Early-life blockade of 5-HT(1A) receptors alters adult anxiety behavior and benzodiazepine sensitivity

Biol Psychiatry. 2010 Feb 15;67(4):309-16. doi: 10.1016/j.biopsych.2009.08.013. Epub 2009 Oct 6.

Abstract

Background: Early-life stress may affect 5-HT(1A) receptor circuitry, which could result in increased anxiety in later life. An increased anxiety phenotype in 5-HT(1A) receptor KO mice (1AKO) mice has been ascribed to 5-HT(1A) receptor absence during the early postnatal period. Thus, subtle and transient serotonergic changes during the early postnatal period may lead to an increased risk for developing stress-related disorders during adulthood.

Methods: Wildtype and 1AKO mice on a Swiss-Webster (SW) background were treated during the early postnatal period with vehicle or the 5-HT(1A) receptor antagonist WAY-100,635.

Results: Pharmacologic 5-HT(1A) receptor blockade during the early postnatal period induced long-lasting effects on anxiety and benzodiazepine sensitivity in adolescent and adult mice on a Swiss-Webster background and resembles the SW 1AKO phenotype. Furthermore, WAY-100,635-treated mice had increased cortical gamma-aminobutyric acid-A receptor (GABA(A)R) alpha(1) and alpha(3) subunit levels and increased hippocampal GABA(A)R alpha(2) subunit levels.

Conclusions: Absence of 5-HT(1A)R signaling during early stages of brain maturation predisposes an organism to affective dysfunction later in life. Because early-life treatment with WAY-100,635 in Swiss-Webster mice reduced diazepam sensitivity and increased GABA(A)R alpha subunit levels in the prefrontal cortex and hippocampus, our data suggest a putative link between early-life disruption of the serotonergic system and the emergence of increased anxiety and decreased benzodiazepine responsivity at adult age. Moreover, early-life 5-HT(1A) receptor functionality appears to be essential for the development of normal GABA(A)R functionality. This study may have clinical implications for psychoactive drug use during pregnancy and for the pharmacogenetic background of benzodiazepine sensitivity.

MeSH terms

  • Age Factors
  • Animals
  • Animals, Newborn
  • Anti-Anxiety Agents / therapeutic use
  • Anxiety / drug therapy
  • Anxiety / genetics*
  • Anxiety / pathology
  • Anxiety / physiopathology*
  • Benzodiazepines / pharmacology*
  • Diazepam / therapeutic use
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Exploratory Behavior / drug effects
  • Gene Expression Regulation, Developmental / drug effects
  • Gene Expression Regulation, Developmental / genetics
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Maze Learning / drug effects
  • Mice
  • Mice, Knockout
  • Piperazines / therapeutic use
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / metabolism
  • Pyridines / therapeutic use
  • RNA, Messenger / metabolism
  • Receptor, Serotonin, 5-HT1A / deficiency*
  • Receptor, Serotonin, 5-HT1A / genetics*
  • Receptors, GABA-A / genetics
  • Receptors, GABA-A / metabolism
  • Serotonin Antagonists / therapeutic use
  • Vocalization, Animal / drug effects

Substances

  • Anti-Anxiety Agents
  • Piperazines
  • Pyridines
  • RNA, Messenger
  • Receptors, GABA-A
  • Serotonin Antagonists
  • Receptor, Serotonin, 5-HT1A
  • Benzodiazepines
  • N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
  • Diazepam