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The mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) potentiates PCP-induced cognitive deficits in rats

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Abstract

Rationale

Recent studies have shown that metabotropic glutamate receptor 5 (mGluR5) can modulate N-methyl-d-aspartate (NMDA) receptor function in vivo. For example, the mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP) can potentiate PCP (phencyclidine)-evoked hyperactivity and PCP-induced disruptions in pre-pulse inhibition (PPI) in rats.

Objective

To extend these previous behavioral findings and determine whether the mGluR5 antagonist MPEP can modulate the disruptions in learning and memory induced by PCP in rats.

Methods

The effects of MPEP, alone and in combination with PCP, were evaluated in rats trained to perform a repeated acquisition procedure (learning) or a delayed non-matching to position (DNMTP) radial maze task (spatial memory).

Results

In the repeated acquisition task, MPEP (0–10 mg/kg, IP) dose-dependently decreased response rates but had no effect on response accuracy. In contrast, PCP (0.625–1.25 mg/kg, SC) reduced response rate and response accuracy in a dose-dependent manner. Although MPEP (10 mg/kg, IP) had no effect when administered alone, the mGluR5 antagonist potentiated the disruptions in learning induced by a low dose of PCP (0.625 mg/kg, SC). In the DNMTP maze task, MPEP (0–10 mg/kg, IP) had no effect on spatial memory, whereas PCP (1.25–2.5 mg/kg, SC) produced a dose-dependent disruption. MPEP (10 mg/kg, IP) potentiated the impairments in memory induced by PCP (1.25 mg/kg, SC).

Conclusion

The mGluR5 antagonist, MPEP, potentiated the disruptions in learning and memory induced by PCP. These behavioral data extend previous behavioral findings and further suggest that mGluR5 can modulate NMDA receptor function in vivo.

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Authors and Affiliations

  1. Department of Pharmacology, Merck Research Laboratories, MRLSDB1, 3535 General Atomics Court, San Diego, CA, 92121, USA

    Una C. Campbell, Kush Lalwani, Lisa Hernandez & Linda J. Bristow

  2. Department of Neuroscience, Merck Research Laboratories, West Point, PA, 19486, USA

    Gene G. Kinney

  3. Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, 37232-6600, USA

    P. Jeffrey Conn

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  1. Una C. Campbell
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  2. Kush Lalwani
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  3. Lisa Hernandez
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  4. Gene G. Kinney
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  5. P. Jeffrey Conn
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  6. Linda J. Bristow
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Correspondence to Una C. Campbell.

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Campbell, U.C., Lalwani, K., Hernandez, L. et al. The mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) potentiates PCP-induced cognitive deficits in rats. Psychopharmacology 175, 310–318 (2004). https://doi.org/10.1007/s00213-004-1827-5

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  • DOI: https://doi.org/10.1007/s00213-004-1827-5

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