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

Abstract

Environmental enrichment (EE) and methylphenidate (MPH) independently confer significant benefit to behavioral recovery after controlled cortical impact (CCI) injury. Given that combinational therapies may be more clinically translatable than monotherapies, the aim of the current study was to test the hypothesis that a combined treatment regimen of EE and MPH would provide greater therapeutic efficacy than either one alone. Anesthetized adult male rats received either a CCI of moderate severity or sham injury and were then randomly assigned to EE or standard (STD) housing where they received either intraperitoneal (ip) MPH (5 mg/kg) or vehicle (VEH; 1.0 mL/kg; ip) beginning 24 h after injury and once daily for 19 days. Motor and cognitive assessments were conducted on post-injury days 1-5 and 14-19, respectively. No differences were observed in sham controls regardless of treatments, and thus their data were pooled. The traumatic brain injury (TBI)+EE+VEH and TBI+EE+MPH groups exhibited enhanced beam balance and beam walk performance relative to the TBI+STD+VEH group ( p < 0.05), but did not differ from one another ( p > 0.05). No effect of MPH treatment alone was observed in either motor task. In contrast, MPH improved spatial learning and memory when presented alone and also when combined with EE relative to VEH-treated STD controls ( p < 0.05). In addition, both EE groups performed significantly better than the TBI+STD+MPH group ( p < 0.05), but did not differ from one another ( p > 0.05). These data replicate previous findings that both EE and MPH confer cognitive benefits after TBI and extend the findings by revealing that combining EE and MPH does not produce effects greater than either treatment alone, which does not support the hypothesis. The lack of an additive effect may be because of the robustness of the EE.

Galantamine and Environmental Enrichment Enhance Cognitive Recovery after Experimental Traumatic Brain Injury But Do Not Confer Additional Benefits When Combined

“…The lack of additive effects with the combinational therapy in adult TBI rats is not entirely surprising as several studies from our laboratory have shown similar effects. 11,52,64,74,76 Importantly, the combination of therapies did not produce negative effects as has been seen with different treatment paradigms. 64 The findings of the current study, and those previously reported, may be due to a floor effect.…”

Combination therapies for neurobehavioral and cognitive recovery after experimental traumatic brain injury: Is more better?

“…Investigating a combination without simultaneously assessing the effects of each monotherapy can give the false impression that a combination is superior to a single treatment, when in reality similar or only slightly different effects may be imparted. Studies by Kline and colleagues saliently highlight this important point as they have shown positive interactions with the 5-HT 1A receptor agonists 8-OH-DPAT and buspirone (Kline et al, 2007, 2010, 2012) as well as the D 2 receptor agonist methylphenidate (Leary et al, 2016) when paired with EE, a preclinical model of neurorehabilitation. However, even though the combination groups performed significantly better than the individual pharmacotherapies, the polytherapy effects were not statistically different from EE alone.…”

“…In clinical TBI, MPH improves attention, memory, processing speed, and mental fatigue (Whyte et al, 2004; Willmott and Ponsford, 2009; Johansson et al, 2015). Based on the benefits conferred by MPH alone, Leary and colleagues (2016) set to test the hypothesis that combining MPH with EE after a CCI injury of moderate severity in adult male rats would produce greater benefits on behavioral recovery than either treatment individually. Beginning 24 hr after TBI or sham injury, MPH (5 mg/kg; i.p.)…”

Rehabilitative Success After Brain Trauma by Augmenting a Subtherapeutic Dose of Environmental Enrichment With Galantamine

“…33,40–42,44 The lack of additional benefit when combining effective drug therapies with the typical EE paradigm is theorized to be due to the robustness of continuous EE affording little room for additional recovery. To this end, the results from the current study indicate that the rehabilitation-relevant abbreviated EE paradigm may provide an experimental model with which to test combination treatments that include limited or sub-therapeutic EE and various potentially efficacious pharmacotherapies.…”