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

Life Sci. 2022 Mar 15:293:120335. doi: 10.1016/j.lfs.2022.120335. Epub 2022 Jan 18.

Abstract

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-HT1A/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-HT1/7, 5-HT1A and 5-HT1D agonists, respectively) reproduced 5-HT-evoked inhibition, the 5-HT2 activation by α-methyl-5-HT augmented the vasoconstrictions. The 5-CT sympatho-inhibition was reversed by 5-HT1A plus 5-HT1D antagonists (WAY-100,635 and LY310762, respectively), whereas ritanserin (5-HT2A 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-HT1A/1D/2A receptors were expressed at vascular level, being 5-HT1A 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-HT1A/1D are involved in the sympatho-inhibition, while 5-HT2A is implicated in the sympatho-potentiation, being both effects pre and/or postjunctional in nature.

Keywords: 5-HT; Diabetes; Fluoxetine; Sympathetic neurotransmission; Vascular tone.

MeSH terms

  • Administration, Oral
  • Animals
  • Blood Pressure / drug effects
  • Blood Pressure / physiology
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetes Mellitus, Type 1 / drug therapy
  • Diabetes Mellitus, Type 1 / metabolism*
  • Fluoxetine / administration & dosage*
  • Male
  • Rats
  • Rats, Wistar
  • Receptors, Serotonin / metabolism*
  • Selective Serotonin Reuptake Inhibitors / administration & dosage*
  • Serotonin / metabolism*
  • Serotonin Antagonists / pharmacology

Substances

  • Receptors, Serotonin
  • Serotonin Antagonists
  • Serotonin Uptake Inhibitors
  • Fluoxetine
  • Serotonin