Stereotyped behavior: effects of d-amphetamine and methylphenidate in the young rat

The proclivity of d-amphetamine and methylphenidate to induce perseverative motoric and vocal side effects detracts from the clinical efficacy of these stimulants in the treatment of Attention-Deficit Hyperactivity Disorder (ADHD). In an attempt to develop a model for these deleterious treatment effects, this study explored the behavioral influences exerted by d-amphetamine and methylphenidate in the young laboratory rat. This experiment revealed that doses of these stimulants that typically induce stereotypy provoke diverging behavioral profiles: while animals given 5 mg/kg d-amphetamine exhibited repetitive sniffing activity, rats treated with 30 mg/kg methyl-phenidate displayed perseverative gnawing behaviors. Although pretreatment with the serotonin synthesis inhibitor p-chlorophenylalanine (PCPA) significantly attenuated both stimulant-induced stereotypies, the effect of PCPA on d-amphetamine-induced sniffing was more profound than on methylphenidate-induced gnawing. High-performance liquid chromatography (HPLC) analysis of monoamine levels in the striatum, frontal cortex, and thalamus indicated that PCPA induced an overall 89% depletion of serotonin across all conditions. These findings shed some light on the neurochemical mechanisms that underlie the differential effects of d-amphetamine and methylphenidate on stereotyped motor activity in the rat, and suggest future experiments for understanding the role of serotonin in such effects. Further, these results have implications for the differential side effects observed from each of these stimulants when used clinically in children with ADHD.