The adenosine A2A antagonist MSX-3 reverses the effects of the dopamine antagonist haloperidol on effort-related decision making in a T-maze cost/benefit procedure

Psychopharmacology (Berl). 2009 May;204(1):103-12. doi: 10.1007/s00213-008-1441-z. Epub 2009 Jan 9.


Rationale: Mesolimbic dopamine (DA) is a critical component of the brain circuitry regulating behavioral activation and effort-related processes. Research involving choice tasks has shown that rats with impaired DA transmission reallocate their instrumental behavior away from food-reinforced tasks with high response requirements and instead select less effortful food-seeking behaviors.

Objective: Previous work showed that adenosine A(2A) antagonism can reverse the effects of the DA antagonist haloperidol in an operant task that assesses effort-related choice. The present work used a T-maze choice procedure to assess the effects of adenosine A(2A) and A(1) antagonism.

Materials and methods: With this task, the two arms of the maze have different reinforcement densities (four vs. two food pellets), and a vertical 44 cm barrier is positioned in the arm with the higher density, presenting the animal with an effort-related challenge. Untreated rats strongly prefer the arm with the high density of food reward and climb the barrier in order to obtain the food.

Results: Haloperidol produced a dose-related (0.05-0.15 mg/kg i.p.) reduction in the number of trials in which the rats chose the high-barrier arm. Co-administration of the adenosine A(2A) receptor antagonist MSX-3 (0.75, 1.5, and 3.0 mg/kg i.p.), but not the A(1) antagonist 8-cyclopentyl-1,3-dipropylxanthine (0.75, 1.5, and 3.0 mg/kg i.p.), reversed the effects of haloperidol on effort-related choice and latency.

Conclusions: Adenosine A(2A) and D2 receptors interact to regulate effort-related decision making, which may have implications for the treatment of psychiatric symptoms such as psychomotor slowing or anergia that can be observed in depression, parkinsonism, and other disorders.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine A1 Receptor Antagonists
  • Adenosine A2 Receptor Antagonists*
  • Animals
  • Behavior, Animal / drug effects
  • Choice Behavior / drug effects*
  • Conditioning, Operant / drug effects
  • Dopamine Antagonists / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Haloperidol / pharmacology*
  • Male
  • Maze Learning / physiology*
  • Motivation
  • Nucleus Accumbens / drug effects
  • Physical Exertion / drug effects
  • Psychomotor Performance / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Adenosine A1 / metabolism
  • Receptors, Adenosine A2 / metabolism
  • Reinforcement Schedule
  • Xanthines / pharmacology*


  • Adenosine A1 Receptor Antagonists
  • Adenosine A2 Receptor Antagonists
  • Dopamine Antagonists
  • MSX 3 compound
  • Receptor, Adenosine A1
  • Receptors, Adenosine A2
  • Xanthines
  • 1,3-dipropyl-8-cyclopentylxanthine
  • Haloperidol