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Evidence for improved performance in cognitive tasks following selective NR2B NMDA receptor antagonist pre-treatment in the rat

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Abstract

Rationale

We previously reported that the NR2B subunit-selective N-methyl-d-aspartate (NMDA) antagonist Ro 63-1908 produced a marked deficit in response control in the five-choice serial reaction time task (5-CSRTT).

Objectives

The present studies were designed to investigate this further by studying the NR2B NMDA antagonists, ifenprodil, traxoprodil (CP101,606), Ro 25-6981 as well as Ro 63-1908 in this test.

Methods

Following training in the 5-CSRTT, separate groups of rats were either tested under (1) standard test conditions [5 s inter-trial interval (ITI), 0.5 s stimulus duration, 100 trials], (2) high (3 s ITI) and low (10 s ITI) event rate of stimulus presentation and (3) a 250-trial protocol in aged 2-year-old rats. In a final study, the effects of traxoprodil were investigated in an operant delayed match to position (DMTP) task, a test of working memory, and compared to dizocilpine and Ro 63-1908.

Results

Similar to Ro 63-1908, both traxoprodil (1–10 mg/kg) and Ro 25-6981 (3–30 mg/kg) increased premature responding but also increased response speed with no error trade-off. Conversely, ifenprodil (1–10 mg/kg) slowed response speed and increased omissions with no effect on premature responding. Tested under a variable ITI, Ro 63-1908 (1 mg/kg) increased premature responding at all ITIs, but this change was proportional to controls. At short ITI (3 s), Ro 63-1908 reliably improved performance both in terms of response speed and accuracy (percent correct). In a 250-trial protocol in aged rats, both Ro 63-1908 (0.1–0.3 mg/kg) and, particularly, traxoprodil (1–3 mg/kg) improved performance—increasing response speed and increasing the number of rewards earned during test. Finally, traxoprodil (1–10 mg/kg) improved accuracy and increased response speed in the DMTP task.

Conclusions

The present studies support the view that selective NR2B NMDA antagonists promote impulsive-type responding in the 5-CSRTT; however, under certain test conditions, drugs of this class—notably traxoprodil—may also improve task performance.

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  1. Guy A. Higgins

    Present address: NPS Pharmaceuticals, 300 Interpace Parkway, Parsippany, NJ, 07054, USA

  2. John A. Kemp

    Present address: Evotec Neurosciences GmbH, Schnackenburgallee 114, 22525, Hamburg, Germany

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  1. PRBN, F. Hoffmann-La Roche Ltd., Basel, Switzerland

    Guy A. Higgins, Theresa M. Ballard, Michel Enderlin, Marie Haman & John A. Kemp

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Correspondence to Guy A. Higgins.

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Higgins, G.A., Ballard, T.M., Enderlin, M. et al. Evidence for improved performance in cognitive tasks following selective NR2B NMDA receptor antagonist pre-treatment in the rat. Psychopharmacology 179, 85–98 (2005). https://doi.org/10.1007/s00213-005-2203-9

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