Sex-dependent effects of long-term oral methylphenidate treatment on spontaneous and learned fear behaviors

In previous studies, chronic low-dose methylphenidate (MPH) administration during early development has been shown to increase emotional responding in adulthood. However, most studies employed male subjects, which generally show enhanced fear relative to females in laboratory tests of anxious behaviors. The present study examined the sex-dependent effects of MPH treatment on innate and learned fear behaviors. Rats were treated for 4 weeks from periadolescence through early adulthood with oral MPH. In open field testing, females showed greater levels of activity than males, and MPH (5 mg/kg) decreased locomotion relative to control and 2 mg/kg treatment in both sexes. In contextual fear conditioning, females exhibited less freezing than males at all retention intervals. Both sexes treated with 5 mg/kg MPH showed increased fear to the shock context, although MPH treatment did not interfere with contextual discrimination in either sex. Upon reexposure to the shock context at 24 h, only females treated with 5 mg/kg MPH exhibited increases in freezing. MPH treatment did not disrupt extinction of contextual fear (48 h post-conditioning) in either sex. These findings illustrate subtle sex differences in the effects of prolonged MPH exposure on fear behaviors, and highlight the need to examine further the underlying mechanisms in both sexes.

► Males and females were treated with low dose oral methylphenidate (MPH) for 4 weeks.
► Low dose (2 or 5 mg/kg) MPH did not produce hyperactivity in males or females.
► 5 mg/kg MPH decreased locomotion in both sexes.
► 5 mg/kg MPH transiently increased fear retention in both sexes.
► MPH did not affect acquisition or extinction of contextual fear in males or females.