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Evidence for a role of inhibition of orexinergic neurons in the anxiolytic and sedative effects of diazepam: A c-Fos study.

Abstract

The classical benzodiazepine diazepam (DZ) induces anxiolysis at low doses and sedation and hypnosis at higher doses. Different brain areas and neuronal populations most likely mediate these different behavioral effects. We used c-Fos immunohistochemistry as an indirect way to study neuronal activation or inhibition induced by DZ at anxiolytic and sedative doses (0.5 and 5mg/kg, respectively) in various brain areas involved in anxiety, arousal, sedation and addiction in C57BL/6J mice. We also focused on the two neuronal populations, orexinergic and dopaminergic neuronal populations, with the help of double-immunohistochemistry using c-Fos and orexin-A antibodies and c-Fos and tyrosine hydroxylase antibodies. We found that different brain areas of unhabituated mice reacted differently to the mild stress induced by vehicle injection. Also the response to anxiolytic or sedative doses of DZ differed between the areas, suggesting that distinct brain areas mediate the behavioral effects of low and high DZ doses. Our findings propose a role for inhibition of orexin neurons in the anxiolytic and sleep-promoting effects of DZ. In addition, the activation of central amygdala neurons by DZ treatment was associated with anxiolytic and sedative effects. On the other hand, the ventral hippocampus, basolateral amygdala, ventral tegmental area and prefrontal cortex were sensitive even to the mild injection stress, but not to the anxiolytic dose of DZ.

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  • Publisher Full Text

    • Authors

    Panhelainen AE, Korpi ER

    Institution

    Institute of Biomedicine, Pharmacology, Biomedicum Helsinki, POB 63 (Haartmaninkatu 8), FI-00014 University of Helsinki, Finland. anne.panhelainen@helsinki.fi

    Source

    Pharmacology, biochemistry, and behavior 101:1 2012 Mar pg 115-24

    MeSH

    Aging
    Amygdala
    Animals
    Anti-Anxiety Agents
    Anxiety
    Diazepam
    Dopaminergic Neurons
    Gene Expression
    Genes, fos
    Hippocampus
    Hypnotics and Sedatives
    Hypothalamus
    Immunohistochemistry
    Intracellular Signaling Peptides and Proteins
    Male
    Mice
    Mice, Inbred C57BL
    Neurons
    Neuropeptides
    Tyrosine 3-Monooxygenase

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22210490