Traumatic Brain Injury-Induced Cognitive and Histological Deficits Are Attenuated by Delayed and Chronic Treatment with the 5-HT_1A-Receptor Agonist Buspirone

Abstract

The aim of this study was to evaluate the potential efficacy of the serotonin 1A (5-HT 1A ) receptor agonist buspirone (BUS) on behavioral and histological outcome after traumatic brain injury (TBI). Ninety-six isofluraneanesthetized adult male rats were randomized to receive either a controlled cortical impact or sham injury, and then assigned to six TBI and six sham groups receiving one of five doses of BUS (0.01, 0.05, 0.1, 0.3, or 0.5 mg/kg) or saline vehicle (VEH, 1.0 mL/kg). Treatments began 24 h after surgery and were administered intraperitoneally once daily for 3 weeks. Motor function (beam-balance/beam-walk tests) and spatial learning/memory (Morris water maze) were assessed on post-operative days 1-5 and 14-19, respectively. Morphologically intact CA1/ CA3 cells and cortical lesion volume were quantified at 3 weeks. No differences were observed among the BUS and VEH sham groups in any end-point measure and thus the data were pooled. Regarding the TBI groups, repeated-measures ANOVAs revealed that the 0.3 mg/kg dose of BUS enhanced cognitive performance relative to VEH and the other BUS doses ( p < 0.05), but did not significantly impact motor function. Moreover, the same dose conferred selective histological protection as evidenced by smaller cortical lesions, but not greater CA1/ CA3 cell survival. No significant behavioral or histological differences were observed among the other BUS doses versus VEH. These data indicate that BUS has a narrow therapeutic dose response, and that 0.3 mg/kg is optimal for enhancing spatial learning and memory in this model of TBI. BUS may have potential as a novel pharmacotherapy for clinical TBI.

Evaluation of a Combined Treatment Paradigm Consisting of Environmental Enrichment and the 5-HT1A Receptor Agonist Buspirone after Experimental Traumatic Brain Injury

“…Third, regarding the histological data, the lack of a difference between the buspirone + EE and vehicle + EE groups suggests that EE, but not necessarily buspirone, mediated the reduction in hippocampal cell loss. This finding is consistent with a recent report from our laboratory showing that while buspirone reduced lesion volume, it did not significantly affect hippocampal cell survival (Olsen et al, 2012). When considering these three points, the findings suggest that the two therapies did not antagonize one another, and that further refinement of the model, including changes in doses, timing of administration, and intensity of rehabilitation, may induce different outcomes via additive or synergistic mechanisms.…”

“…To date there is only one study reporting on the beneficial effects of a delayed (24 h after injury) and chronic (21 days) treatment regimen with the 5-HT 1A -receptor agonist buspirone after CCI injury (Olsen et al, 2012). The goal of the current, and novel, study was to determine whether the combination of EE and buspirone would result in greater behavioral recovery and histological protection after CCI injury than that produced by either treatment individually.…”

“…Buspirone (0.3 mg/kg), or a comparable volume of vehicle (1.0 mL/kg), was administered intraperitoneally beginning 24 h after CCI or sham injury and once daily for 3 weeks. The dose of buspirone and route of administration were selected based on previous data from our laboratory showing this regimen to be optimal after chronic treatment (Olsen et al, 2012).…”

“…The second therapy in this combined treatment approach is the systemic administration of the serotonin 1A (5-HT 1A )-receptor agonist buspirone. A recent dose-response study from our laboratory showed that buspirone facilitated spatial learning in a well-established water maze task and reduced the size of TBI-induced cortical lesions (Olsen et al, 2012), which replicates the results of studies evaluating other 5-HT 1A -receptor agonists, such as 8-OH-DPAT Kline et al, 2002cKline et al, ,2004Kline et al, ,2007Kline et al, ,2010, and repinotan HCl (Kline et al, 2001). The advantage of evaluating buspirone in an experimental model of TBI is that it is used clinically as a treatment for anxiety and depression, and therefore safety and tolerability issues are well known (Chew and Zafonte, 2009).…”

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] 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.…”