5-HT1A AND ALPHA-2 ADRENERGIC-RECEPTORS MEDIATE THE HYPERGLYCEMIC AND HYPOINSULINEMIC EFFECTS OF 8-HYDROXY-2-(DI-N-PROPYLAMINO)TETRALIN IN THE CONSCIOUS RAT

  • 1 December 1987
    • journal article
    • research article
    • Vol. 243  (3) , 1159-1166
Abstract
The ability of the 5-hydroxytryptamine (5-HT)1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) to affect plasma glucose levels and insulin release was assessed in rats bearing chronic jugular catheters. The i.v. administration of 8-OH-DPAT (150 .mu.g/kg) rapidly promoted a transient hyperglycemia. Despite high glucose levels, insulinemia remained constant. Dose-response curves revealed that maximal hyperglycemia was associated with hypoinsulinemia. Increased glycemia, which was also found to be induced by other 5-HT direct and indirect agonists, lasted longer in food-deprived rats. Evidence for a strong inhibitory effect of 8-OH-DPAT on insulin release was reported in rats submitted to i.v. glucose tolerance tests. Pretreatments with the dopaminergic blocker haloperidol, the alpha-1 adrenoceptor antagonist prazosin or the 5-HT2 blocker ketanserin were ineffective. In contrast, the alpha-2 adrenoceptor antagonist idazoxan and the unspecific 5-HT antagonist methiotepin prevented the hyperglycemic and the hypoinsulinemic effects of 8-OH-DPAT. Blockade of these changes by (.sbd.)-propranolol (a 5-HT1 blocker), but not by (+)-propranolol, indicated that 5-HT1 and alpha-2 adrenergic receptors mediated 8-OH-DPAT-induced hyperglycemia. Reserpine pretreatment did not prevent the effects of 8-OH-DPAT. Central injection of 8-OH-DPAT induced hyperglycemia, the amplitude of which was equivalent to that measured after i.v. administration. Selective degeneration of serotonergic nerve cells by 5,7-dihydroxytryptamine did not prevent 8-OH-DPAT-induced alterations, thus rendering a key role for presynaptic mechanisms unlikely. Because the nanomolar administration of 8-OH-DPAT promoted hyperglycemia and inhibition of insulin release, it is suggested that the "A" subtype of 5-HT1 recognition sites (and alpha-2 adrenoceptors) mediates these changes.