Oxidative metabolism of limbic structures after acute administration of diazepam, alprazolam and zolpidem

The effects of acute administration of two benzodiazepines and a non-benzodiazepine hypnotic on behavior and brain metabolism were evaluated in rats. After testing the behavioral action of the benzodiazepines on the open field and the elevated plus-maze, the effects of the three drugs on neuronal metabolism of particular limbic regions were measured using cytochrome c oxidase (CO) histochemistry. Diazepam (5 mg/kg i.p.) and alprazolam (0.5 mg/kg i.p.) induced clear anxiolytic effects and a decrease in locomotion, whereas zolpidem (2 mg/kg i.p.) caused an intense hypnotic effect. The anxiolytic effects of alprazolam were distinguishable from diazepam due to the pharmacological and clinical profile of this triazolobenzodiazepine. CO activity decreased significantly in almost all the limbic regions evaluated after zolpidem administration. However, significant prominent decreases in CO activity were found after diazepam treatment in the medial mammillary nucleus, anteroventral thalamus, cingulate cortex, dentate gyrus and basolateral amygdala. Alprazolam caused similar decreases in CO activity, with the exception of the prelimbic and cingulate cortices, where significant increases were detected. In agreement with previous studies using other functional mapping techniques, our results indicate that particular benzodiazepines and non-benzodiazepine hypnotics induce selective changes in brain oxidative metabolism.

[1]  M. Bourin,et al.  Role of dopaminergic and serotonergic systems on behavioral stimulatory effects of low-dose alprazolam and lorazepam , 2001, European Neuropsychopharmacology.

[2]  L. Sokoloff,et al.  Effects of diazepam and ketamine administered individually or in combination on regional rates of glucose utilization in rat brain. , 1999, British journal of anaesthesia.

[3]  L. Eriksson,et al.  Imaging of [11C]-labelled Ro 15-1788 binding to benzodiazepine receptors in the human brain by positron emission tomography. , 1985, Journal of psychiatric research.

[4]  J. Pratt,et al.  Neuroadaptive processes in GABAergic and glutamatergic systems in benzodiazepine dependence. , 2003, Pharmacology & therapeutics.

[5]  R. Hughes,et al.  Effects on open-field behavior of diazepam and buspirone alone and in combination with chronic caffeine. , 1993, Life sciences.

[6]  J. Palacios,et al.  Benzodiazepine receptor sites in the human brain: Autoradiographic mapping , 1988, Neuroscience.

[7]  T. Robbins,et al.  Prefrontal executive and cognitive functions in rodents: neural and neurochemical substrates , 2004, Neuroscience & Biobehavioral Reviews.

[8]  J. Palacios,et al.  Mapping of benzodiazepine-like immunoreactivity in the rat brain as revealed by a monoclonal antibody to benzodiazepines , 1991, Journal of Chemical Neuroanatomy.

[9]  A. Bidziński,et al.  Effects of Buspirone, Diazepam, and Zolpidem on Open Field Behavior, and Brain [3H]Muscimol Binding After Buspirone Pretreatment , 2000, Pharmacology Biochemistry and Behavior.

[10]  C. Belzung,et al.  The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. , 2003, European journal of pharmacology.

[11]  F. Gonzalez-Lima.  Cytochrome Oxidase in Neuronal Metabolism and Alzheimer’s Disease , 2013, Springer US.

[12]  C. Nemeroff.  Anxiolytics: past, present, and future agents. , 2003, The Journal of clinical psychiatry.

[13]  R. McNamara,et al.  Tolerance Develops to the Spatial Learning Deficit Produced by Diazepam in Rats , 1997, Pharmacology Biochemistry and Behavior.

[14]  J. Pratt,et al.  Flumazenil induces localised increases in glucose utilization during diazepam withdrawal in rats , 1993, Brain Research.

[15]  S. File,et al.  Anxiolytic and anxiogenic drug effects on exploratory activity in an elevated plus-maze: A novel test of anxiety in the rat , 1986, Pharmacology Biochemistry and Behavior.

[16]  M. Wong-Riley.  Cytochrome oxidase: an endogenous metabolic marker for neuronal activity , 1989, Trends in Neurosciences.

[17]  F. Graeff,et al.  Ethopharmacological analysis of rat behavior on the elevated plus-maze , 1994, Pharmacology Biochemistry and Behavior.

[18]  W. Young,et al.  Radiohistochemical localization of benzodiazepine receptors in rat brain. , 1980, The Journal of pharmacology and experimental therapeutics.

[19]  P. Skolnick,et al.  Anxioselective anxiolytics: can less be more? , 2004, European Journal of Pharmacology.

