Chronic methylphenidate administration inhibits brain-derived neurotrophic factor gene expression in juvenile rat brain

Partha Banerjee, Tyra Zetterstrom
De Montfort University, Leicester, United Kingdom

The number of prescriptions for the central stimulant methylphenidate (MPH) for treatment of attention deficit hyperactivity disorders (ADHD) in young children is increasing exponentially in the UK (NHS, NICE 2006). However, very little is known about the drug’s long-term effects on brain structure and function. We have recently shown that acute administration of MPH to young rats, causes marked decreases in mRNA expression of brain-derived neurotrophic factor (BDNF) in hippocampal and cortical regions, but less so in adults (Proceedings of the British Pharmacological Society at http://www.pA2online.org/abstracts/Vol4Issue2abst066P.pdf; Banerjee et al, 2007). In the present study we have investigated whether this effect is sustained after repeated administration.

Twenty days old male Sprague-Dawley rats (55-60g) were injected twice daily (9am and 5pm) with MPH (2 mg/kg, i.p.) or saline (1ml/kg) for 2 weeks. Rats were killed at 2 and 24 hours after the last injection, their brains isolated, frozen in isopentane, cut on a cryostat into 20 μm sections and pre-treated using standard protocols. BDNF mRNAs were analysed by in situ hybridisation histochemistry using a 35S-dATP labelled oligonucleotide probe (Zetterström et al, 1998). Relative abundances of BDNF mRNA were determined by densitometric analysis of autoradiograms using MCID basicTM software.

MPH significantly decreased BDNF mRNA expression in hippocampus and parietal cortex at both time points after the last injection. The most pronounced decrease of BDNF mRNA levels was recorded in the CA3 region of the hippocampus (-35%) at the 2 hour time point, comparable values for dentate gyrus (DG) and parietal cortex (par cx) were: (-33%) and (-32%) respectively. The reductions were slightly less at 24 hours with BDNF mRNA decreases being 30% for CA3, 25% for DG and 29% for par cx, for details of optical density values, see Table 1.

Data (nCi/g) expressed as mean value ±SEM (n=6). *P<0.05 vs. saline; **P<0.001 vs. saline. (Newman-Keuls post-hoc test following two-way ANOVA).

In conclusion, chronic administration of MPH decreases gene expression for BDNF in the juvenile rat brain, a neurotrophic factor proven to be vital for normal brain development.

Banerjee, P.S. et al (2007). J Psychopharmacol (suppl)., 21(7), A19.

National Health Services: NICE implementation uptake report (2006): ADHD.

Zetterström, T.S.C. et al. (1998). Mol Brain Res., 57, 106-110.