Impulsive action and impulsive choice are mediated by distinct neuropharmacological substrates in rat

Int J Neuropsychopharmacol. 2012 Nov;15(10):1473-87. doi: 10.1017/S1461145711001635. Epub 2011 Nov 18.

Abstract

Impulsivity is a heterogeneous construct according to clinical and preclinical behavioural measures and there is some preliminary evidence indicating distinct neurobiological substrates underlying the sub-components of impulsivity. Two preclinical assays, the five-choice serial reaction time task (5-CSRTT) and the delayed discounting task (DDT), are hypothesized to provide measures of impulsive action (premature responding) and impulsive choice (percent choice for delayed reward), respectively. In the present studies, we show that the norepinephrine reuptake inhibitor atomoxetine attenuated premature responding in the 5-CSRTT, but was ineffective in the DDT. The mixed dopamine/norepinephrine reuptake inhibitor methylphenidate exhibited an opposite profile of effects. In addition, blockade of 5-HT2A/C receptors via ketanserin decreased premature responding but had no effects on percent choice for delayed reward; blockade of 5-HT2C receptors via SB 242084 had opposite effects. Follow-up studies provided some limited evidence of additive effects of 5-HT2A/C receptor blockade on the effects of atomoxetine on impulsive action. These studies demonstrate dissociable profiles of stimulant vs. non-stimulant attention deficit hyperactivity disorder medications and 5-HT subtype-selective ligands, in the 5-CSRTT and DDT assays. Thus, the present findings support the sub-categorization of impulsivity and suggest that 5-HT receptor subtype-selective antagonists may provide therapeutic targets for disorders characterized by different forms of impulsivity.

MeSH terms

  • Adrenergic Uptake Inhibitors / pharmacology*
  • Adrenergic Uptake Inhibitors / therapeutic use
  • Aminopyridines / pharmacology
  • Aminopyridines / therapeutic use
  • Animals
  • Atomoxetine Hydrochloride
  • Choice Behavior / drug effects*
  • Choice Behavior / physiology
  • Dopamine Uptake Inhibitors / pharmacology*
  • Dopamine Uptake Inhibitors / therapeutic use
  • Impulsive Behavior / drug therapy*
  • Impulsive Behavior / physiopathology
  • Impulsive Behavior / psychology
  • Indoles / pharmacology
  • Indoles / therapeutic use
  • Ketanserin / pharmacology
  • Ketanserin / therapeutic use
  • Male
  • Methylphenidate / pharmacology
  • Methylphenidate / therapeutic use
  • Propylamines / pharmacology
  • Propylamines / therapeutic use
  • Rats
  • Rats, Long-Evans
  • Reaction Time / drug effects*
  • Reaction Time / physiology
  • Serotonin 5-HT2 Receptor Antagonists / pharmacology*
  • Serotonin 5-HT2 Receptor Antagonists / therapeutic use

Substances

  • 6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline
  • Adrenergic Uptake Inhibitors
  • Aminopyridines
  • Dopamine Uptake Inhibitors
  • Indoles
  • Propylamines
  • Serotonin 5-HT2 Receptor Antagonists
  • Methylphenidate
  • Atomoxetine Hydrochloride
  • Ketanserin
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