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Correlated species differences in the effects of cannabinoid ligands on anxiety and on GABAergic and glutamatergic synaptic transmission.

Abstract

Cannabinoid ligands show therapeutic potential in a variety of disorders including anxiety. However, the anxiety-related effects of cannabinoids remain controversial as agonists show opposite effects in mice and rats. Here we compared the effects of the cannabinoid agonist WIN-55,212 and the CB1 antagonist AM-251 in CD1 mice and Wistar rats. Special attention was paid to antagonist-agonist interactions, which had not yet been studied in rats. In mice, WIN-55,212 decreased whereas AM-251 increased anxiety. The antagonist abolished the effects of the agonist. In contrast, WIN-55,212 increased anxiety in rats. Surprisingly, the antagonist potentiated this effect. Cannabinoids affect both GABAergic and glutamatergic functions, which play opposite roles in anxiety. We hypothesized that discrepant findings resulted from species differences in the relative responsiveness of the two transmitter systems to cannabinoids. We investigated this hypothesis by studying the effects of WIN-55,212 on evoked hippocampal inhibitory and excitatory postsynaptic currents (IPSCs and EPSCs). IPSCs were one order of magnitude more sensitive to WIN-55,212 in mice than in rats. In mice, IPSCs were more sensitive than EPSCs to WIN-55,212. This is the first study showing that the relative cannabinoid sensitivity of GABA and glutamate neurotransmission is species-dependent. Based on behavioural and electrophysiological findings, we hypothesize that WIN-55,212 reduced anxiety in mice by affecting GABA neurotransmission whereas it increased anxiety in rats via glutamatergic mechanisms. In rats, AM-251 potentiated this anxiogenic effect by inhibiting the anxiolytic GABAergic mechanism. We suggest that the anxiety-related effects of cannabinoids depend on the relative cannabinoid responsiveness of GABAergic and glutamatergic neurotransmission.

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  • Authors+Show Affiliations

    ,

    Institute of Experimental Medicine, Department of Behavioral Neurobiology, 1450 Budapest, PO Box 67, Hungary. haller@koki.hu

    , , , , , , ,

    Source

    The European journal of neuroscience 25:8 2007 Apr pg 2445-56

    MeSH

    Analgesics
    Animals
    Anti-Anxiety Agents
    Anxiety
    Benzoxazines
    Cannabinoids
    Chlordiazepoxide
    Excitatory Postsynaptic Potentials
    Exploratory Behavior
    Glutamic Acid
    Hippocampus
    Inhibitory Postsynaptic Potentials
    Ligands
    Male
    Mice
    Morpholines
    Naphthalenes
    Patch-Clamp Techniques
    Piperidines
    Pyrazoles
    Rats
    Rats, Wistar
    Receptor, Cannabinoid, CB1
    Synaptic Transmission
    gamma-Aminobutyric Acid

    Pub Type(s)

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

    Language

    eng

    PubMed ID

    17445240

    Citation

    Haller, J, et al. "Correlated Species Differences in the Effects of Cannabinoid Ligands On Anxiety and On GABAergic and Glutamatergic Synaptic Transmission." The European Journal of Neuroscience, vol. 25, no. 8, 2007, pp. 2445-56.
    Haller J, Mátyás F, Soproni K, et al. Correlated species differences in the effects of cannabinoid ligands on anxiety and on GABAergic and glutamatergic synaptic transmission. Eur J Neurosci. 2007;25(8):2445-56.
    Haller, J., Mátyás, F., Soproni, K., Varga, B., Barsy, B., Németh, B., ... Hájos, N. (2007). Correlated species differences in the effects of cannabinoid ligands on anxiety and on GABAergic and glutamatergic synaptic transmission. The European Journal of Neuroscience, 25(8), pp. 2445-56.
    Haller J, et al. Correlated Species Differences in the Effects of Cannabinoid Ligands On Anxiety and On GABAergic and Glutamatergic Synaptic Transmission. Eur J Neurosci. 2007;25(8):2445-56. PubMed PMID: 17445240.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Correlated species differences in the effects of cannabinoid ligands on anxiety and on GABAergic and glutamatergic synaptic transmission. AU - Haller,J, AU - Mátyás,F, AU - Soproni,K, AU - Varga,B, AU - Barsy,B, AU - Németh,B, AU - Mikics,E, AU - Freund,T F, AU - Hájos,N, PY - 2007/4/21/pubmed PY - 2007/7/13/medline PY - 2007/4/21/entrez SP - 2445 EP - 56 JF - The European journal of neuroscience JO - Eur. J. Neurosci. VL - 25 IS - 8 N2 - Cannabinoid ligands show therapeutic potential in a variety of disorders including anxiety. However, the anxiety-related effects of cannabinoids remain controversial as agonists show opposite effects in mice and rats. Here we compared the effects of the cannabinoid agonist WIN-55,212 and the CB1 antagonist AM-251 in CD1 mice and Wistar rats. Special attention was paid to antagonist-agonist interactions, which had not yet been studied in rats. In mice, WIN-55,212 decreased whereas AM-251 increased anxiety. The antagonist abolished the effects of the agonist. In contrast, WIN-55,212 increased anxiety in rats. Surprisingly, the antagonist potentiated this effect. Cannabinoids affect both GABAergic and glutamatergic functions, which play opposite roles in anxiety. We hypothesized that discrepant findings resulted from species differences in the relative responsiveness of the two transmitter systems to cannabinoids. We investigated this hypothesis by studying the effects of WIN-55,212 on evoked hippocampal inhibitory and excitatory postsynaptic currents (IPSCs and EPSCs). IPSCs were one order of magnitude more sensitive to WIN-55,212 in mice than in rats. In mice, IPSCs were more sensitive than EPSCs to WIN-55,212. This is the first study showing that the relative cannabinoid sensitivity of GABA and glutamate neurotransmission is species-dependent. Based on behavioural and electrophysiological findings, we hypothesize that WIN-55,212 reduced anxiety in mice by affecting GABA neurotransmission whereas it increased anxiety in rats via glutamatergic mechanisms. In rats, AM-251 potentiated this anxiogenic effect by inhibiting the anxiolytic GABAergic mechanism. We suggest that the anxiety-related effects of cannabinoids depend on the relative cannabinoid responsiveness of GABAergic and glutamatergic neurotransmission. SN - 0953-816X UR - https://www.unboundmedicine.com/medline/citation/17445240/Correlated_species_differences_in_the_effects_of_cannabinoid_ligands_on_anxiety_and_on_GABAergic_and_glutamatergic_synaptic_transmission_ L2 - https://dx.doi.org/10.1111/j.1460-9568.2007.05476.x DB - PRIME DP - Unbound Medicine ER -