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

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.

[1]  C. Mathiesen,et al.  GABAA Receptor-Mediated Bidirectional Control of Synaptic Activity, Intracellular Ca2+, Cerebral Blood Flow, and Oxygen Consumption in Mouse Somatosensory Cortex In Vivo. , 2015, Cerebral cortex.

[2]  S. Richa,et al.  Non-Antidepressant Treatment of Generalized Anxiety Disorder. , 2013, Current clinical pharmacology.

[3]  O. Paulsen,et al.  Development of dendritic tonic GABAergic inhibition regulates excitability and plasticity in CA1 pyramidal neurons. , 2014, Journal of neurophysiology.

[4]  Yujuan Zhang,et al.  Zolpidem Arouses Patients in Vegetative State After Brain Injury: Quantitative Evaluation and Indications , 2014, The American journal of the medical sciences.

[5]  E. Laska,et al.  Residual effects of low-dose sublingual zolpidem on highway driving performance the morning after middle-of-the-night use. , 2014, Sleep.

[6]  B. T. Wright,et al.  The behavioral pharmacology of zolpidem: evidence for the functional significance of α1-containing GABAA receptors , 2014, Psychopharmacology.

[7]  P. Bonaventure,et al.  Orexin-1 receptor blockade dysregulates REM sleep in the presence of orexin-2 receptor antagonism , 2014, Front. Neurosci..

[8]  J. Maguire,et al.  The impact of tonic GABAA receptor-mediated inhibition on neuronal excitability varies across brain region and cell type , 2014, Front. Neural Circuits.

[9]  Y. Urade,et al.  A mouse model mimicking human first night effect for the evaluation of hypnotics , 2014, Pharmacology Biochemistry and Behavior.

[10]  Gerry Leisman,et al.  Zolpidem arousing effect in persistent vegetative state patients: autonomic, EEG and behavioral assessment. , 2013, Current pharmaceutical design.

[11]  S. Sacco,et al.  Pharmacological modulation of the state of awareness in patients with disorders of consciousness: an overview. , 2013, Current pharmaceutical design.

[12]  S. Sacco,et al.  Silencing the brain may be better than stimulating it. The GABA effect. , 2013, Current pharmaceutical design.

[13]  Steven Laureys,et al.  Effect of zolpidem in chronic disorders of consciousness: a prospective open-label study. , 2014, Functional neurology.

[14]  Dacheng Wang,et al.  Structural basis of the ultrasensitive calcium indicator GCaMP6 , 2014, Science China Life Sciences.

[15]  Steven V. Fox,et al.  Dual orexin receptor antagonists show distinct effects on locomotor performance, ethanol interaction and sleep architecture relative to gamma-aminobutyric acid-A receptor modulators , 2013, Front. Neurosci..

[16]  K. Deisseroth,et al.  Engineering Approaches to Illuminating Brain Structure and Dynamics , 2013, Neuron.

[17]  Caleb Kemere,et al.  Rapid and Continuous Modulation of Hippocampal Network State during Exploration of New Places , 2013, PloS one.

[18]  Stefan R. Pulver,et al.  Ultra-sensitive fluorescent proteins for imaging neuronal activity , 2013, Nature.

[19]  J. Born,et al.  Sleep for preserving and transforming episodic memory. , 2013, Annual review of neuroscience.

[20]  R. Behrendt.  Hippocampus and consciousness , 2013, Reviews in the neurosciences.

[21]  K. Harris,et al.  Sleep and the single neuron: the role of global slow oscillations in individual cell rest , 2013, Nature Reviews Neuroscience.

[22]  Philipp J. Keller,et al.  Whole-brain functional imaging at cellular resolution using light-sheet microscopy , 2013, Nature Methods.

[23]  W. Sieghart,et al.  Patterns of mRNA and protein expression for 12 GABAA receptor subunits in the mouse brain , 2013, Neuroscience.

[24]  Steven V. Fox,et al.  Orexin Receptor Antagonists Differ from Standard Sleep Drugs by Promoting Sleep at Doses That Do Not Disrupt Cognition , 2013, Science Translational Medicine.

