SEROTONERGIC MODULATION OF L-GLUTAMIC ACID-EVOKED RELEASE OF ENDOGENOUS NOREPINEPHRINE FROM RAT HYPOTHALAMUS

Hypothalamic slices (400 mu) from male Sprague-Dawley rats were perfus ed with a Mg++-free medium containing nomifensine (10 muM) and tyrosin e (50 muM). Spontaneous release of endogenous norepinephrine (NE), mea sured by high-performance liquid chromatography-electrochemical detect ion, 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. Preincu bation with serotonin (5-HT) (0.1-10 muM) produced no change in sponta neous NE release but caused a concentration-dependent decrease Of L-GL U-induced NE release with a maximal reduction of about 60 to 70%. 2-Me thylserotonin, a 5-HT3 receptor agonist (0.07-10 muM), mimicked the 5- HT response. A highly selective 5-HT3 receptor antagonist, (3alpha-tro panyl)1H-indole-3-carboxylic acid ester, 1 nM, inhibited the effect of both agonists. Neither ritanserin (1 muM) nor methysergide (1 muM) mo dified either spontaneous or 1 MM L-GLU-evoked release of NE. However, if added to the superfusion medium simultaneously with 5-HT, they pot entiated significantly the inhibition produced by 5-HT. Alpha-methylse rotonin (1 muM) if added alone to the perfusion medium had no effect o n 1 mM L-GLU-evoked release of NE but reversed the inhibition induced by 1 muM 2-methylserotonin. These observations provide direct evidence of a dual modulation by 5HT Of L-GLU-evoked release of endogenous NE from slices of rat hypothalamus: An inhibition mediated by 5-HT3 recep tors and an opposing action mediated by receptors of the 5-HT1C/2 type .