Activation of 5-HT 1A Receptors in the Hypothalamic Paraventricular Nuclei Negatively Regulates Cytochrome P450 Expression and Activity in Rat Liver

Drug Metab Dispos. 2018 Jun;46(6):786-793. doi: 10.1124/dmd.117.079632. Epub 2018 Mar 19.

Abstract

Our recent work suggested a negative effect for the serotonergic innervation of the paraventricular nuclei (PVN) of the hypothalamus on growth hormone secretion and growth hormone-dependent expression of CYP2C11. The aim of our present research was to determine the effect of the activation of the 5-hydroxytryptamine [(5-HT) serotonin] 5-HT1 or 5-HT2 receptors in the PVN on the expression and activity of cytochrome P450 in male rat liver. The serotonergic agonists 5-carboxyamidotryptamine [(5-CT), a 5-HT1 receptor-type agonist], 8-hydroxy-2-(di-n-propyloamino)-tetralin [(8-OH-DPAT), a 5-HT1A receptor agonist], sumatriptan (a 5-HT1B/D receptor agonist), and 2,5-dimethoxy-4-iodoamphetamine [(DOI), a 5-HT2A/C receptor agonist] were individually injected into the PVN. The liver cytochrome P450 activity and expression and the levels of serum and pituitary and hypothalamic hormones were measured. 5-CT and 8-OH-DPAT significantly decreased the activity and expression of CYP2C11 at both the mRNA and protein levels, which was accompanied by an increase in pituitary and hypothalamic somatostatin levels and a decrease in the serum growth hormone concentration. The expression of CYP3A1/23 also decreased. The serum corticosterone concentration declined after the injection of 8-OH-DPAT. The obtained results indicated that 5-HT1A but not the 5-HT1B/D or 5-HT2 receptors in the PVN are engaged in the negative neuroendocrine regulation of cytochrome P450 via the stimulation of hypothalamic somatostatin secretion and in the decreases in the serum growth hormone and corticosterone concentrations. Since the affected enzymes metabolize steroids and drugs and 5-HT1A receptors are engaged in the action of psychotropic drugs, the results obtained may be of both physiologic and pharmacological meaning.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 8-Hydroxy-2-(di-n-propylamino)tetralin / pharmacology
  • Animals
  • Aryl Hydrocarbon Hydroxylases / metabolism*
  • Corticosterone / metabolism
  • Cytochrome P450 Family 2 / metabolism*
  • Growth Hormone / metabolism
  • Liver
  • Male
  • Paraventricular Hypothalamic Nucleus / drug effects
  • Paraventricular Hypothalamic Nucleus / metabolism*
  • Rats
  • Rats, Wistar
  • Receptor, Serotonin, 5-HT1A / metabolism*
  • Serotonin / metabolism
  • Serotonin Receptor Agonists / pharmacology
  • Steroid 16-alpha-Hydroxylase / metabolism*

Substances

  • Serotonin Receptor Agonists
  • Receptor, Serotonin, 5-HT1A
  • Serotonin
  • 8-Hydroxy-2-(di-n-propylamino)tetralin
  • Growth Hormone
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C11 protein, rat
  • Cytochrome P450 Family 2
  • Steroid 16-alpha-Hydroxylase
  • Corticosterone