[25]  Elizabeth A. McDevitt,et al.  The Critical Role of Sleep Spindles in Hippocampal-Dependent Memory: A Pharmacology Study , 2013, The Journal of Neuroscience.

[26]  N. Gunja.  In the Zzz Zone: The Effects of Z-Drugs on Human Performance and Driving , 2013, Journal of Medical Toxicology.

[27]  Rafael Yuste,et al.  Nanotools for neuroscience and brain activity mapping. , 2013, ACS nano.

[28]  B. Kuehn.  FDA warning: Driving may be impaired the morning following sleeping pill use. , 2013, JAMA.

[29]  Lacey J. Kitch,et al.  Long-term dynamics of CA1 hippocampal place codes , 2013, Nature Neuroscience.

[30]  John A. King,et al.  How vision and movement combine in the hippocampal place code , 2012, Proceedings of the National Academy of Sciences.

[31]  Thomas Knöpfel,et al.  Genetically encoded optical indicators for the analysis of neuronal circuits , 2012, Nature Reviews Neuroscience.

[32]  D. Maurice,et al.  EEG spectral power density profiles during NREM sleep for gaboxadol and zolpidem in patients with primary insomnia , 2012, Journal of psychopharmacology.

[33]  R. McCarley,et al.  Control of sleep and wakefulness. , 2012, Physiological reviews.

[34]  K. A. Zanin,et al.  Effects of zolpidem on sedation, anxiety, and memory in the plus-maze discriminative avoidance task , 2012, Psychopharmacology.

[35]  D. Greenblatt,et al.  Zolpidem for insomnia , 2012, Expert opinion on pharmacotherapy.

[36]  Daniel L. Schacter,et al.  Constructive memory: past and future , 2012, Dialogues in clinical neuroscience.

[37]  R. Griffiths,et al.  Acute effects of zolpidem extended-release on cognitive performance and sleep in healthy males after repeated nightly use. , 2012, Experimental and clinical psychopharmacology.

[38]  I. Módy,et al.  Extrasynaptic GABAA Receptors: Their Function in the CNS and Implications for Disease , 2012, Neuron.

[39]  Jian-Sheng Lin,et al.  Effects of GF-015535-00, a novel α1 GABA A receptor ligand, on the sleep-wake cycle in mice, with reference to zolpidem. , 2012, Sleep.

[40]  M. Palkovits,et al.  Astrocytes convert network excitation to tonic inhibition of neurons , 2012, BMC Biology.

[41]  Daesoo Kim,et al.  The amount of astrocytic GABA positively correlates with the degree of tonic inhibition in hippocampal CA1 and cerebellum , 2011, Molecular Brain.

[42]  P. Scheiffele,et al.  Distinct mechanisms regulate GABAA receptor and gephyrin clustering at perisomatic and axo‐axonic synapses on CA1 pyramidal cells , 2011, The Journal of physiology.

[43]  A. Gamal,et al.  Miniaturized integration of a fluorescence microscope , 2011, Nature Methods.

[44]  A. Krystal,et al.  Pharmacological advances in the treatment of insomnia. , 2011, Current pharmaceutical design.

[45]  H. M. Murphy,et al.  Zolpidem-induced changes in activity, metabolism, and anxiety in rats , 2011, Pharmacology Biochemistry and Behavior.

[46]  K. Olkkola,et al.  Enhancement of GABAergic Activity: Neuropharmacological Effects of Benzodiazepines and Therapeutic Use in Anesthesiology , 2011, Pharmacological Reviews.

[47]  R. Pearce,et al.  How we recall (or don’t): the hippocampal memory machine and anesthetic amnesia , 2011, Canadian journal of anaesthesia = Journal canadien d'anesthesie.

[48]  Yaniv Ziv,et al.  Time-lapse imaging of disease progression in deep brain areas using fluorescence microendoscopy , 2011, Nature Medicine.

