||Dopamine (DA) and Norepinephrine (NE), brain pathways have been involved in different aspects of information processing, cognition and behaviour. Thus DA and NE are involved in neuropsychiatric syndromes e.g. Schizophrenia, Autism and Attention Deficit Hyperactivity Disorder (ADHD). The aim of this study was to investigate long-term effects of prepuberal methylphenidate (MPH) and atomoxetine (ATX) on adult behaviour and forebrain DA, NE, Serotonin (5HT) and their metabolite tissue content in Naples High-Excitability rats (NHE). They have been used as genetic model for mesocortical variant of ADHD. Male NHE rats were given an intra peritoneal injection of 1.0 mg/kg of MPH, ATX or vehicle, daily for 14 days in the 5th and 6th week of life. At the age of 70-75 days, rats were exposed to spatial novelty in the Làt and in a radial maze (Olton type). Behaviour was analyzed for indices of activity horizontal (HA), vertical (VA), non selective (NSA) and selective spatial attention (SSA). Results indicated that only MPH significantly reduced HA in both novelty paradigms in NHE rats only for MPH. No differences were found for frequency and duration of rearings in both tests. Likewise, no treatment effect was observed for orientation in the radial maze. DA, NE, 5-HT and their metabolites were assessed by HPLC in the prefrontal cortex (PFC), cortical motor area (MC), dorsal and ventral striatum (DS,VS), hippocampus (HPC), and mesencephalon (MES). Results indicated that MPH decreased i) DA, NE, 5-HT and their metabolites in the PFC; ii) DA, DOPAC, HVA, 5-HT, 5-HIAA in DS iii) DA, DOPAC, HVA and MHPG but increased NE in VS, and iv) NE, 5HT and their metabolites in HPC. ATX increased DA but decreased MHPG in the PFC and decreased DA, DOPAC, HVA, 5HT,5HIAA in DS and MHPG in VS. Therefore MPH treatment in prepuberal NHE rats yielded long-lasting effects on a cognitive behavioural trait, i.e. HA, in two spatial novelty contexts. This in turn may be related to a differential rearrangement of DA, NE and 5HT circuitries in PFC, DS and VS.