||4. Pharmacol Res. 2010 Dec;62(6):523-9. Epub 2010 Aug 5. Sub-chronic exposure to atomoxetine up-regulates BDNF expression and signalling in the brain of adolescent spontaneously hypertensive rats: comparison with methylphenidate. Fumagalli F, Cattaneo A, Caffino L, Ibba M, Racagni G, Carboni E, Gennarelli M, Riva MA. Center of Neuropharmacology, Department of Pharmacological Sciences, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milan, Italy. The stimulant methylphenidate and the non-stimulant atomoxetine are widely used for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD), but the molecular mechanisms of their therapeutic action are not fully understood. The aim of our study was to investigate, in adolescent rats, the sub-chronic effect of these two drugs on neuronal plasticity, through a detailed analysis of BDNF expression and signalling in order to establish the contribution of these mechanisms in the pharmacotherapy of ADHD. Atomoxetine (ATX) up-regulated BDNF mRNA levels in the hippocampus whereas methylphenidate (MPH) increased BDNF gene expression in the nucleus accumbens and caudate-putamen. Opposite effects were seen in the prefrontal cortex, a critical region in attention disorders, where ATX increased while MPH reduced total and exon IV BDNF mRNA levels. Analysis of BDNF-mediated signalling in the prefrontal cortex revealed that ATX enhanced AKT and GSK3β phosphorylation whereas MPH reduced the synaptic levels of trkB, the high-affinity BDNF receptor, and ERK1/2 activation. Our findings show that ATX and MPH exert an opposite modulation of the BDNF system, primarily in prefrontal cortex that, independently from the behavioral control exerted by the two drugs, may be important for long-term consequences on cognitive function.