Acute treatment with the 5-HT1A receptor agonist 8-OH-DPAT and chronic environmental enrichment confer neurobehavioral benefit after experimental brain trauma

Physical Medicine & Rehabilitation, University of Pittsburgh, Pittsburgh, PA 15213, United States.
Behavioural Brain Research (Impact Factor: 3.39). 03/2007; 177(2):186-94. DOI: 10.1016/j.bbr.2006.11.036
Source: PubMed

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.


Available from: Anthony E. Kline, Jan 06, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The brain's life-long capacity for experience-dependent plasticity allows adaptation to new environments or to changes in the environment, and to changes in internal brain states such as occurs in brain damage. Since the initial discovery by Hebb (1947) that environmental enrichment (EE) was able to confer improvements in cognitive behavior, EE has been investigated as a powerful form of experience-dependent plasticity. Animal studies have shown that exposure to EE results in a number of molecular and morphological alterations, which are thought to underpin changes in neuronal function and ultimately, behavior. These consequences of EE make it ideally suited for investigation into its use as a potential therapy after neurological disorders, such as traumatic brain injury (TBI). In this review, we aim to first briefly discuss the effects of EE on behavior and neuronal function, followed by a review of the underlying molecular and structural changes that account for EE-dependent plasticity in the normal (uninjured) adult brain. We then extend this review to specifically address the role of EE in the treatment of experimental TBI, where we will discuss the demonstrated sensorimotor and cognitive benefits associated with exposure to EE, and their possible mechanisms. Finally, we will explore the use of EE-based rehabilitation in the treatment of human TBI patients, highlighting the remaining questions regarding the effects of EE.
    Frontiers in Systems Neuroscience 09/2014; 8. DOI:10.3389/fnsys.2014.00156
  • [Show abstract] [Hide abstract]
    ABSTRACT: Traumatic brain injury is a serious cause of morbidity and mortality worldwide. After traumatic brain injury, the blood-brain barrier, the protective barrier between the brain and the intravascular compartment, becomes dysfunctional, leading to leakage of proteins, fluid, and transmigration of immune cells. As this leakage has profound clinical implications, including edema formation, elevated intracranial pressure and decreased perfusion pressure, much interest has been paid to better understanding the mechanisms responsible for these events. Various molecular pathways and numerous mediators have been found to be involved in the intricate process of regulating blood-brain barrier permeability following traumatic brain injury. This review provides an update to the existing knowledge about the various pathophysiological pathways and advancements in the field of blood-brain barrier dysfunction and hyperpermeability following traumatic brain injury, including the role of various tight junction proteins involved in blood-brain barrier integrity and regulation. We also address pitfalls of existing systems and propose strategies to improve the various debilitating functional deficits caused by this progressive epidemic.
    Metabolic Brain Disease 01/2015; DOI:10.1007/s11011-015-9651-7 · 2.40 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The rodent has been the preferred research model for evaluating the mechanisms related to, and potential treatments for, traumatic brain injury (TBI). Many therapies previously determined to be effective in pre-clinical investigations have failed to show the same effectiveness in clinical trials. The environment a rodent is housed in plays an important role in brain and behavioral development. Housing rodents in non-enriched environments significantly alters the development of the rodent brain and its behavioral profile, negatively impacting the ecological validity of the rodent model. This investigation employed 113 male Long-Evans rats assigned to either an enriched environment (EE) or standard environment (SE) from post-natal day 25. At four months of age, rats received either a controlled cortical impact (CCI) to the medial frontal cortex (mFC) or sham injury. Rats assigned to EE or SE pre-injury were re-assigned to remain in, or switch to, EE or SE post-injury. The open-field test (OFT), vermicelli handling test (VHT) Morris water maze (MWM), and rotor-rod (RR), were used to evaluate the animals response to TBI. The data from the current investigation indicates that the performance of TBI rats assigned to pre-injury EE was improved on the MWM compared to the TBI rats assigned to pre-injury SE. However, those that were reared in the EE performed better on the MWM if placed into a SE post-injury as compared to those placed into the EE after insult. The TBI and sham groups that were raised, and remained, in the SE performed worse than any of the EE groups on the RR. TBI rats that were placed in the EE had larger cortices and more cells in the hippocampus than the TBI rats housed in the SE. These data strongly suggest that the pre-injury housing environment should be considered as investigators refine pre-clinical models of TBI.
    Behavioural Brain Research 09/2014; 275. DOI:10.1016/j.bbr.2014.08.056 · 3.39 Impact Factor