RESUMEN
Exposure to heavy ions during a Mars mission might damage the brain, thus compromising mission success and the quality of life of returning astronauts. Several workers have suggested that the dopamine system is particularly sensitive to heavy ion radiation, but direct evidence for this notion is lacking. We examined measures of brain dopamine viability at times up to 15 months after acute exposure of rats to (56)Fe (1.2-2.4 Gy). No effects were seen in brain sections stained for tyrosine hydroxylase, the classical marker for dopamine cells and nerve terminals. Locomotion stimulated by cocaine, which directly activates the dopamine system, was reduced at 6 months but not at 12 months. Furthermore, in a visually cued lever-pressing test, reaction times, which are prolonged by dopamine system damage, were identical in irradiated and control animals. However, learning times were increased by irradiation. Our data suggest that the midbrain dopamine system is not especially sensitive to damage by (56)Fe particles at doses much higher than would be associated with travel to and from Mars.
Asunto(s)
Dopamina/metabolismo , Dopamina/efectos de la radiación , Hierro , Animales , Encéfalo/efectos de la radiación , Cocaína/farmacología , Radiación Cósmica , Señales (Psicología) , Medio Ambiente Extraterrestre , Masculino , Radiobiología , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción , Tirosina 3-Monooxigenasa/metabolismo , Visión OcularRESUMEN
G-protein coupled receptors exist in both high and low agonist affinity conformations, with tracer levels of agonist radioligands preferentially binding to the former. The goal of the present study was to characterize the in vivo binding of the aminoalkyindole-based, CB1 receptor agonist, R-[125/131I]AM2233 ((2-[125/131I]iodo-phenyl)-[1-(1-methyl-piperidin-2-yl-methyl)-1H-indol-3-yl]-methanone), and to use this radiotracer to selectively measure the receptor occupancy by the related CB1 receptor agonist, WIN55212-2, to the agonist-preferring affinity state of the receptor. In mouse locomotor assays, both WIN55212-2 and AM2233 (racemic) produced an approximately 60% reduction in activity at 1 mg/kg, (i.v.) and completely inhibited activity at 3 mg/kg, confirming their agonist nature. In ex vivo autoradiography, preferential uptake of R-[131I]AM2233 was apparent in CB1 receptor-rich areas, including globus pallidus, substantia nigra, striatum, cerebellum, and hippocampus. Overall brain uptake of R-[131I]AM2233 was 1.3% injected activity/g at 5 min in mice. Coinjection of 3 mg/kg (i.v.) SR141716A, a CB1 receptor antagonist, with R-[125I]AM2233 inhibited the radiotracer binding almost to nonspecific levels in the striatum, globus pallidus, and substantia nigra, although residual binding to a non-CB1 receptor remained in the hippocampus. In contrast to the effect of SR141716A, coinjection of 10 mg/kg (i.v.) WIN55212-2, a high dose that produced an immediate and profound immobility and catalepsy in the mice, reduced CB1 receptor-specific binding of R-[125I]AM2233 in CB1 receptor-rich areas by only 21-43%. These observations suggest that the behavioral effects of CB1 receptor agonists are manifested with a relatively small fraction of the agonist-preferring affinity state of the receptor occupied.