[20]  S. Paul,et al.  Low-dose alprazolam augments motor activity in mice , 1988, Pharmacology Biochemistry and Behavior.

[21]  J. Pratt,et al.  Benzodiazepine Dependence: From Neural Circuits to Gene Expression , 1998, Pharmacology Biochemistry and Behavior.

[22]  J. Mcculloch,et al.  The effect of diazepam upon local cerebral glucose use in the conscious rat , 1986, Neuroscience.

[23]  Y. Gomita,et al.  The mammillary body is a potential site of antianxiety action of benzodiazepines , 1982, Brain Research.

[24]  J. Pratt,et al.  The neuroanatomical basis of anxiety. , 1992, Pharmacology & therapeutics.

[25]  J. Fritschy,et al.  A new benzodiazepine pharmacology. , 2002, The Journal of pharmacology and experimental therapeutics.

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

[27]  K. Zyo,et al.  Retrograde double‐labeling study of the marnmillothalamic and the mammillotegmental projections in the rat , 1989, The Journal of comparative neurology.

[28]  S. File,et al.  The effects of triazolobenzodiazepines in two animal tests of anxiety and in the holeboard , 1985, British journal of pharmacology.

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

[30]  M. Ernst,et al.  Effects of Triazolam on Brain Activity During Episodic Memory Encoding: A PET Study , 2001, Neuropsychopharmacology.

[31]  B. Scatton,et al.  Autoradiographic Localization of [3H]Zolpidem Binding Sites in the Rat CNS: Comparison with the Distribution of [3H]Flunitrazepam Binding Sites , 1987, Journal of neurochemistry.

[32]  G. Perrault,et al.  The use of the rat elevated plus-maze to discriminate between non-selective and BZ-1 (ω1) selective, benzodiazepine receptor ligands , 1996, Psychopharmacology.

[33]  J. Pratt,et al.  Local cerebral glucose utilization following subacute and chronic diazepam pretreatment: differential tolerance , 1989, Brain Research.

[34]  E. Moyse,et al.  Benzodiazepine binding sites in the human hypothalamus. Autoradiographic study. , 1999, Journal fur Hirnforschung.

[35]  C. Cannizzaro,et al.  Antidepressant and anxiolytic effects of alprazolam versus the conventional antidepressant desipramine and the anxiolytic diazepam in the forced swim test in rats. , 1992, European journal of pharmacology.

[36]  A. Herz,et al.  Specific changes in local cerebral glucose utilization in the rat brain induced by acute and chronic diazepam , 1985, Brain Research.

[37]  L. Santín,et al.  Ethanol- and diazepam-induced cytochrome oxidase activity in mammillary bodies , 1996, Pharmacology Biochemistry and Behavior.

[38]  J. W. Papez.  A PROPOSED MECHANISM OF EMOTION , 1937 .

[39]  J. Cimadevilla,et al.  Changes of cytochrome oxidase activity in rat suprachiasmatic nucleus , 1997, Brain Research.

[40]  J. Carlson,et al.  Sedative and anxiolytic effects of zopiclone's enantiomers and metabolite. , 2001, European journal of pharmacology.

[41]  S. File,et al.  Profiles of the antipanic compounds, triazolobenzodiazepines and phenelzine, in two animal tests of anxiety , 1988, Psychiatry Research.

[42]  J. Atack.  The benzodiazepine binding site of GABAA receptors as a target for the development of novel anxiolytics , 2005, Expert opinion on investigational drugs.

[43]  D. Stephens,et al.  Differential effects of anxiolytic and non‐anxiolytic benzodiazepine receptor ligands on performance of a differential reinforcement of low rate (DRL) schedule , 1994, Behavioural pharmacology.

[44]  S. Morato,et al.  Effect of different illumination levels on rat behavior in the elevated plus-maze , 2005, Physiology & Behavior.

[45]  J. Prince,et al.  A histochemical demonstration of altered cytochrome oxidase activity in the rat brain by neuroleptics , 1998, European Neuropsychopharmacology.

[46]  L. Sokoloff,et al.  Measurement of local cerebral glucose utilization and its relation to local functional activity in the brain. , 1991, Advances in experimental medicine and biology.

[47]  Dirk Jones,et al.  Quantitative mapping of cytovhrome oxidase activity in the central auditory system of the gerbil: a study with calibrated activity standards and metal-intensified histochemistry , 1994, Brain Research.

[48]  A A Borbély,et al.  Functional neuroanatomy of human sleep states after zolpidem and placebo: A H215O‐PET study , 2000, Journal of sleep research.