Oral fluoxetine treatment changes serotonergic sympatho-regulation in experimental type 1 diabetes.

Aims: This study investigated whether fluoxetine treatment changes the 5-HT regulation on vascular sympathetic neurotransmission in type 1 diabetes.
Main Methods: Four-week diabetes was obtained by a single alloxan s.c. administration in male Wistar rats, administering fluoxetine for 14 days (10 mg/kg/day; p.o.). Systolic blood pressure, heart rate, glycaemia, body weight (BW) evolution, creatinine, and blood urea nitrogen (BUN) were monitored. Afterward, rats were pithed to perform the vascular sympathetic stimulation. 5-HT _1A/1D/2A receptors expression was analysed by Western blot in thoracic aorta. Both i.v. norepinephrine and the electrical stimulation of the spinal sympathetic drive evoked vasoconstrictor responses.
Key Findings: Fluoxetine treatment significantly reduced the BW gain, hyperglycaemia, creatinine, and BUN in diabetic rats. The electrical-produced vasopressor responses were greater in untreated than in fluoxetine-treated diabetic rats. 5-HT decreased the sympathetic-produced vasopressor responses. While 5-CT, 8-OH-DPAT and L-694,247 (5-HT _1/7 , 5-HT _1A and 5-HT _1D agonists, respectively) reproduced 5-HT-evoked inhibition, the 5-HT ₂ activation by α-methyl-5-HT augmented the vasoconstrictions. The 5-CT sympatho-inhibition was reversed by 5-HT _1A plus 5-HT _1D antagonists (WAY-100,635 and LY310762, respectively), whereas ritanserin (5-HT _2A antagonist) blocked the α-methyl-5-HT potentiating effect. Norepinephrine-generated vasoconstrictions were increased or diminished by α-methyl-5-HT or 5-CT, respectively. 5-HT _1A/1D/2A receptors were expressed at vascular level, being 5-HT _1A expression increased by fluoxetine in diabetic rats.
Significance: Our findings suggest that fluoxetine improves metabolic and renal profiles, changes the vasopressor responses, and 5-HT receptors modulating sympathetic activity in diabetic rats: 5-HT _1A/1D are involved in the sympatho-inhibition, while 5-HT _2A is implicated in the sympatho-potentiation, being both effects pre and/or postjunctional in nature.
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