Local perfusion of corticosterone in the rat medial hypothalamus potentiates D-fenfluramine-induced elevations of extracellular 5-HT concentrations.
The dorsomedial hypothalamus (DMH) plays an important role in coordinating physiological and behavioral responses to stress-related stimuli. In vertebrates, DMH serotonin (5-HT) concentrations increase rapidly in response to acute stressors or corticosterone (CORT). Recent studies suggest that CORT inhibits postsynaptic clearance of 5-HT from the extracellular fluid in the DMH by blocking organic cation transporter 3 (OCT3), a polyspecific CORT-sensitive transport protein. Because OCTs are low-affinity, high-capacity transporters, we hypothesized that CORT effects on extracellular 5-HT are most pronounced in the presence of elevated 5-HT release. We predicted that local application of CORT into the DMH would potentiate the effects of d-fenfluramine, a 5-HT-releasing agent, on extracellular 5-HT. These experiments were conducted using in vivo microdialysis in freely-moving male Sprague-Dawley rats implanted with a microdialysis probe into the medial hypothalamus (MH), which includes the DMH. In Experiment 1, rats simultaneously received intraperitoneal (i.p.) injections of 1 mg/kg D-fenfluramine or saline and either 200 ng/mL CORT or dilute ethanol (EtOH) vehicle delivered to the MH by reverse-dialysis for 40 min. In Experiment 2, 5 microM D-fenfluramine and either 200 ng/mL CORT or EtOH vehicle were concurrently delivered to the MH for 40 min using reverse-dialysis. CORT potentiated the increases in extracellular 5-HT concentrations induced by either i.p. or intra-MH administration of D-fenfluramine. Furthermore, CORT and D-fenfluramine interacted to alter home cage behaviors. Our results support the hypothesis that CORT inhibition of OCT3-mediated 5-HT clearance from the extracellular fluid contributes to stress-induced increases in extracellular 5-HT and 5-HT signaling.
Feng
Na
N
Department of Biology and Neuroscience Group, University of South Dakota, Vermillion, SD 57069, USA.
Telefont
Martin
M
Kelly
Kyle J
KJ
Orchinik
Miles
M
Forster
Gina L
GL
Renner
Kenneth J
KJ
Lowry
Christopher A
CA
D000704:Analysis of Variance; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003345:Corticosterone / Q000378:metabolism*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005277:Fenfluramine / Q000008:administration & dosage*; D006120:Grooming / Q000187:drug effects / Q000502:physiology; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D008297:Male; D017551:Microdialysis / Q000379:methods; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D018490:Serotonin Agents / Q000008:administration & dosage*
D018490:Serotonin Agents; D005277:Fenfluramine; D012701:Serotonin; D003345:Corticosterone