Evaluation of a Combined Treatment Paradigm Consisting of Environmental Enrichment and the 5-HT_1A Receptor Agonist Buspirone after Experimental Traumatic Brain Injury

Abstract

Environmental enrichment (EE) and serotonin 1A (5-HT 1A )-receptor agonists provide significant benefit after experimental traumatic brain injury (TBI). The aim of this study was to test the hypothesis that combining these therapies would produce an effect that is more robust than either therapy alone. Anesthetized adult male rats received a cortical impact or sham injury and then were randomly assigned to EE or standard (STD) housing where they received either buspirone (0.3 mg/kg) or vehicle (1.0 mL/kg) once daily for 3 weeks. Motor and cognitive assessments were conducted on post-injury days 1-5 and 14-19, respectively. CA1/3 neurons were quantified at 3 weeks. No differences were observed among buspirone and vehicle sham groups in any task regardless of housing condition and thus the data were pooled. CA3 cell loss was reduced in the TBI + EE + buspirone and TBI + EE + vehicle groups. Motor recovery, spatial learning, and memory retention were enhanced in the TBI + EE + buspirone, TBI + EE + vehicle, and TBI + STD + buspirone groups versus the TBI + STD + vehicle group ( p £ 0.005). Moreover, spatial learning was significantly better in the TBI + EE + buspirone group versus the TBI + STD + buspirone group ( p < 0.0001). No differences were revealed between the buspirone and vehicle EE groups. These data show that EE and buspirone benefit functional outcome after TBI, but their combination is not more robust than either alone, which does not support the hypothesis. The lack of an additive effect may be due to the early-and-continuous EE paradigm on its own producing marked benefits, resulting in a ceiling effect. The evaluation of buspirone in a delayed-and-abbreviated EE paradigm is ongoing in our laboratory.

A Combined Therapeutic Regimen of Buspirone and Environmental Enrichment Is More Efficacious than Either Alone in Enhancing Spatial Learning in Brain-Injured Pediatric Rats

“…[18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]36 EE alone, however, did not lead to an increase in memory retention, which is in contrast to that seen in adult models. 23,26,29,33 As reported for Experiment 1, the buspirone (0.1 mg/kg) STD-housed group was also significantly better than the STD vehicle group in the MWM. The data also showed that the combination group (buspirone, 0.1 mg/ kg + EE) performed markedly better than the single therapy groups (i.e., EE plus vehicle and STD buspirone) in both the acquisition of spatial learning and memory retention, which suggests an additive effect.…”

“…[18][19][20][21][22][23][24][25][26] Likewise, EE has also been shown to confer neurobehavioral and histological benefits in adult male rats after CCI 20,23,[26][27][28][29][30][31][32][33][34] and fluid percussion brain injury. [35][36][37][38][39][40] Recently, the benefits of EE have also been extended to female rats after CCI.…”

“…This cumulative effect on cognition is novel after CCI injury because it has not been observed in adult rats using these therapies. 26 Mechanisms for the synergy between EE and buspirone in the developing versus the adult rodent brain remain undetermined, but some comments are warranted. Regarding the benefits conferred by buspirone alone in adult rats, possible mechanisms may include those previously reported for other 5-HT 1A receptor agonists, such as 8-OH-DPAT and repinotan HCL.…”

“…[18][19][20][21][22][23][24] More recently, buspirone, also a 5-HT 1A receptor agonist, has been reported to enhance cognitive performance as well as significantly reduce cortical lesion volume after TBI. 25,26 This therapeutic paradigm, however, has not been evaluated as a treatment for experimental pediatric brain injury.…”

“…Environmental enrichment (EE), in particular, has been evaluated extensively in adult, and to a much lesser extent, in pediatric rodents as a pre-clinical model of neurorehabilitation. EE consists of expansive accommodations, which include cognitive and social stimulation that results in the reduction of histological damage and enhancement of functional recovery 27 induced by either controlled cortical impact (CCI) 20,23,[26][27][28][29][30][31][32][33][34] or fluid percussion. [35][36][37][38][39][40] Given that the 5-HT 1A receptor agonist buspirone and EE confer recovery in adult rats after brain trauma, the goals of this study were to evaluate the potential efficacy of these therapies alone and in combination after pediatric TBI.…”