Resumo

Attention deficit hyperactivity disorder (ADHD) involves dopaminergic dysfunction affecting prefrontal cortex (PFC) and striatum (ST) circuits, resulting in cognitive and motor abnormalities. This is the most prevalent psychiatric disorder in children and is characterized primarily hyperactivity, inattention and impulsivity; although three ADHD subtypes can be diagnosed: predominantly hyperactive-impulsive, predominantly inattentive and the combined subtype. Since adenosine and dopamine neuromodulation is tightly inter-twinned, we now tested if caffeine (non-selective adenosine receptor antagonist) prevented behavioral and neurochemical modifications in Spontaneously Hypertensive Rats (SHR/NCrl compared to WKY/NIcoCrl), a genetic ADHD model with face, construct, and predictive validity. Male SHR and WKY were treated with caffeine during adolescence and tested in adulthood in the attentional set-shifting, open field and Y-maze tasks before sacrifice for neurochemical analysis of dopamine uptake by nerve terminals and levels of dopamine transporter (DAT), D1, D2 and A2A receptors. SHR showed hyperactivity and poor performance in the attentional set-shifting and Y-maze paradigms compared with the WKY; caffeine treatment improved memory and attentional deficits in SHR, while having no effect in WKY. SHR displayed increased levels of DAT and increased dopamine uptake in prefrontal cortex and striatal terminals; chronic caffeine treatment eliminated strain differences in DAT levels and dopamine uptake. Finally, A2A, D1 and D2 receptor densities were increased in PFC terminals of SHR. These findings show that memory and attentional performance deficits of an animal model of ADHD were prevented by caffeine treatment during period of adolescence, suggesting that the caffeine effects might be associated with normalization of corticostriatal dopaminergic hypofunction. Considering the sintomatology of ADHD and that the SHR/NCrl strain compared with WKY/NIcoCrl represents a validated model for the combined subtype, our data provide new evidence for the caffeine potential treatment on predominantly inattentive subtype of ADHD. Caffeine is recognized as safe and the promising pharmacological profile encourages additional studies to investigated potential therapeutic value of adenosinergic antagonists in ADHD patients.