Both acute and subchronic treatments with pindolol, a 5-HT(1A) and β₁ and β₂ adrenoceptor antagonist, elevate regional serotonin synthesis in the rat brain: an autoradiographic study

Neurochem Int. 2012 Dec;61(8):1417-23. doi: 10.1016/j.neuint.2012.10.006. Epub 2012 Oct 22.

Abstract

Antidepressant treatments, including those that increase serotonin (5-HT) neurotransmission, require several weeks or months until the onset of the therapeutic effect in depressed patients. The negative feedback on 5-HT transmission exhibited by the 5-HT(1A) and 5-HT(1B) autoreceptors has been postulated as a possible delaying factor. The aim of the present study was to assess the effect of the acute and subchronic treatment with pindolol, a 5-HT(1A/1B,) β₁ and β₂ adrenoceptor antagonist, on 5-HT synthesis, one of the key parameters of 5-HT neurotransmission. Male Sprague-Dawley (SPD) rats (180-220 g) were treated with pindolol or an adequate volume of saline, administered either acutely (15 mg/kg i.p.; SPD-AC-SAL, SPD-AC-TR) or subchronically (15 mg/kg day i.p. for 7 days; SPD-SUBCHR-SAL, SPD-SUBCHR-TR). Thirty minutes following the single i.p. injection (acute experiment) or at the 8th day following the commencement of the subchronic treatment (subchronic experiment), 5-HT synthesis was measured using α-[¹⁴C]methyl-L-tryptophan autoradiography. The analysis of variance (ANOVA), followed by the Benjamini-Hochberg correction for multiple comparisons, revealed: (1) a significant increase of 5-HT synthesis in the SPD-AC-TR rats, relative to the SPD-AC-SAL rats in all brain regions examined except the substantia nigra--pars reticularis, dorsal subiculum, inferior olive, raphe magnus and raphe obscurus and (2) a significant increase of 5-HT synthesis in the SPD-SUBCHR-TR rats, relative to the SPD-SUBCHR-SAL rats in all brain regions except the median raphe, hypothalamus and raphe pontine. On the basis of these results, we hypothesized that the antagonism of the 5-HT(1A/1B) receptors prevents the negative feedback mediated by these receptors on 5-HT synthesis, resulting in a persistent increase of 5-HT synthesis. The results accord with clinical reports on the utility of pindolol in the augmentation of antidepressant treatment.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-1 Receptor Antagonists / pharmacology*
  • Adrenergic beta-2 Receptor Antagonists / pharmacology*
  • Animals
  • Autoradiography
  • Brain / drug effects*
  • Brain / metabolism
  • Carbon Radioisotopes / analysis
  • Drug Administration Schedule
  • Feedback, Physiological
  • Injections, Intraperitoneal
  • Male
  • Organ Specificity
  • Pindolol / administration & dosage
  • Pindolol / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Serotonin / biosynthesis*
  • Serotonin 5-HT1 Receptor Antagonists / pharmacology*
  • Tryptophan / analogs & derivatives
  • Tryptophan / analysis
  • Tryptophan / blood

Substances

  • Adrenergic beta-1 Receptor Antagonists
  • Adrenergic beta-2 Receptor Antagonists
  • Carbon Radioisotopes
  • Serotonin 5-HT1 Receptor Antagonists
  • alpha-methyltryptophan
  • Serotonin
  • Tryptophan
  • Pindolol