Stimulant effects of adenosine antagonists on operant behavior

Differential actions of selective A2A and A1 antagonists

Patrick Arthur Randall, Eric J. Nunes, Simone L. Janniere, Colin M. Stopper, Andrew M. Farrar, Thomas N. Sager, Younis Baqi, Jörg Hockemeyer, Christa E. Müller, John D. Salamone

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Rationale: Adenosine A2A antagonists can reverse many of the behavioral effects of dopamine antagonists, including actions on instrumental behavior. However, little is known about the effects of selective adenosine antagonists on operant behavior when these drugs are administered alone. Objective: The present studies were undertaken to investigate the potential for rate-dependent stimulant effects of both selective and nonselective adenosine antagonists. Methods: Six drugs were tested: two nonselective adenosine antagonists (caffeine and theophylline), two adenosine A1 antagonists (DPCPX and CPT), and two adenosine A2A antagonists (istradefylline (KW6002) and MSX-3). Two schedules of reinforcement were employed; a fixed interval 240-s (FI-240 sec) schedule was used to generate low baseline rates of responding and a fixed ratio 20 (FR20) schedule generated high rates. Results: Caffeine and theophylline produced rate-dependent effects on lever pressing, increasing responding on the FI-240 sec schedule but decreasing responding on the FR20 schedule. The A2A antagonists MSX-3 and istradefylline increased FI-240 sec lever pressing but did not suppress FR20 lever pressing in the dose range tested. In fact, there was a tendency for istradefylline to increase FR20 responding at a moderate dose. A1 antagonists failed to increase lever pressing rate, but DPCPX decreased FR20 responding at higher doses. Conclusions: These results suggest that adenosine A2A antagonists enhance operant response rates, but A1 antagonists do not. The involvement of adenosine A2A receptors in regulating aspects of instrumental response output and behavioral activation may have implications for the treatment of effort-related psychiatric dysfunctions, such as psychomotor slowing and anergia in depression.

Original languageEnglish (US)
Pages (from-to)173-186
Number of pages14
JournalPsychopharmacology
Volume216
Issue number2
DOIs
StatePublished - Jul 1 2011

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Adenosine
Appointments and Schedules
Theophylline
Caffeine
Adenosine A2A Receptors
Reinforcement Schedule
Dopamine Antagonists
Pharmaceutical Preparations
Psychiatry
Depression
istradefylline

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Randall, Patrick Arthur ; Nunes, Eric J. ; Janniere, Simone L. ; Stopper, Colin M. ; Farrar, Andrew M. ; Sager, Thomas N. ; Baqi, Younis ; Hockemeyer, Jörg ; Müller, Christa E. ; Salamone, John D. / Stimulant effects of adenosine antagonists on operant behavior : Differential actions of selective A2A and A1 antagonists. In: Psychopharmacology. 2011 ; Vol. 216, No. 2. pp. 173-186.
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title = "Stimulant effects of adenosine antagonists on operant behavior: Differential actions of selective A2A and A1 antagonists",
abstract = "Rationale: Adenosine A2A antagonists can reverse many of the behavioral effects of dopamine antagonists, including actions on instrumental behavior. However, little is known about the effects of selective adenosine antagonists on operant behavior when these drugs are administered alone. Objective: The present studies were undertaken to investigate the potential for rate-dependent stimulant effects of both selective and nonselective adenosine antagonists. Methods: Six drugs were tested: two nonselective adenosine antagonists (caffeine and theophylline), two adenosine A1 antagonists (DPCPX and CPT), and two adenosine A2A antagonists (istradefylline (KW6002) and MSX-3). Two schedules of reinforcement were employed; a fixed interval 240-s (FI-240 sec) schedule was used to generate low baseline rates of responding and a fixed ratio 20 (FR20) schedule generated high rates. Results: Caffeine and theophylline produced rate-dependent effects on lever pressing, increasing responding on the FI-240 sec schedule but decreasing responding on the FR20 schedule. The A2A antagonists MSX-3 and istradefylline increased FI-240 sec lever pressing but did not suppress FR20 lever pressing in the dose range tested. In fact, there was a tendency for istradefylline to increase FR20 responding at a moderate dose. A1 antagonists failed to increase lever pressing rate, but DPCPX decreased FR20 responding at higher doses. Conclusions: These results suggest that adenosine A2A antagonists enhance operant response rates, but A1 antagonists do not. The involvement of adenosine A2A receptors in regulating aspects of instrumental response output and behavioral activation may have implications for the treatment of effort-related psychiatric dysfunctions, such as psychomotor slowing and anergia in depression.",
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Randall, PA, Nunes, EJ, Janniere, SL, Stopper, CM, Farrar, AM, Sager, TN, Baqi, Y, Hockemeyer, J, Müller, CE & Salamone, JD 2011, 'Stimulant effects of adenosine antagonists on operant behavior: Differential actions of selective A2A and A1 antagonists', Psychopharmacology, vol. 216, no. 2, pp. 173-186. https://doi.org/10.1007/s00213-011-2198-3

