The Therapeutic Efficacy Conferred by the 5-HT1A Receptor Agonist 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) after Experimental Traumatic Brain Injury Is Not Mediated by Concomitant Hypothermia

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Abstract
We recently reported that the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) attenuated traumatic brain injury (TBI)-induced cognitive deficits and histopathology. However, 8-OH-DPAT also produced mild hypothermia (Hypo), which may have contributed to the benefit. To clarify this issue, we conducted an experiment similar to the previous, but included an 8-OH-DPAT group that was maintained at 37 ± 0.5°C (normothermia; Normo). Isoflurane-anesthetized rats received either a cortical impact (2.7-mm deformation at 4 m/sec) or sham injury and then were randomly assigned to two saline (Sham/Vehicle, n = 5; Injury/Vehicle, n = 10) or three 8-OH-DPAT (Sham/DPAT, n = 5; Injury/DPAT + Normo, n = 10; Injury/DPAT + Hypo, n = 10) groups. 8-OH-DPAT (0.5 mg/kg) or a comparable volume of saline was administered intraperitoneally 15 min after cortical impact or sham injury. Core temperatures were taken prior to treatment and every 15 min thereafter for 2 h. Function was assessed by established motor and cognitive tasks on post-operative days 1-5 and 14-20, respectively. Hippocampal CA1/CA3 cell survival and cortical lesion volume were quantified at 4 weeks. Both the Injury/DPAT + Normo and Injury/DPAT + Hypo groups exhibited enhanced cognitive performance (spatial acquisition and retention) and reduced histopathology (CA3 cell loss and cortical lesion volume) versus the Injury/ Vehicle group (P < 0.05), but did not differ from one another despite a rapid (15 min), mild (34.4-34.9°C), and transient (~1 h) hypothermic effect in the latter. These data confirm that a single systemic administration of 8-OH-DPAT confers neurological protection after TBI, and demonstrate that the beneficial effect is not mediated by concomitant hypothermia. The mechanisms for the protective effects of 8-OH-DPAT after TBI require further inquiry.