Gender associations with chronic methylphenidate treatment and behavioral performance following experimental traumatic brain injury

Abstract

Evidence suggests that dopamine (DA) agonists improve cognition after traumatic brain injury (TBI). Methylphenidate (MPH) is a DA agonist that blocks the dopamine transporter (DAT). Moreover, female sex hormones modulate DAT expression. Therefore, the purpose of this study was to evaluate how MPH affects behavioral performance in male and female rats. Under anesthesia, rats underwent either controlled cortical impact (CCI) or sham injury operations. Beginning post-operative day one, rats received daily intraperitoneal injections of MPH (5mg/kg) or saline. Beam balance (BB) and beam walking (BW) were assessed on postoperative days 1-5. Exploratory behavior was assessed using an open field free choice novelty (FCN) task on day 13. Spatial memory was assessed with a Morris water maze (MWM) task on days 14-20. Multivariate analyses showed TBI females performed better than TBI males on both motor tasks (P<0.05 both comparisons), and MPH improved BB performance for both male and female injury groups (P=0.05) compared to their respective vehicle treated injury groups. Multivariate analysis showed that MPH enhanced MWM performance (spatial learning and retention) after TBI. Significant improvements were noted in injured males treated with MPH compared to their vehicle control (P<0.05) with respect to improvements in memory acquisition and retention. Further, injured females treated with MPH had faster swimming speeds than all other groups (P<0.05 all comparisons), and MPH increased activity in TBI females but not males in the FCN task (P<0.05). These results suggest that MPH is beneficial after TBI. However there are gender specific drug differences in behavioral performance and sensitivity to treatment with MPH that may have implications for treatment efficacy and dosing clinically after TBI.

The Therapeutic Efficacy of Environmental Enrichment and Methylphenidate Alone and in Combination after Controlled Cortical Impact Injury

“…14,[22][23][24][25][26][27][28][29][30][31][32]35 Concurrently, many other therapeutic interventions have also been reported to enhance behavioral outcome after TBI using various pre-clinical models; [9][10][11][12][13][14][15][16][17][18] however, most of these strategies have not successfully translated from the bench to the bedside. 19,20 While numerous factors may account for the lack of translation, one salient reason may be the use of single therapies for a disease that exhibits multiple pathophysiological events.…”

“…[22][23][24][25][26][27][28][29][30][31][32] The second strategy, daily methylphenidate (MPH) administration, which is a dopamine (DA) reuptake inhibitor acting on the DA transporter and a D 2 receptor agonist, 33 has also been shown to confer benefits to cognitive recovery after experimental TBI. 14,35,36 MPH has been associated with improvements in motor speed, attention, memory, processing speed, and mental fatigue in clinical patients with TBI. [37][38][39][40][41][42] In addition, MPH is currently regarded as the first-line treatment for attention and processing speed deficits in patients with TBI.…”

Performance of Male and Female C57BL/6J Mice on Motor and Cognitive Tasks Commonly Used in Pre-Clinical Traumatic Brain Injury Research

“…Clinical data indicate that adverse effects of drugs are more common and more severe in women, 103 and some pre-clinical studies also suggest differential effects of treatments, including efficacy, on functional improvements in male and female animals post-TBI. 29,104,105 However, follow-ups to these studies often do not confirm initial findings of sex differences in response to treatment or lack of efficacy in one sex, 30 emphasizing the need for replications of basic research and pre-clinical trials. The data presented here would also benefit from replication in other laboratory environments and using alternative and additional testing procedures.…”

“…27 Male rats subjected to controlled cortical impact (CCI) also showed inferior motor performance to females assessed using beam balance and walking tasks, but cognitive performance on the Morris water maze (MWM) was equally impaired in both sexes. 28,29 In female rats, estrous cycle stage (and resulting levels of circulating hormones) at the time of TBI had a slight effect on motor performance shortly after the injury, but hormonal level had no effect on MWM performance 2 weeks postinjury. 28 Further, a recent study also demonstrated that certain motor and cognitive tasks were unaffected by estrous cycle stage at the time of CCI in female rats housed in standard cages or enriched environments.…”

Effects of Methylphenidate on Working Memory in Traumatic Brain Injury: A Preliminary fMRI Investigation

“…Given gender differences of methylphenidate on learning and retention in rats after TBI (Wagner et al 2007), a further limitation of this study is that gender differences were not examined. Finally, our sample was heterogeneous in terms of injury severity and time since injury, and the small sample size precluded an examination of these variables.…”