Drug-Induced Changes of Brain Serotoninergic Tone and Insulin-Induced Growth Hormone Release in the Dog

Abstract

Drugs capable of modifying central serotoninergic neurotransmission were studied for their ability to affect the release of growth hormone (GH) which follows insulin-induced hypoglycemia in the unanesthetized dogs. Chlorimipramine, a blocker of serotonin (5-HT) re-uptake, induced a striking suppression of the GH response during the first 90 min post-insulin administration, but was unable to suppress GH levels at later time intervals (90-180 min). Two long-lasting 5-HT re-uptake blockers, FG 4963 [(+)-trans-3-(4-methoxy-phenoxy)-methyl-1-methyl-4-phenylpiperidine hydrochloride] and Fluoxetine (Lilly 110140), induced a sustained inhibition of the hypoglycemia-induced GH rise. Fenfluramine, a rapid releaser of 5-HT neuronal stores and hence functional activator of 5-HT neurotransmission, was capable of blunting the GH response to the metabolic stimulus. An inhibitory role for 5-HT in the GH response to insulin hypoglycemia in the dog was suggested. In contrast, administration of both cyproheptadine (Cy) and methysergide (Meth), 2 alleged 5-HT receptor blockers, inhibited insulin-induced GH rise. The discrepancy between previous and the latter findings may indicate that the inhibitory effect of Cy and Meth was due to reason(s) alien to 5-HT receptor blockage. Methergoline, another drug endowed with 5-HT antagonistic activity, enhanced the GH response to insulin. An explanation for the inhibitory effect of Cy, whose anti-histaminic properties are well known, may be offered by the observation that out of 3 anti-histaminic drugs used, clemastine proved capable of reducing the GH response to the insulin stimulus. Blockade of dopamine (DA) receptors by pimozide blocked the GH response to insulin does not exclude that the effect of Cy and Meth may be due to their known anti-dopaminergic properties.