[49]  Gabriel A. Silva,et al.  A Framework for Simulating and Estimating the State and Functional Topology of Complex Dynamic Geometric Networks , 2009, Neural Computation.

[50]  T. Buclin,et al.  [Pharmacovigilance update]. , 2011, Revue medicale suisse.

[51]  G. Tononi,et al.  Electrophysiological correlates of sleep homeostasis in freely behaving rats. , 2011, Progress in brain research.

[52]  J. Kehne,et al.  Emergence of anti-conflict effects of zolpidem in rhesus monkeys following extended post-injection intervals , 2011, Psychopharmacology.

[53]  T. Miyaoka,et al.  Adverse reactions to zolpidem: case reports and a review of the literature. , 2010, Primary care companion to the Journal of clinical psychiatry.

[54]  P. Somogyi,et al.  Quantitative localisation of synaptic and extrasynaptic GABAA receptor subunits on hippocampal pyramidal cells by freeze‐fracture replica immunolabelling , 2010, The European journal of neuroscience.

[55]  Richard N Henson,et al.  Predictive, interactive multiple memory systems , 2010, Hippocampus.

[56]  A. Scheinberg,et al.  Zolpidem for Persistent Vegetative State – A Placebo-Controlled Trial in Pediatrics , 2010, Neuropediatrics.

[57]  K. Henke.  A model for memory systems based on processing modes rather than consciousness , 2010, Nature Reviews Neuroscience.

[58]  S. Auerbach,et al.  Effects of eszopiclone and zolpidem on sleep–wake behavior, anxiety-like behavior and contextual memory in rats , 2010, Behavioural Brain Research.

[59]  Loren J. Martin,et al.  α5 Subunit-containing GABAA receptors mediate a slowly decaying inhibitory synaptic current in CA1 pyramidal neurons following Schaffer collateral activation , 2010, Neuropharmacology.

[60]  D. Peričić,et al.  Zolpidem is a potent anticonvulsant in adult and aged mice , 2010, Brain Research.

[61]  J. White,et al.  Gain Control in CA1 Pyramidal Cells Using Changes in Somatic Conductance , 2010, The Journal of Neuroscience.

[62]  S. Hughes,et al.  The slow (<1 Hz) rhythm of non-REM sleep: a dialogue between three cardinal oscillators , 2010, Nature Neuroscience.

[63]  T. Leufkens,et al.  Highway driving performance and cognitive functioning the morning after bedtime and middle‐of‐the‐night use of gaboxadol, zopiclone and zolpidem , 2009, Journal of sleep research.

[64]  Catherine Berthelon,et al.  Residual effects of hypnotic drugs in aging drivers submitted to simulated accident scenarios: an exploratory study , 2009, Psychopharmacology.

[65]  M. Packard.  Anxiety, cognition, and habit: A multiple memory systems perspective , 2009, Brain Research.

[66]  Mark J. Schnitzer,et al.  Automated Analysis of Cellular Signals from Large-Scale Calcium Imaging Data , 2009, Neuron.

[67]  P. Bonaventure,et al.  Blockade of Orexin-1 Receptors Attenuates Orexin-2 Receptor Antagonism-Induced Sleep Promotion in the Rat , 2009, Journal of Pharmacology and Experimental Therapeutics.

[68]  R. Shrivastava,et al.  Zolpidem Extended-Release Improves Sleep and Next-Day Symptoms in Comorbid Insomnia and Generalized Anxiety Disorder , 2009, Journal of clinical psychopharmacology.

[69]  D. Peričić,et al.  Effects of acute and repeated zolpidem treatment on pentylenetetrazole-induced seizure threshold and on locomotor activity: Comparison with diazepam , 2009, Neuropharmacology.

[70]  John Whyte,et al.  Incidence of Clinically Significant Responses to Zolpidem Among Patients with Disorders of Consciousness: A Preliminary Placebo Controlled Trial , 2009, American journal of physical medicine & rehabilitation.

