Nimodipine Reverses the Elevation of Synaptic Striatal Dopamine and Serotonin During In Vivo Hypoxia

Abstract

Introduction: Moderate hypoxia has been implicated in the development of delirium. One mechanism may be an increase of Dopamine (DA) and Serotonin (5-HT) levels. Our previous studies indicated that hypoxia increased levels of both neurotransmitters (NT) and that nimodipine (NIMO) administered immediately after hypoxia preserved short term memory. We tested the hypothesis that these observations may be related to a NIMO dependent reduction of hypoxia in- duced NT elevation. Methods: Following IACUC approval, In Vivo microvoltammetry sensors (BRODERICK PROBE ® ) were implanted in the dorsal striatum of Na Pentobarbital anesthetized adult Sprague-Dawley rats. Extracellular NT levels were recorded for 15m during the establishment of baseline values in room air (N=6). Three sequential thirty-minute periods under hypoxia (10% O2) followed. First: under hypoxia alone; second after i.p. injection of NIMO (0.1mg/kg); and third following i.p. injection of NIMO (1.0mg/kg). Measurements were analyzed with ANOVA with post hoc Tukeys test. P-values less than 0.05 were considered significant. Results: NT levels are expressed as percentages of baseline values. Treatment values were averaged over each sequential thirty-minute period following each intervention. Moderate hypoxia resulted in the increase of DA to 172% (SEM=18) and 5-HT to 68% (SEM=4) above baseline. Under continuing hypoxia, NIMO (0.1mg/kg) caused DA levels to fall to 112% (SEM=14) and 5-HT to 13% (SEM=5) above baseline. NIMO (1.0mg/kg) caused DA levels to fall to 34% (SEM=6) above baseline and 5-HT to 20% (SEM=2) below baseline. Conclusion: Moderate hypoxia increased levels of DA and 5-HT in the striatum of rats. NIMO administration during on- going hypoxia caused the levels of both neurotransmitters to fall towards baseline. The results may have implications for understanding and treating cognitive decline due to hypoxia.