Sex Differences in Induction and Expression of Methylphenidate Sensitization and Brain-Derived Neurotrophic Factor (BDNF) in Adolescent Rats

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Methylphenidate (MPH) is a psychostimulant that is used for the treatment of attention-deficit hyperactivity disorder that is often recreationally abused. Past studies have primarily analyzed the effects of MPH on behavior and BDNF using males as subjects, with studies showing a lack of behavioral sensitization, although the effect of MPH on BDNF has yielded contradictory results. BDNF is a neurotrophin ubiquitously found throughout the brain that plays an important role in synaptic maintenance and development and has been implicated in addiction. This study analyzed sex differences in induction and expression of MPH locomotor sensitization in adolescent male and female rats as well as the effects of MPH on BDNF protein in two brain areas of drug reward: the nucleus accumbens (NAcc) and striatum (STR), after both induction and expression of sensitization. After habituation to a locomotor arena, animals (N=6-8 per group) were administered MPH (5 mg/kg) or saline every other day from postnatal day (P)33 to 49 and tested for 30 min in the same arena with activity counts recorded. In one group, brain tissue was removed one day following testing and the NAcc and STR assayed for BDNF at P50. A different group of animals was raised to P60 and given an MPH (or saline) challenge. One day following the challenge, brain tissue was removed and the NAcc and STR were assayed for BDNF at P61. Females administered MPH demonstrated behavioral sensitization from P33 to P41, and then decreased in activity from P41 to P49. Females demonstrated a robust increase in locomotor activation as compared to males, which failed to demonstrate sensitization to MPH. However, both groups given MPH demonstrated an increase in activity compared to controls throughout sensitization testing. On the challenge at P60, females administered MPH demonstrated higher levels of activity compared to all other groups and were equivalent to their final day of sensitization. Males administered MPH also expressed sensitization, as they demonstrated increased behavioral activation as compared to saline-treated controls. Neurochemical analyses at P50 revealed that MPH produced a significant increase in striatal BDNF in males, but a significant decrease in striatal BDNF in females. There were no changes in the NAcc. At P61, BDNF was increased in both STR and NAcc in males, and female data will be presented. These data demonstrate robust sex differences in behavioral activation and sensitization to MPH that is both induced and expressed in females, but only expressed in males. Further, MPH produces sex-dependent effects on BDNF, indicating sex differences in the brain plasticity response to MPH in adolescence.


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The author(s) retain copyright to the abstract. The abstract was originally published by the Society of Neuroscience.

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