Chronic low dose Adderall XR® down-regulates cfos expression in infantile and prepubertal rat striatum and cortex

Abstract

We previously reported that treatment of prepubertal male rats with low, injected or oral, doses of methylphenidate stimulated cfos, fosB and arc expression in many areas of the developing brain. In the present study our objective was to determine whether the widely prescribed psychostimulant Adderall XR® (ADD) exerted similar effects in infantile and prepubertal rat brain. We report here, for the first time, that low threshold doses of oral ADD, an extended-release mixture of amphetamine salts, now routinely used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD), also increased cfos expression in infantile (postnatal day 10; PD10) and prepubertal (PD24) rat brain. These threshold doses were correlated with blood levels of amphetamine determined by liquid chromatography–mass spectrometry. Moreover, we observed that chronic treatment with oral ADD (1.6 mg/kg; ×14 days) not only significantly down-regulated cfos expression following a final challenge dose of ADD in prepubertal (PD24) rat striatum and cortex, quantified in terms of FOS immunoreactivity (FOS-ir), but did so at a daily dose that was without effect with methylphenidate (MPH); that is a much higher oral dose of MPH (7.5 mg/kg; ×14 days) failed to induce down-regulation of cfos expression. Similar experiments in infantile rats (PD10), but using a threshold injected dose of ADD (1.25 mg/kg sc) also significantly reduced striatal and cingulate cortical FOS-ir. An additional finding in the prepubertal rats was that oral ADD-induced FOS-ir was observed in the cerebral cortex following doses lower than the threshold dose necessary to increase FOS-ir in the striatum. This was not the case in the PD10 rats. In conclusion, our efforts to calibrate biological responses, such as immediate early gene expression, to clinically relevant blood levels of stimulants confirmed that expression of cfos is very sensitive to repeated low doses of Adderall XR®. It is now feasible to examine whether other genes are also affected in these young rats and if the changes we report are reversible. The implications of such studies should be relevant to the putative effects of psychostimulant treatment of very young children.