamics of neural circuitry and behavioral states, this approach has the potential to contribute substantially to the development of new therapeutics for the treatment of CNS disorders.

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Section: Introductionmentioning

confidence: 99%

Zolpidem Reduces Hippocampal Neuronal Activity in Freely Behaving Mice: A Large Scale Calcium Imaging Study with Miniaturized Fluorescence Microscope

et al. 2014

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“…Theoretically, zolpidem activates selective GABA-nergic inhibitory neurons in the Gpi and SNpr, and thus, this mechanism should restore the thalamus and motor cortex. By another mechanism, decreased subthalamic excitatory signals by zolpidem decrease the GABAnergic inhibitory neurotransmitter of the Gpi and subsequently induce an excitatory thalamic effect in the cortical motor system 7) . In our patient, this effect may have led to the transient improvement after she took zolpidem.…”

Section: Discussionmentioning

confidence: 99%

The Effects of Zolpidem on Akinesia in a Parkinson Disease Patient: A Case Report

Kim

2015

J Korean Geriatr Soc

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Zolpidem, an imidazopyridine drug that affects the gamma-aminobutyric acid receptor, is typically used as a hypnotic sedative. It has been reported that this drug improves motor symptoms in patients with various movement disorders, including Parkinson disease. We presented a patient with advanced Parkinson disease who demonstrated improved akinesia after taking zolpidem without sleep induction or consciousness changes.

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“…24,25 Other BZ-site drugs such as zolpidem have some GABAA subtype selectivity for a1-subunit containing receptors and exert preferential effects at this subtype. 26 Furthermore, several antihistamines, antidepressants and antipsychotics have been used as sedative-hypnotics, e.g. trazodone and doxepin.…”

Section: The Main Mechanisms Of Small Molecules Supporting or Causingmentioning

confidence: 99%

Polypharmacological in Silico Bioactivity Profiling and Experimental Validation Uncovers Sedative-Hypnotic Effects of Approved and Experimental Drugs in Rat

et al. 2017

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In this work, we describe the computational ("in silico") mode-of-action analysis of CNS-active drugs, which is taking both multiple simultaneous hypotheses as well as sets of protein targets for each mode-of-action into account, and which was followed by successful prospective in vitro and in vivo validation. Using sleep-related phenotypic readouts describing both efficacy and side effects for 491 compounds tested in rat, we defined an "optimal" (desirable) sleeping pattern. Compounds were subjected to in silico target prediction (which was experimentally confirmed for 21 out of 28 cases), followed by the utilization of decision trees for deriving polypharmacological bioactivity profiles. We demonstrated that predicted bioactivities improved classification performance compared to using only structural information. Moreover, DrugBank molecules were processed via the same pipeline, and compounds in many cases not annotated as sedative-hypnotic (alcaftadine, benzatropine, palonosetron, ecopipam, cyproheptadine, sertindole, and clopenthixol) were prospectively validated in vivo. Alcaftadine, ecopipam cyproheptadine, and clopenthixol were found to promote sleep as predicted, benzatropine showed only a small increase in NREM sleep, whereas sertindole promoted wakefulness. To our knowledge, the sedative-hypnotic effects of alcaftadine and ecopipam have not been previously discussed in the literature. The method described extends previous single-target, single-mode-of-action models and is applicable across disease areas.

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The behavioral pharmacology of zolpidem: evidence for the functional significance of α1-containing GABAA receptors

Cited by 34 publications

References 250 publications

Zolpidem Reduces Hippocampal Neuronal Activity in Freely Behaving Mice: A Large Scale Calcium Imaging Study with Miniaturized Fluorescence Microscope

Zolpidem Reduces Hippocampal Neuronal Activity in Freely Behaving Mice: A Large Scale Calcium Imaging Study with Miniaturized Fluorescence Microscope

The Effects of Zolpidem on Akinesia in a Parkinson Disease Patient: A Case Report

Polypharmacological in Silico Bioactivity Profiling and Experimental Validation Uncovers Sedative-Hypnotic Effects of Approved and Experimental Drugs in Rat

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