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cAMP and Extracellular Signal-Regulated Kinase Signaling in Response to D-Amphetamine and Methylphenidate in the Prefrontal Cortex in Vivo: Role of 1-Adrenoceptors

Signal Transduction and Plasticity in the Nervous System, Unité Mixte Recherche 536, Institut National de la Sante et de la Recherche Medicale and Université Pierre et Marie Curie, Institut du Fer à Moulin, Paris, France (V.P., E.V., J.-C.C., A.-G.C., J.-A.G., D.H.); and Chaire de Neuropharmacologie, Unité Mixte Recherche 114, Institut National de la Sante et de la Recherche Medicale and Collège de France, Paris, France (J.-P.T.)

D-Amphetamine and methylphenidate are widely used in the treatment of attention-deficit/hyperactivity disorder. Both drugs increase extracellular norepinephrine and dopamine in the prefrontal cortex, where they are believed to exert their therapeutic effects. However, the molecular mechanisms underlying their action are poorly understood. To investigate the intracellular signaling pathways activated by D-amphetamine and methylphenidate in the prefrontal cortex in vivo in mice, we measured the cAMP-dependent Ser845 phosphorylation of -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor GluR1 subunit and the active form of extracellular signal-regulated kinase (ERK). Administration of D-amphetamine (5–10 mg/kg) or methylphenidate (10–20 mg/kg) increased phosphorylation of GluR1. Basal and D-amphetamine–induced GluR1 phosphorylation was reduced by propranolol, a general -adrenoceptor antagonist, and betaxolol, a 1-antagonist, but not by (±)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol (ICI-118,515), a 2-antagonist. The effect of methylphenidate was also blocked by propranolol and betaxolol. The D-amphetamine effect was slightly potentiated by prazosin, an 1-adrenoceptor antagonist, and mimicked by yohimbine, an 2 antagonist. Blockade of dopamine or N-methyl-D-aspartate (NMDA) receptors or serotonin depletion had no effect on D-amphetamine–induced GluR1 phosphorylation. D-amphetamine but not methylphenidate increased ERK phosphorylation. This effect required multiple signaling pathways because it was blocked by 1- and 1-adrenoceptor antagonists, by dizocilpine maleate (MK801), an NMDA antagonist, and by serotonin depletion. In contrast, blockade of dopamine receptors had no effect on D-amphetamine–induced ERK phosphorylation. Propranolol and betaxolol increased the hyperlocomotion produced by D-amphetamine and methylphenidate. Thus, both D-amphetamine and methylphenidate potently activate the cAMP pathway in the prefrontal cortex through 1-adrenergic receptors. This activation could have behavioral consequences and contribute to the treatment of attention-deficit/hyperactivity disorder.

Address correspondence to: Dr. Denis Hervé, INSERM/UPMC UMR 536, Institut du Fer à Moulin, 17 rue du Fer à Moulin, 75005 Paris, France. E-mail: herve{at}fer-a-moulin.inserm.fr