Received for publication February 4, 2005.
Revised May 10, 2005.
Accepted for publication May 10, 2005.

cAMP and ERK signaling in response to D-amphetamine and methylphenidate in the prefrontal cortex in vivo: Role of 1-adrenoceptors

Abstract

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 thought 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 Ser-845 phosphorylation of AMPA receptor GluR1 subunit and the active form of 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 ICI-118,515, a 2-antagonist. The effect of methylphenidate was also blocked by propranolol and betaxolol. D-amphetamine effect was slightly potentiated by prazosin, an 1-adrenoceptor antagonist, and mimicked by yohimbine, an 2 antagonist. Blockade of dopamine or 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 since it was blocked by 1- and 1-adrenoceptor antagonists, by 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.

Key words: Adrenergic, Dopamine, Serotonin, Glutamate, Ion channel regulation, cAMP, Protein Kinase A, Phosphorylation/Dephosphorylation, MAP Kinase, Amphetamines