[71]  P. Bonaventure,et al.  5-HT7 receptor deletion enhances REM sleep suppression induced by selective serotonin reuptake inhibitors, but not by direct stimulation of 5-HT1A receptor , 2009, Neuropharmacology.

[72]  N. Zisapel,et al.  Effects of prolonged‐release melatonin, zolpidem, and their combination on psychomotor functions, memory recall, and driving skills in healthy middle aged and elderly volunteers , 2008, Human psychopharmacology.

[73]  M. Moser,et al.  Understanding memory through hippocampal remapping , 2008, Trends in Neurosciences.

[74]  R. Farber,et al.  Post-bedtime dosing with indiplon in adults and the elderly: results from two placebo-controlled, active comparator crossover studies in healthy volunteers* , 2008, Current medical research and opinion.

[75]  M. Hamon,et al.  Sleep-stabilizing effects of E-6199, compared to zopiclone, zolpidem and THIP in mice. , 2008, Sleep.

[76]  D. S. Štrac,et al.  Sedative and anticonvulsant effects of zolpidem in adult and aged mice , 2008, Journal of Neural Transmission.

[77]  K. Abe.  Zolpidem therapy for movement disorders. , 2008, Recent patents on CNS drug discovery.

[78]  K. Ressler,et al.  Forebrain and midbrain distribution of major benzodiazepine-sensitive GABAA receptor subunits in the adult C57 mouse as assessed with in situ hybridization , 2007, Neuroscience.

[79]  F. Da Settimo,et al.  GABA A/Bz receptor subtypes as targets for selective drugs. , 2007, Current medicinal chemistry.

[80]  J. Verster,et al.  Zolpidem and traffic safety - the importance of treatment compliance. , 2007, Current drug safety.

[81]  N. Harrison.  Mechanisms of sleep induction by GABA(A) receptor agonists. , 2007, The Journal of clinical psychiatry.

[82]  P. Érdi,et al.  Pharmacological and computational analysis of alpha-subunit preferential GABAA positive allosteric modulators on the rat septo-hippocampal activity , 2007, Neuropharmacology.

[83]  Joseph A Lieberman,et al.  Update on the safety considerations in the management of insomnia with hypnotics: incorporating modified-release formulations into primary care. , 2007, Primary care companion to the Journal of clinical psychiatry.

[84]  M. Wilson,et al.  Coordinated memory replay in the visual cortex and hippocampus during sleep , 2007, Nature Neuroscience.

[85]  R. Tashjian,et al.  Zolpidem Reduces Postoperative Pain, Fatigue, and Narcotic Consumption Following Knee Arthroscopy: A Prospective Randomized Placebo-Controlled Double-Blinded Study , 2010, The journal of knee surgery.

[86]  Sean M Montgomery,et al.  Integration and Segregation of Activity in Entorhinal-Hippocampal Subregions by Neocortical Slow Oscillations , 2006, Neuron.

[87]  Federico Ranieri,et al.  GABAA receptor subtype specific enhancement of inhibition in human motor cortex , 2006, The Journal of physiology.

[88]  Thomas A. Ban,et al.  The role of serendipity in drug discovery , 2006, Dialogues in clinical neuroscience.

[89]  B. Mohammadi,et al.  Selective and nonselective benzodiazepine agonists have different effects on motor cortex excitability , 2006, Muscle & nerve.

[90]  B. Birnir,et al.  Graded response to GABA by native extrasynaptic GABAA receptors , 2006, Journal of neurochemistry.

[91]  S. Schreiber,et al.  The antinociceptive effect of zolpidem and zopiclone in mice , 2005, Pharmacology Biochemistry and Behavior.

[92]  O. Bjerrum,et al.  Centrally-mediated antinociceptive actions of GABA(A) receptor agonists in the rat spared nerve injury model of neuropathic pain. , 2005, European journal of pharmacology.

[93]  P. Somogyi,et al.  Loss of zolpidem efficacy in the hippocampus of mice with the GABAA receptor γ2 F77I point mutation , 2005, The European journal of neuroscience.