Stimulant effects of adenosine antagonists on operant behavior : Differential actions of selective A2A and A1 antagonists. / Randall, Patrick Arthur; Nunes, Eric J.; Janniere, Simone L.; Stopper, Colin M.; Farrar, Andrew M.; Sager, Thomas N.; Baqi, Younis; Hockemeyer, Jörg; Müller, Christa E.; Salamone, John D.

In: Psychopharmacology, Vol. 216, No. 2, 01.07.2011, p. 173-186.

Research output: Contribution to journalArticle

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T1 - Stimulant effects of adenosine antagonists on operant behavior

T2 - Differential actions of selective A2A and A1 antagonists

AU - Randall, Patrick Arthur

AU - Nunes, Eric J.

AU - Janniere, Simone L.

AU - Stopper, Colin M.

AU - Farrar, Andrew M.

AU - Sager, Thomas N.

AU - Baqi, Younis

AU - Hockemeyer, Jörg

AU - Müller, Christa E.

AU - Salamone, John D.

PY - 2011/7/1

Y1 - 2011/7/1

N2 - Rationale: Adenosine A2A antagonists can reverse many of the behavioral effects of dopamine antagonists, including actions on instrumental behavior. However, little is known about the effects of selective adenosine antagonists on operant behavior when these drugs are administered alone. Objective: The present studies were undertaken to investigate the potential for rate-dependent stimulant effects of both selective and nonselective adenosine antagonists. Methods: Six drugs were tested: two nonselective adenosine antagonists (caffeine and theophylline), two adenosine A1 antagonists (DPCPX and CPT), and two adenosine A2A antagonists (istradefylline (KW6002) and MSX-3). Two schedules of reinforcement were employed; a fixed interval 240-s (FI-240 sec) schedule was used to generate low baseline rates of responding and a fixed ratio 20 (FR20) schedule generated high rates. Results: Caffeine and theophylline produced rate-dependent effects on lever pressing, increasing responding on the FI-240 sec schedule but decreasing responding on the FR20 schedule. The A2A antagonists MSX-3 and istradefylline increased FI-240 sec lever pressing but did not suppress FR20 lever pressing in the dose range tested. In fact, there was a tendency for istradefylline to increase FR20 responding at a moderate dose. A1 antagonists failed to increase lever pressing rate, but DPCPX decreased FR20 responding at higher doses. Conclusions: These results suggest that adenosine A2A antagonists enhance operant response rates, but A1 antagonists do not. The involvement of adenosine A2A receptors in regulating aspects of instrumental response output and behavioral activation may have implications for the treatment of effort-related psychiatric dysfunctions, such as psychomotor slowing and anergia in depression.

AB - Rationale: Adenosine A2A antagonists can reverse many of the behavioral effects of dopamine antagonists, including actions on instrumental behavior. However, little is known about the effects of selective adenosine antagonists on operant behavior when these drugs are administered alone. Objective: The present studies were undertaken to investigate the potential for rate-dependent stimulant effects of both selective and nonselective adenosine antagonists. Methods: Six drugs were tested: two nonselective adenosine antagonists (caffeine and theophylline), two adenosine A1 antagonists (DPCPX and CPT), and two adenosine A2A antagonists (istradefylline (KW6002) and MSX-3). Two schedules of reinforcement were employed; a fixed interval 240-s (FI-240 sec) schedule was used to generate low baseline rates of responding and a fixed ratio 20 (FR20) schedule generated high rates. Results: Caffeine and theophylline produced rate-dependent effects on lever pressing, increasing responding on the FI-240 sec schedule but decreasing responding on the FR20 schedule. The A2A antagonists MSX-3 and istradefylline increased FI-240 sec lever pressing but did not suppress FR20 lever pressing in the dose range tested. In fact, there was a tendency for istradefylline to increase FR20 responding at a moderate dose. A1 antagonists failed to increase lever pressing rate, but DPCPX decreased FR20 responding at higher doses. Conclusions: These results suggest that adenosine A2A antagonists enhance operant response rates, but A1 antagonists do not. The involvement of adenosine A2A receptors in regulating aspects of instrumental response output and behavioral activation may have implications for the treatment of effort-related psychiatric dysfunctions, such as psychomotor slowing and anergia in depression.

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