Urotensin II evokes neurotransmitter release from rat cerebrocortical slices

Urotensin II (UII) has been reported to modulate rapid eye movement (REM) sleep via activation of brainstem cholinergic neurons and REM sleep is regulated by locus coerleus (LC)-cerebrocortical noradrenergic neurons. We hypothesized that UII may activate LC-cerebrocortical noradrenergic neurons. To test this hypothesis, we have examined the effects of UII on norepinephrine release from rat cerebrocortical slices. In addition, the effect of the putative UT receptor antagonist [Pen(5), DTrp(7), Dab(8)]UII(4-11) (UFP-803) was assessed. We have compared this with other wakefulness-promoting neurotransmitters such as dopamine, glutamate, serotonin and histamine. We also studied the effects of UII and UFP-803 on intracellular Ca(2+) ([Ca(2+)]i) in HEK293 cells stably expressing rat UT receptor (HEK293-rUT cells). UII produced a time- (peaking at approximately 10 min following stimulation with 10nM) and concentration-dependent increase in norepinephrine release with pEC(50) and E(max) (% of basal) values of 8.78+/-0.17 (1.65 nM) and 138+/-2%, respectively. UII also evoked dopamine, serotonin and histamine release with similar pEC(50) values. UII increased glutamate release but only at high concentrations (<100 nM) and this failed to saturate. UII markedly increased [Ca(2+)](i) in HEK293-rUT cells in a concentration-dependent manner with pEC(50) of 8.26+/-0.24. The UT antagonist UFP-803 reversed both UII-increased norepinephrine release from the cerebrocortical slices (pK(B)=8.98) and [Ca(2+)](i) (pK(B)=8.87) in HEK293-rUT cells. Collectively these data suggest that UII evokes the release of norepinephrine via UT receptor activation and produces similar effects on other wakefulness-promoting neurotransmitters: these neurochemical actions of UII may be important for the control of the sleep-wake cycle.