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| Original Article | |
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| Neuropsychopharmacology (1999) 20 346-356.10.1038/sj.npp.1395268 The Vigilance Promoting Drug Modafinil Increases Extracellular Glutamate Levels in the Medial Preoptic Area and the Posterior Hypothalamus of the Conscious Rat: Prevention by Local GABAA Receptor Blockade Luca Ferraro1 Pharm D, Tiziana Antonelli1 MD, Sergio Tanganelli1 Pharm D, William T O'Connor2 Ph.D, Miguel Perez de la Mora3 MD, Jesus Mendez-Franco3, Francis A Rambert4 Ph.D and Kjell Fuxe5 MD | |
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| 1Department of Clinical and Experimental Medicine, Pharmacology Section, University of Ferrara, Ferrara, Italy 2Department of Human Anatomy and Physiology, University College of Dublin, Dublin, Ireland 3Department of Biophysics,, Istituto de Fisiologia Celular, Universidad Nacional Autonoma de Mexico, Mexico City, Mexico 4Neuropsychopharmacologie, Centre de Recherches, Laboratoire L. Lafon, Maisons-Alfort, France 5Department of Neuroscience, Karolinska Institute, Stockholm, Sweden Correspondence: Dr Kjell Fuxe, Department of Neuroscience, Division of Cellular and Molecular Neurochemistry, Karolinska Institutet, S-171 77 Stockholm, Sweden | |
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| ABSTRACT | |
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The effects of modafinil on glutamatergic and GABAergic transmission in the rat medial preoptic area (MPA) and posterior hypothalamus (PH), are analysed. Modafinil (30-300 mg/kg) increased glutamate and decreased GABA levels in the MPA and PH. Local perfusion with the GABAA agonist muscimol (10  M), reduced, while the GABAA antagonist bicuculline (1 M and 10 M) increased glutamate levels. The modafinil (100 mg/kg)-induced increase of glutamate levels was antagonized by local perfusion with bicuculline (1 M). When glutamate levels were increased by the local perfusion with the glutamate uptake inhibitor L-trans-PDC (0.5 mM), modafinil produced an additional enhancement of glutamate levels. Modafinil (1-33 M) failed to affect [3H]glutamate uptake in hypothalamic synaptosomes and slices. These findings show that modafinil increases glutamate and decreases GABA levels in MPA and PH. The evidence that bicuculline counteracts the modafinil-induced increase of glutamate levels strengthens the evidence for an inhibitory GABA/glutamate interaction in the above regions controlling the sleep-wakefulness cycle.Keywords: Medial preoptic area; Posterior hypothalamus; Extracellular glutamate levels; Vigilance; GABAA agonist; GABAA antagonist | |
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