ACTIONS OF A LONG-ACTING SOMATOSTATIN ANALOG SMS201-995 (SANDOSTATIN) ON RAT LOCUS-COERULEUS NEURONS

The actions of sandostatin involving rat locus coeruleus (LC) neurons were examined using an intracellular recording in a brain slice preparation. Bath application of sandostatin (5-100nM) reversibly decreased the firing rate of all neurons tested in a dose-dependent manner. Sandostatin was 9.5 times more potent than somatostatin in light of an inhibition of the spontaneous firing rate. In addition to the inhibition of spontaneous firing, larger concentrations of sandostatin (30-100nM) also hyperpolarized the neurons of the locus coeruleus and simultaneously caused a reduction in input resistance. At the highest concentration (100nM) applied, sandostatin produced complete inhibition of firing of all neurons tested (n=49); the inhibition was associated with a 11.6mV hyperpolarization (range 2.2-26.4 mV, n=49) and a 21.8% reduction in input resistance (range 2.6-55.2%, n=39). The voltage-current relationship of the resting cell revealed an inward-going rectification that became enhanced after the perfusion of sandostatin (100nM) for 5 min. The reversal potential for the sandostatin-induced hyperpolarization was -111 +/- 1 mV (n=10), which is approximately the potassium equilibrium potential. This hyperpolarization was blocked by both caesium chloride and barium chloride. Our results also showed that sandostatin displayed an antagonistic action on mu opiate receptors. Both the somatostatin-agonistic and opiate-antagonistic activities of sandostatin were conclusively found to be stronger than those of somatostatin; in addition, the inhibitory actions of sandostatin on LC neurons were due to an opening of the inward-going rectification potassium channels.