Serotonergic modulation of L-glutamic acid-evoked release of endogenous norepinephrine from rat hypothalamus

Hypothalamic slices (400 μ) from male Sprague-Dawley rats were perfused with a Mg⁺⁺-free medium containing nomifensine (10 μM) and tyrosine (50 μM). Spontaneous release of endogenous norepinephrine (NE), measured by high-performance liquid chromatography-electrochemical detection, averaged 102 ± 13 (N = 76) fmol/mg of protein/3 min. L-Glutamic acid (L-GLU) (1 mM) more than doubled the rate of NE release. Preincubation with serotonin (5- HT) (0.1-10 μM) produced no change in spontaneous NE release but caused a concentration-dependent decrease of L-GLU-induced NE release with a maximal reduction of about 60 to 70%. 2-Methylserotonin, a 5-HT₃ receptor agonist (0.07-10 μM), mimicked the 5-HT response. A highly selective 5-HT₃ receptor antagonist, (3α-tropanyl)1H-indole-3-carboxylic acid ester, 1 nM, inhibited the effect of both agonists. Neither ritanserin (1 μM) nor methysergide (1 μM) modified either spontaneous or 1 mM L-GLU-evoked release of NE. However, if added to the superfusion medium simultaneously with 5-HT, they potentiated significantly the inhibition produced by 5-HT. Alpha-methylserotonin (1 μM) if added alone to the perfusion medium had no effect on 1 mM L-GLU-evoked release of NE but reversed the inhibition induced by 1 μM 2-methylserotonin. These observations provide direct evidence of a dual modulation by 5-HT of L- GLU-evoked release of endogenous NE from slices of rat hypothalamus: An inhibition mediated by 5-HT₃ receptors and an opposing action mediated by receptors of the 5-HT(1C/2) type.