| This research determined the effectiveness of biomedical countermeasures to mitigate the effects of space radiation on central nervous system (CNS) function. Using an animal analog of the human Psychomotor Vigilance Test (PVT) that is used for human risk assessment, the studies assessed the effectiveness of a number of Food and Drug Administration (FDA)-approved compounds to lessen the deleterious effects of radiation exposure on CNS function (sustained attention) in rats. Rats were trained in a rodent version of the human PVT, exposed to proton irradiation at NASA's Space Radiation Laboratory at Brookhaven National Laboratory, and returned to Johns Hopkins for post-exposure testing to 1) identify long-term neurobehavioral deficits, and 2) assess the effectiveness of pharmacologic compounds to mitigate the deficits. Mechanisms of action were evaluated by employing different types of potential mitigating compounds (i.e., given after radiation exposure), such as those that directly alter dopaminergic (DA) signaling by binding to the DA transporter protein (DAT; e.g., methylphenidate), those that directly alter DA signaling by binding to receptors from the D2 receptor family (e.g., aripiprazole), and those that indirectly alter DA and other monoamine levels (e.g., NE reuptake inhibition, atomoxetine). Two FDA-approved compounds – the putative DNA repair targeting drug cholorquine (CLQ), and the hemopoietic growth factor erythropoietin (EPO) – were also assessed for their potential radioprotective effects (i.e., given prior to radiation exposure) and their alternative mechanisms of action.
Key Findings from this 2-year project include:
Psychostimulants as potential countermeasures for proton-induced deficits in neurobehavioral function
• The psychostimulant d-amphetamine (DA releaser, indirect DA agonist) produced dose-dependent recovery of both accuracy and reaction time in radiation-sensitive animals, but produced performance decrements in radiation-insensitive animals.
• The DA/NE reuptake inhibitor methylphenidate also produced dose-dependent recovery of performance in radiation-sensitive animals, but did not impair performances in radiation-insensitive animals.
• The NE reuptake inhibitor atomoxetine showed no differential effects on rPVT performance in radiation-sensitive or radiation-insensitive rats.
• SCH 39166, a D1 receptor antagonist, blocked amphetamine's effects on percent correct responding, indicating that D1 receptors are responsible for amphetamine-induced changes in rPVT performance.
• L-741,626, a D2 receptor antagonist, did not block amphetamine's effects, indicating that D2 receptors are not involved in the amphetamine-induced changes in rPVT performance.
• Both pramipexole (a D3 agonist) and aripiprazole (a partial D2 agonist) produced dose-dependent recovery of radiation-induced slowing of reaction times, suggesting that altered dopamine D2-like receptor signaling is involved in these deficits. Further, the improvements following aripiprazole suggest that DA tone could differ in various brain regions, with this partial agonist acting like an antagonist in areas of high DA tone and acting like an agonist in areas of low DA tone.
• The data provide evidence of the specific involvement of both D1-like and D2-like dopamine receptor systems in radiation-induced neurobehavioral deficits. Studies of potential radiation-protective compounds
• EPO – a compound involved in the brain's response to various insults, including radiation – did not improve the radiation-induced deficits in performance in radiation-sensitive rats at any doses tested.
• CLQ – a drug that improves clinical outcomes following whole-brain radiotherapy – also did not lessen radiation-induced deficits in rPVT performance; fine-grain analyses of these data are still ongoing.
Changes in Dopaminergic Modulation following Radiation
• Differences in dopamine-agonist induced yawning and its antagonism by a dopamine D2 receptor antagonist (L-741,626) were found between radiation-sensitive and radiation-insensitive rats. Greater levels of yawning were found in radiation insensitive rats, whereas radiation sensitive rats displayed reduced levels of induced yawning. ED50 values (the dose effective in 50% of subjects) also significantly differed between the radiation sensitive and insensitive rats. Thus D2 dopamine receptors are altered in radiation sensitive rats, and D3 receptors may be altered in radiation insensitive rats.
Predicting an individual's sensitivity via analyses of pre-exposure rPVT performances
• Prior to irradiation, rats that were to subsequently show sensitivity to radiation were found to be more prone to exhibit higher levels of premature responding and lower levels of lapses in attention, thus suggesting a potential method for predicting pre-exposure individual sensitivity to radiation (see Main Findings in Task Progress section).
Two new publications during this reporting period:
• The rodent psychomotor vigilance test (rPVT): A method for assessing neurobehavioral performance in rats and mice is both a publication and a video demonstrating the procedure and documenting that rats show a high degree of similarity to human PVT performances, including similarities in lapses in attention, reaction times, decrements across a session (i.e., human time-on-task effects), and the human response-stimulus interval (RSI) effect.
• Whole-Body Oxygen Ion Exposure-Induced Impairments in Social Odor Recognition Memory in Rats are Dose and Time Dependent demonstrated that at 1 month post-exposure, irradiated rats display a memory deficit for recall of a conspecific odor experienced 24 hours prior. At 6 months post-exposure, 25 cGy-exposed rats show persistent deficits in 24-hr recognition memory, while the 5 cGy-exposed rats show recovery of recognition memory, demonstrating that space-relevant 16O ion exposure has deleterious effects on the central nervous system related to exposure dose and time post-exposure.