Effect of repeated methylphenidate administration on presynaptic dopamine and behaviour in young adult rats

Methylphenidate, a dopamine reuptake inhibitor, is the most common treatment for attention-deficit hyperactivity disorder and may be prescribed for years, despite little evidence of any long-term benefit, nor knowledge of potential chronic side-effects. Therefore, this study examined the acute and longer-term behavioural effects and assessed striatal dopamine function following subchronic methylphenidate administration to adolescent rats. Male hooded Lister rats received methylphenidate (4 mg/kg i.p. twice daily for 4 days) or saline (1 ml/kg) and the acute locomotor and stereotype behaviour was monitored on days 1 and 4, novel object exploration on day 2 and, following 12 days drug withdrawal, the long-term effect examined on social interaction on day 16. Ex-vivo K+ (20 mM)- and methylphenidate (0.1 mM)-induced [3H]dopamine release from striatal slices and striatal monoamine content were measured on day 18. Compared with saline, methylphenidate induced mild hyperactivity without stereotypy but did not alter novel object exploration and, following withdrawal, had no long-term effect on social interaction. In striatal slices from controls, both K+ and methylphenidate elevated [3H]dopamine release (p < 0.01) while only combined treatment elevated release in methylphenidate pretreated rats, although striatal monoamine content was unaltered compared with control rats. In summary, a repeated dose of methylphenidate that had acute behavioural effects produced no long-term alteration in social interaction but attenuated presynaptic striatal dopamine function.