[94]  S. Tufik,et al.  Acute neurophysiological effects of the hypnotic zolpidem in healthy volunteers , 2005, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[95]  J. Prado,et al.  Effect of a single dose (10 mg) of zolpidem on visual and spectral analysis of sleep in young poor sleepers , 1994, Psychopharmacology.

[96]  D. Sanger.  The Pharmacology and Mechanisms of Action of New Generation, Non-Benzodiazepine Hypnotic Agents , 2004, CNS Drugs.

[97]  I. Tobler,et al.  Sleep EEG changes after zolpidem in mice , 2004, Neuroreport.

[98]  H. Eichenbaum.  Hippocampus Cognitive Processes and Neural Representations that Underlie Declarative Memory , 2004, Neuron.

[99]  R. Olsen,et al.  Altered Pharmacology of Synaptic and Extrasynaptic GABAA Receptors on CA1 Hippocampal Neurons Is Consistent with Subunit Changes in a Model of Alcohol Withdrawal and Dependence , 2004, Journal of Pharmacology and Experimental Therapeutics.

[100]  B. McNaughton,et al.  The contributions of position, direction, and velocity to single unit activity in the hippocampus of freely-moving rats , 1983, Experimental Brain Research.

[101]  D. Kullmann,et al.  GABA uptake regulates cortical excitability via cell type–specific tonic inhibition , 2003, Nature Neuroscience.

[102]  B. Orser,et al.  Tonically activated GABAA receptors in hippocampal neurons are high-affinity, low-conductance sensors for extracellular GABA. , 2003, Molecular pharmacology.

[103]  F. Elsen,et al.  Prolongation of hippocampal miniature inhibitory postsynaptic currents in mice lacking the GABA(A) receptor alpha1 subunit. , 2002, Journal of neurophysiology.

[104]  E. Maguire,et al.  The Human Hippocampus and Spatial and Episodic Memory , 2002, Neuron.

[105]  G. Sperk,et al.  Subunit composition, distribution and function of GABA(A) receptor subtypes. , 2002, Current topics in medicinal chemistry.

[106]  S. Khanna,et al.  Selective destruction of medial septal cholinergic neurons attenuates pyramidal cell suppression, but not excitation in dorsal hippocampus field ca1 induced by subcutaneous injection of formalin , 2001, Neuroscience.

[107]  J. Kramer,et al.  The Importance of Residual Effects When Choosing a Hypnotic: The Unique Profile of Zaleplon. , 2001, Primary care companion to the Journal of clinical psychiatry.

[108]  J. Luebke,et al.  Development and Modulation of GABAA Receptor-mediated Neurotransmission in the CA1 Region of Prenatally Protein Malnourished Rats , 2001, Nutritional neuroscience.

[109]  D. Monti,et al.  Conventional and power spectrum analysis of the effects of zolpidem on sleep EEG in patients with chronic primary insomnia. , 2000, Sleep.

[110]  U. Rudolph,et al.  Mechanism of action of the hypnotic zolpidem in vivo , 2000, British journal of pharmacology.

[111]  G. Sperk,et al.  GABAA receptors: immunocytochemical distribution of 13 subunits in the adult rat brain , 2000, Neuroscience.

[112]  R. Mckernan,et al.  Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABAA receptor α1 subtype , 2000, Nature Neuroscience.

[113]  M. Murasaki,et al.  The effect of zolpidem and zopiclone on memory. , 2000, Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology.

[114]  T. Yoshioka,et al.  Developmental change of GABAA receptor-mediated current in rat hippocampus , 2000, Neuroscience.

[115]  G. Sperk,et al.  GABA(A) receptors: immunocytochemical distribution of 13 subunits in the adult rat brain. , 2000, Neuroscience.

[116]  W. Cevallos,et al.  A comparison of the residual effects of zaleplon and zolpidem following administration 5 to 2 h before awakening. , 2001, British journal of clinical pharmacology.

[117]  J. Benson,et al.  Benzodiazepine actions mediated by specific γ-aminobutyric acidA receptor subtypes , 1999, Nature.

