Evaluation of a Combined Therapeutic Regimen of 8-OH-DPAT and Environmental Enrichment after Experimental Traumatic Brain Injury

Abstract

When provided individually, both the serotonin (5-HT 1A )-receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and environmental enrichment (EE) enhance behavioral outcome and reduce histopathology after experimental traumatic brain injury (TBI). The aim of this study was to determine whether combining these therapies would yield greater benefit than either used alone. Anesthetized adult male rats received a cortical impact or sham injury and then were randomly assigned to enriched or standard (STD) housing, where either 8-OH-DPAT (0.1 mg/kg) or vehicle (1.0 mL/kg) was administered intraperitoneally once daily for 3 weeks. Motor and cognitive assessments were conducted on post-injury days 1-5 and 14-19, respectively. CA1/ CA3 neurons and choline acetyltransferase-positive (ChAT þ ) medial septal cells were quantified at 3 weeks. 8-OH-DPAT and EE attenuated CA3 and ChAT þ cell loss. Both therapies also enhanced motor recovery, acquisition of spatial learning, and memory retention, as verified by reduced times to traverse the beam and to locate an escape platform in the water maze, and a greater percentage of time spent searching in the target quadrant during a probe trial in the TBI þ STD þ 8-OH-DPAT, TBI þ EE þ 8-OH-DPAT, and TBI þ EE þ vehicle groups versus the TBI þ STD þ vehicle group ( p 0.0016). No statistical distinctions were revealed between the TBI þ EE þ 8-OH-DPAT and TBI þ EE þ vehicle groups in functional outcome or CA1/CA3 cell survival, but there were significantly more ChAT þ cells in the former ( p ¼ 0.003). These data suggest that a combined therapeutic regimen of 8-OH-DPAT and EE reduces TBI-induced ChAT þ cell loss, but does not enhance hippocampal cell survival or neurobehavioral performance beyond that of either treatment alone. The findings underscore the complexity of combinational therapies and of elucidating potential targets for TBI.

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

“…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).…”

“…To reduce counting errors associated with falsepositive identification of dying neurons, the total number of CA1 and CA3 morphologically-intact neurons (i.e., those with a clearly defined cell body and nucleus) were counted using a Nikon Eclipse E600 microscope with a 40 · objective. For consistency and replication, the data are presented as the percent of total neurons in the ipsilateral (injured) CA1 and CA3 regions relative to the contralateral (uninjured) hippocampus, as previously reported Dixon et al, 1999;Hoffman et al, 2008;Kline et al, 2004Kline et al, ,2010Sozda et al, 2010).…”

“…The workshop leaders focused exclusively on the potential for combinatorial pharmacological agents to promote recovery. While this is a commendable start, there is certainly real potential and value in including non-invasive therapies, such as environmental enrichment (EE) or exercise (Gomez-Pinilla et al, 2011;Griesbach et al, 2009;Hamm et al, 1996;Hicks et al, 2002;Hoffman et al, 2008;Kline et al, 2007Kline et al, ,2010Matter et al, 2011;Passineau et al, 2001;de Witt et al, 2011), in combinational therapy paradigms for promoting recovery and perhaps augmenting the pharmacological effects, particularly in rehabilitation settings.…”

“…This paradigm has consistently shown improvements in behavioral and histological outcome after brain trauma and can therefore be considered a reasonable approach to preclinical rehabilitation. Importantly, the benefits conferred by EE span clinically-relevant models of experimental TBI, such as controlled cortical impact (CCI; Chen et al, 2005;de Witt et al, 2011;Hoffman et al, 2008;Kline et al, 2007Kline et al, ,2010Matter et al, 2011;Sozda et al, 2010) and fluid percussion (Hamm et al, 1996;Hicks et al, 2002;Gaulke et al, 2005;Giza et al, 2005;Maegele et al, 2005;Passineau et al, 2001). The second therapy in this combined treatment approach is the systemic administration of the serotonin 1A (5-HT 1A )-receptor agonist buspirone.…”

A Combined Therapeutic Regimen of Buspirone and Environmental Enrichment Is More Efficacious than Either Alone in Enhancing Spatial Learning in Brain-Injured Pediatric Rats

“…[15][16][17] Several studies have shown that systemic administration of early-and-single (i.e., acute) as well as delayed-and-multiple (i.e., chronic) treatments with the 5-HT 1A receptor agonists repinotan HCL and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) confer neurobehavioral benefits after TBI. [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.…”