Evaluation of a combined treatment paradigm consisting of environmental enrichment and the 5-HT1A 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.

FIG. 1.

Mean (±standard error of the mean) time (sec) maintaining balance on an elevated narrow beam before and after TBI or sham injury (*p≤0.0009 versus TBI+STD+vehicle; **p≤0.001 versus all TBI groups). No other group comparisons were significant (p≤0.47; TBI, traumatic brain injury; EE, environmental enrichment; STD, standard environment).

FIG. 2.

Mean (±standard error of the mean) time to traverse an elevated narrow beam after TBI or sham injury (*p≤0.005 versus TBI+STD+vehicle; **p≤0.0001 versus all TBI groups). No other group comparisons were significant (EE, environmental enrichment; STD, standard environment; TBI, traumatic brain injury).

FIG. 3.

Mean (±standard error of the mean) time (sec) to locate a hidden (submerged) platform in a water maze (*p≤0.0001 versus TBI+STD+vehicle, 1.0 mL/kg; **p≤0.0001 versus TBI+STD+buspirone, 0.3 mg/kg, and TBI+STD+vehicle, 1.0 mL/kg; ^p≤0.0001 versus TBI+STD+buspirone, 0.3 mg/kg). No other group comparisons were significant (EE, environmental enrichment; STD, standard environment; TBI, traumatic brain injury).

FIG. 4.

Mean (±standard error of the mean) percentage of time spent in the target quadrant (i.e., where the platform was previously located), following a single-probe trial 19 days after TBI or sham injury (*p≤0.003 versus TBI+STD+vehicle, 1.0 mL/kg; **p<0.0001 versus TBI+STD+vehicle, 1.0 mL/kg). No other group comparisons were significant. The dotted line represents performance at the chance level (25%; EE, environmental enrichment; STD, standard environment; TBI, traumatic brain injury).

FIG. 5.

Mean (±standard error of the mean) morphologically-intact CA3 neurons (% of contralateral hippocampus) quantified 3 weeks after TBI or sham injury. (*p≤0.003 versus TBI+STD+vehicle, 1.0 mL/kg; **p<0.0001 versus all TBI groups). No other group comparisons were significant (EE, environmental enrichment; STD, standard environment; TBI, traumatic brain injury).