Biphasic effects of 5-HT 1A agonism on impulsive responding are dissociable from effects on anxiety in the variable consecutive number task

Naunyn Schmiedebergs Arch Pharmacol. 2019 Nov;392(11):1455-1464. doi: 10.1007/s00210-019-01684-5. Epub 2019 Jul 9.


The serotonergic 5-HT1A receptor is known to be involved in both impulsivity and anxiety-related behavior. Although anxiety and impulsivity are different constructs, it has been shown that anxiogenesis can result in impulsiveness. It is therefore important to determine if the 5-HT1A receptor is involved in the commission of impulsive actions independent of its effects on anxiety. The 5-HT1A agonist 8-OH-DPAT (0.0125-0.1 mg/kg subcutaneous) increased impulsive action at low doses, but decreased it at higher doses, on the novel paced variable consecutive number with discriminative stimulus task (VCN). Neither the 5-HT1A antagonist WAY 100,635 (0.2-1.2 mg/kg subcutaneous), nor the noradrenergic antagonist and pharmacological stressor yohimbine (1-2 mg/kg intraperitoneal) altered measures of impulsivity. Stress induced by yohimbine was sufficient to produce anxiety-like behavior in the elevated zero maze, confirming that the VCN task is a selective assay of impulsive action that is not affected by anxiety. We hypothesize that the biphasic effect of 8-OH-DPAT is due to actions on presynaptic raphe 5-HT1A autoreceptors, and also postsynaptic 5-HT1A receptors. These results suggest that this receptor mediates impulsive action and that this is not secondary to its role in anxiety.

Keywords: 5-HT1A receptors; Anxiety; Norepinephrine; Operant; Serotonin; Stress.

MeSH terms

  • 8-Hydroxy-2-(di-n-propylamino)tetralin / pharmacology*
  • Animals
  • Anxiety / metabolism*
  • Anxiety / psychology
  • Autoreceptors / drug effects
  • Autoreceptors / metabolism
  • Behavior, Animal / drug effects*
  • Discrimination, Psychological / drug effects
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Impulsive Behavior / drug effects*
  • Male
  • Piperazines / pharmacology
  • Pyridines / pharmacology
  • Raphe Nuclei / drug effects
  • Raphe Nuclei / metabolism
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT1A / metabolism*
  • Serotonin 5-HT1 Receptor Agonists / pharmacology*
  • Yohimbine / pharmacology


  • Autoreceptors
  • Piperazines
  • Pyridines
  • Serotonin 5-HT1 Receptor Agonists
  • Receptor, Serotonin, 5-HT1A
  • Yohimbine
  • N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
  • 8-Hydroxy-2-(di-n-propylamino)tetralin