Acute treatment with the 5-HT(1A) receptor agonist 8-OH-DPAT and chronic environmental enrichment confer neurobehavioral benefit after experimental brain trauma

Abstract

Acute treatment with the 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) or chronic environmental enrichment (EE) hasten behavioral recovery after experimental traumatic brain injury (TBI). The aim of this study was to determine if combining these interventions would confer additional benefit. Anesthetized adult male rats received either a cortical impact or sham injury followed 15min later by a single intraperitoneal injection of 8-OH-DPAT (0.5mg/kg) or saline vehicle (1.0mL/kg) and then randomly assigned to either enriched or standard (STD) housing. Behavioral assessments were conducted utilizing established motor and cognitive tests on post-injury days 1-5 and 14-18, respectively. Hippocampal CA(1)/CA(3) neurons were quantified at 3 weeks. Both 8-OH-DPAT and EE attenuated CA(3) cell loss. 8-OH-DPAT enhanced spatial learning in a Morris water maze (MWM) as revealed by differences between the TBI+8-OH-DPAT+STD and TBI+VEHICLE+STD groups (P=0.0014). EE improved motor function as demonstrated by reduced time to traverse an elevated narrow beam in both the TBI+8-OH-DPAT+EE and TBI+VEHICLE+EE groups versus the TBI+VEHICLE+STD group (P=0.0007 and 0.0016, respectively). EE also facilitated MWM learning as evidenced by both the TBI+8-OH-DPAT+EE and TBI+VEHICLE+EE groups locating the escape platform quicker than the TBI+VEHICLE+STD group (P's<0.0001). MWM differences were also observed between the TBI+8-OH-DPAT+EE and TBI+8-OH-DPAT+STD groups (P=0.0004) suggesting that EE enhanced the effect of 8-OH-DPAT. However, there was no difference between the TBI+8-OH-DPAT+EE and TBI+VEHICLE+EE groups. These data replicate previous results from our laboratory showing that both a single systemic administration of 8-OH-DPAT and EE improve recovery after TBI and extend those findings by elucidating that the combination of treatments in this particular paradigm did not confer additional benefit. One explanation for the lack of an additive effect is that EE is a very effective treatment and thus there is very little room for 8-OH-DPAT to confer additional statistically significant improvement.

Fig. 1

Photograph of the enrichment cage. Note the multiple levels, wide array of sensory stimuli in the form of balls, tunnels, ramps, ropes, etc. Ten to twelve rats are housed at any given time and are removed only briefly for behavioral assessments.

Fig. 2

Mean (± SE) walking ability as measured by time (sec) to traverse an elevated wooden beam prior to, and after, TBI or SHAM injury. All TBI groups exhibited significant initial impairment vs. SHAM controls, but both EE groups displayed facilitated recovery. *P < 0.05 vs. TBI+VEHICLE+STD.

Fig. 3

Mean (± SE) time (sec) to locate either a hidden (submerged) or visible (raised) platform in a water maze. All TBI groups, except the TBI+8-OH-DPAT+EE group, had significant difficulty with the cognitive task vs. SHAM controls. However, over the subsequent 5 days of training, all groups, except the TBI+VEHICLE+STD group, became proficient at locating the escape platform. *P < 0.05 vs. TBI+VEHICLE+STD. #P < 0.05 vs. TBI+8-OH-DPAT+STD. No differences were observed in locating the visible platform.

Fig. 4

Mean (± SE) morphologically intact CA₃ neurons (% of contralateral hippocampus) at three weeks after a controlled cortical impact or sham injury. All injured groups expressed significantly fewer normal appearing neurons compared to the SHAM controls. **P < 0.05 vs. all TBI groups. *P < 0.05 vs. TBI+VEHICLE+STD.