[118]  A. Doble.  New Insights Into The Mechanism of Action of Hypnotics , 1999, Journal of psychopharmacology.

[119]  R. Macdonald,et al.  Functional GABAA receptor heterogeneity of acutely dissociated hippocampal CA1 pyramidal cells. , 1999, Journal of neurophysiology.

[120]  E. Tietz,et al.  Benzodiazepine tolerance at GABAergic synapses on hippocampal CA1 pyramidal cells , 1999, Synapse.

[121]  N. Ropert,et al.  Effect of Zolpidem on Miniature IPSCs and Occupancy of Postsynaptic GABAA Receptors in Central Synapses , 1999, The Journal of Neuroscience.

[122]  J. Benson,et al.  Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes. , 1999, Nature.

[123]  A. Członkowska,et al.  The role of the hippocampus and 5-HT/GABA interaction in the central effects of benzodiazepine receptor ligands , 1999, Journal of Neural Transmission.

[124]  C. Davies,et al.  Pharmacological modulation of GABAA receptor‐mediated postsynaptic potentials in the CA1 region of the rat hippocampus , 1998, British journal of pharmacology.

[125]  Y. Koshino,et al.  Differences in the effects of zolpidem and diazepam on recurrent inhibition and long-term potentiation in rat hippocampal slices , 1998, Neuroscience Letters.

[126]  M. Moser,et al.  Functional differentiation in the hippocampus , 1998, Hippocampus.

[127]  G. Sperk,et al.  GABAA receptor subunits in the rat hippocampus I: Immunocytochemical distribution of 13 subunits , 1997, Neuroscience.

[128]  G. Perrault,et al.  Comparison of the pharmacological profiles of the hypnotic drugs, zaleplon and zolpidem. , 1996, European journal of pharmacology.

[129]  F. Besnard,et al.  Pharmacological profile of benzodiazepine site ligands with recombinant GABAA receptor subtypes , 1996, European Neuropsychopharmacology.

[130]  Robert Kerchner,et al.  Interim Report , 1996 .

[131]  M. A. Raja,et al.  Spatial- and locomotion-related neural representation in rat hippocampus following long-term survival from ischemia. , 1995, Behavioral neuroscience.

[132]  C. Wilkinson.  The acute effects of zolpidem, administered alone and with alcohol, on cognitive and psychomotor function. , 1995, The Journal of clinical psychiatry.

[133]  W. Kostowski.  Recent advances in the GABA-A-benzodiazepine receptor pharmacology. , 1995, Polish journal of pharmacology.

[134]  J. Hodges.  Memory, Amnesia and the Hippocampal System , 1995 .

[135]  Y. Ben-Ari,et al.  Developmental study of benzodiazepine effects on monosynaptic GABAA-mediated IPSPs of rat hippocampal neurons. , 1993, Journal of neurophysiology.

[136]  T. Hergueta,et al.  Comparison of the Effects of Zolpidem and Triazolam on Memory Functions, Psychomotor Performances, and Postural Sway in Healthy Subjects , 1993, Journal of clinical psychopharmacology.

[137]  H. Eichenbaum,et al.  Memory, amnesia, and the hippocampal system , 1993 .

[138]  L. Squire,et al.  The Neuropsychology of Memory , 1990 .

[139]  R. Griffiths,et al.  Zolpidem and triazolam in humans: behavioral and subjective effects and abuse liability. , 1990, The Journal of pharmacology and experimental therapeutics.

[140]  C. A. Castro,et al.  Spatial selectivity of rat hippocampal neurons: dependence on preparedness for movement. , 1989, Science.

[141]  G. Perrault,et al.  Zolpidem, a novel nonbenzodiazepine hypnotic. I. Neuropharmacological and behavioral effects. , 1986, The Journal of pharmacology and experimental therapeutics.

[142]  T Hamanaka,et al.  [Neuropsychology of memory]. , 1985, No to shinkei = Brain and nerve.