A delayed and chronic treatment regimen with the 5-HT1A receptor agonist 8-OH-DPAT after cortical impact injury facilitates motor recovery and acquisition of spatial learning

Abstract

An early (i.e., 15min) single systemic administration of the 5-HT(1A) receptor agonist 8-OH-DPAT enhances behavioral recovery after experimental traumatic brain injury (TBI). However, acute administration of pharmacotherapies after TBI may be clinically challenging and thus the present study sought to investigate the potential efficacy of a delayed and chronic 8-OH-DPAT treatment regimen. Forty-eight isoflurane-anesthetized adult male rats received either a controlled cortical impact or sham injury and beginning 24h later were administered 8-OH-DPAT (0.1 or 0.5mg/kg) or saline vehicle (1.0mL/kg) intraperitoneally once daily until all behavioral assessments were completed. Neurobehavior was assessed by motor and cognitive tests on post-operative days 1-5 and 14-19, respectively. The lower dose of 8-OH-DPAT (0.1mg/kg) enhanced motor performance, acquisition of spatial learning, and memory retention vs. both the higher dose (0.5mg/kg) and vehicle treatment (p<0.05). These data replicate previous findings from our laboratory showing that 8-OH-DPAT improves neurobehavior after TBI, and extend those results by demonstrating that the benefits can be achieved even when treatment is withheld for 24h. A delayed and chronic treatment regimen may be more clinically feasible.

Fig. 1

Mean (± SE) time (sec) balancing on an elevated narrow beam prior to, and after, TBI or Sham injury. *p < 0.05 vs. TBI + 8-OH-DPAT (0.5 mg/kg). **p < 0.05 vs. TBI + Vehicle and TBI + 8-OH-DPAT (0.5 mg/kg), but not TBI + 8-OH-DPAT (0.1 mg/kg).

Fig. 2

Mean (± SE) time (sec) to traverse an elevated narrow beam prior to, and after, TBI or Sham injury. *p < 0.05 vs. TBI + Vehicle and TBI + 8-OH-DPAT (0.5 mg/kg). **p < 0.05 vs. all TBI groups.

Fig. 3

Mean (± SE) distance traveled along an elevated narrow beam prior to, and after, TBI or Sham injury. *p < 0.05 vs. TBI + Vehicle and TBI + 8-OH-DPAT (0.5 mg/kg). **p < 0.05 vs. all TBI groups.

Fig. 4

Mean (± SE) time (sec) to locate either a hidden (submerged) or visible (raised) platform in a water maze. *p < 0.05 vs. TBI + Vehicle and TBI + 8-OH-DPAT (0.5 mg/kg). **p < 0.05 vs. TBI + Vehicle and TBI + 8-OH-DPAT (0.5 mg/kg), but not TBI + 8-OH-DPAT (0.1 mg/kg). No significant differences were revealed for time to locate the visible platform.

Fig. 5

Mean (± SE) percentage of time spent in the target quadrant (i.e., where platform was previously located) following a single probe trial 19 days after cortical impact or sham injury. The dotted line represents performance at the chance level (25%). *p < 0.05 vs. TBI + Vehicle and TBI + 8-OH-DPAT (0.5 mg/kg). **p < 0.05 vs. TBI + Vehicle and TBI + 8-OH-DPAT (0.5 mg/kg), but not TBI + 8-OH-DPAT (0.1 mg/kg).

Fig. 6

Mean (± SE) swim speed (cm/sec). No differences were observed among groups, regardless of injury assignment or drug treatment, suggesting that spatial learning was not influenced by motor deficits.