Impaired response of experimental diabetic mice to tricyclics: a possible beta-adrenergic mechanism.
Diabetes is reportedly associated with alterations in peripheral and central noradrenergic systems. The latter might be involved in the antidepressant effects of imipramine-like drugs in both humans and animals. Therefore, it is possible that diabetics show an impaired responsiveness to tricyclics. To test this possibility the effects of streptozotocin (STZ)-induced experimental diabetes in mice were assessed in two psychopharmacological tests: 1) the reversal of apomorphine- (16 mg/kg) induced hypothermia and 2) the hypoactivity induced by a direct beta-agonist (clenbuterol 0.06 mg/kg). At day 15 after STZ or vehicle treatment, imipramine (4 mg/kg) antagonized the apomorphine-induced hypothermia in diabetic (D) and nondiabetic (ND) mice and clenbuterol produced hypoactivity in both groups. At day 30 and 45, the ability of imipramine (1, 2, 4, 8, 16 mg/kg), clomipramine (8 mg/kg) and desipramine (2 mg/kg) to reverse apomorphine-induced hypothermia disappeared at the same time that clenbuterol lost its ability to induce hypomotility in D mice. These impaired responses on both tests were corrected by a short period of insulin therapy. These two tests may reflect central beta-adrenergic functions. Therefore, these data suggest that the impaired responsiveness of diabetic mice might be due at least in part to a noradrenergic dysfunction. Possibly, in diabetes, a beta-adrenoceptor desensitization identical to that observed at the peripheral level occurs in the central nervous system. The possibility that a thyroid hormone deficiency may be involved was also tested. Decreased T3 plasma levels were found in D mice concomitant with the impaired pharmacological responses and T3 supplementation turned these responses to normal.(ABSTRACT TRUNCATED AT 250 WORDS)
Massol
J
J
Service de Diabétologie-Endocrinologie, Hôpital J. Minjoz, Besançon, France.
Martin
P
P
Chatelain
F
F
Soubrié
P
P
Puech
A J
AJ
D000818:Animals; D002976:Clenbuterol / Q000494:pharmacology; D002997:Clomipramine / Q000494:pharmacology*; D003891:Desipramine / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D007036:Hypothermia, Induced; D007099:Imipramine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D013974:Thyroxine / Q000097:blood; D014284:Triiodothyronine / Q000097:blood
D011943:Receptors, Adrenergic, beta; D014284:Triiodothyronine; D002997:Clomipramine; D007099:Imipramine; D013974:Thyroxine; D003891:Desipramine; D002976:Clenbuterol