title: Clenbuterol activates the central IL-1 system via the β2-adrenoceptor without provoking inflammatory response related behaviours in rats.
abstract: The long-acting, highly lipophilic, β2-adrenoceptor agonist clenbuterol may represent a suitable therapeutic agent for the treatment of neuroinflammation as it drives an anti-inflammatory response within the CNS. However, clenbuterol is also known to increase the expression of IL-1β in the brain, a potent neuromodulator that plays a role in provoking sickness related symptoms including anxiety and depression-related behaviours. Here we demonstrate that, compared to the immunological stimulus lipopolysaccharide (LPS, 250μg/kg), clenbuterol (0.5mg/kg) selectively up-regulates expression of the central IL-1 system resulting in a mild stress-like response which is accompanied by a reduction in locomotor activity and food consumption in rats. We provide further evidence that clenbuterol-induced activation of the central IL-1 system occurs in a controlled and selective manner in tandem with its negative regulators IL-1ra and IL-1RII. Furthermore, we demonstrate that peripheral β2-adrenoceptors mediate the suppression of locomotor activity and food consumption induced by clenbuterol and that these effects are not linked to the central induction of IL-1β. Moreover, despite increasing central IL-1β expression, chronic administration of clenbuterol (0.03mg/kg; twice daily for 21days) fails to induce anxiety or depressive-like behaviour in rats in contrast to reports of the ability of exogenously administered IL-1 to induce these symptoms in rodents. Overall, our findings suggest that clenbuterol or other selective β2-adrenoceptor agonists could have the potential to combat neuroinflammatory or neurodegenerative disorders without inducing unwanted symptoms of depression and anxiety.
authors.affiliation: Neuroimmunology Research Group, Trinity College Institute of Neuroscience, Department of Physiology & School of Medicine, Trinity College, Dublin 2, Ireland.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Ryan
authors.affiliation: Neuroimmunology Research Group, Trinity College Institute of Neuroscience, Department of Physiology & School of Medicine, Trinity College, Dublin 2, Ireland.
authors.forename: Éadaoin W
authors.initials: ÉW
authors.lastname: Griffin
authors.affiliation: Neuroimmunology Research Group, Trinity College Institute of Neuroscience, Department of Physiology & School of Medicine, Trinity College, Dublin 2, Ireland.
authors.forename: Katie J
authors.initials: KJ
authors.lastname: Ryan
authors.affiliation: Neuroimmunology Research Group, Trinity College Institute of Neuroscience, Department of Physiology & School of Medicine, Trinity College, Dublin 2, Ireland.
authors.forename: Riffat
authors.initials: R
authors.lastname: Tanveer
authors.affiliation: Neuropsychopharmacology Research Group, School of Pharmacy and Pharmaceutical Sciences & Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland.
authors.forename: Natacha
authors.initials: N
authors.lastname: Vanattou-Saifoudine
authors.affiliation: Neuroimmunology Research Group, Trinity College Institute of Neuroscience, Department of Physiology & School of Medicine, Trinity College, Dublin 2, Ireland.
authors.forename: Eoin N
authors.initials: EN
authors.lastname: McNamee
authors.affiliation: Neuroimmunology Research Group, Trinity College Institute of Neuroscience, Department of Physiology & School of Medicine, Trinity College, Dublin 2, Ireland.
authors.forename: Emer
authors.initials: E
authors.lastname: Fallon
authors.affiliation: Neuroimmunology Research Group, Trinity College Institute of Neuroscience, Department of Physiology & School of Medicine, Trinity College, Dublin 2, Ireland.
authors.forename: Sheena
authors.initials: S
authors.lastname: Heffernan
authors.affiliation: Neuropsychopharmacology Research Group, School of Pharmacy and Pharmaceutical Sciences & Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland. Electronic address: aharkin@tcd.ie.
authors.forename: Andrew
authors.initials: A
authors.lastname: Harkin
authors.affiliation: Neuroimmunology Research Group, Trinity College Institute of Neuroscience, Department of Physiology & School of Medicine, Trinity College, Dublin 2, Ireland.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Connor
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D001007:Anxiety / Q000139:chemically induced*; D001522:Behavior, Animal / Q000187:drug effects*; D002976:Clenbuterol / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D003863:Depression / Q000139:chemically induced*; D055809:Illness Behavior / Q000187:drug effects*; D053583:Interleukin-1beta / Q000187:drug effects*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; C000594089:IL1B protein, rat; D053583:Interleukin-1beta; D002976:Clenbuterol
keywords: Anhedonia; Anxiety; Clenbuterol; Cytokine; Depression; Food consumption; IL-1β; Locomotor activity; Sickness behaviour; β(2)-Adrenoceptor