Effects of 5-hydroxytryptamine on neuronal activities in the rat dorsolateral septal nucleus

Abstract

The ionic channels and signal transduction pathways underlying the 5- hydroxytryptamine (5-HT)-induced hyperpolarization in neurons of the rat dorsolateral septal nucleus (DLSN) were examined by using intracellular and voltage-clamp recording techniques. Application of 5-HT (1-50 μM) caused a hyperpolarizing response associated with a decreased membrane resistance in DLSN neurons. The hyperpolarization induced by 5-HT was blocked by Ba2+ (1 mM) but not by tetraethylammonium (TEA, 3 mM), glibenclamide (100 μM) and extracellular Cs+ (2 mM). 8-Hydroxy-di-n-propylamino tetralin (8-OH-DPAT; 3 μM), a selective agonist for the 5-HT(1A) receptor, mimicked 5-HT in producing the hyperpolarization. The 5-HT hyperpolarization was blocked by NAN-190 (5 μM), a 5-HT(1A) receptor antagonist. CP93129 (100 μM), a 5- HT(1B) receptor agonist, and L-694-247 (100 μM), a 5-HT(1B/1D) receptor agonist, also produced hyperpolarizing responses. The order of agonist potency was 8-OH-DPAT >> CP93129 ≥ L-694-247. (±)-2,5-Dimethoxy-4- iodoamphetamine hydrochloride (DOI, 100 μM), a 5-HT2 receptor agonist, and RS67333 (100 μM), a 5-HT4 receptor agonist, caused no hyperpolarizing response. The voltage-clamp study showed that 5-HT caused an outward current (I(5-HT)) in a concentration-dependent manner. I(5-HT) was associated with an increased membrane conductance. I(5-HT) reversed the polarity at the equilibrium potential for K+ calculated by the Nernst equation. I(5-HT) showed inward rectification at membrane potentials more negative than -70 mV. Ba2+ (100 μM) blocked the inward rectifier K+ current induced by 5-HT. I(5-HT) was irreversibly depressed by intracellular application of guanosine 5'-O-(3-thiotriphosphate)(GTP-γS) but not by guanosine 5'-O-(2- thiodiphosphate) (GDP βS). These results suggest that in rat DLSN neurons activation of 5-HT(1A) receptors causes a hyperpolarizing response by activating mainly the inward rectifier K+ channels through a GTP-binding protein.