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.
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 micrograms/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 (-)-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.(ABSTRACT TRUNCATED AT 250 WORDS)
Chaouloff
F
F
Laboratoire de Pharmacologie, INSERM U7, Faculté de Médecine Necker-Enfants Malades, Paris, France.
Jeanrenaud
B
B
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000818:Animals; D001786:Blood Glucose / Q000032:analysis*; D001921:Brain / Q000187:drug effects; D005215:Fasting; D007328:Insulin / Q000097:blood*; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology*; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D011985:Receptors, Serotonin / Q000502:physiology*; D012110:Reserpine / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*
D001786:Blood Glucose; D007328:Insulin; D009281:Naphthalenes; D011942:Receptors, Adrenergic, alpha; D011985:Receptors, Serotonin; D013764:Tetrahydronaphthalenes; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D012110:Reserpine; D007650:Ketanserin; D011433:Propranolol