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Attenuation of nicotine-taking and nicotine-seeking behavior by the mGlu2 receptor positive allosteric modulators AZD8418 and AZD8529 in rats

Abstract

Rationale

Numerous medication development strategies seek to decrease nicotine consumption and prevent relapse to tobacco smoking by blocking glutamate transmission. Decreasing glutamate release by activating presynaptic inhibitory metabotropic glutamate (mGlu)2/3 receptors inhibits the reinforcing effects of nicotine and blocks cue-induced reinstatement of nicotine-seeking behavior in rats. However, the relative contribution of mGlu2 receptors in nicotine dependence is still unknown.

Objectives

The present study evaluated the role of mGlu2 receptors in nicotine-taking and nicotine-seeking behavior using the novel, relatively selective mGlu2 positive allosteric modulators (PAMs) AZD8418 and AZD8529.

Results

Acute treatment with AZD8418 (0.37, 1.12, 3.73, 7.46, and 14.92 mg/kg) and AZD8529 (1.75, 5.83, 17.5, and 58.3 mg/kg) deceased nicotine self-administration and had no effect on food-maintained responding. Chronic treatment with AZD8418 attenuated nicotine self-administration, but tolerance to this effect developed quickly. The inhibition of nicotine self-administration by chronic AZD8529 administration persisted throughout the 14 days of treatment. Chronic treatment with either PAMs inhibited food self-administration. AZD8418 (acute) and AZD8529 (acute and subchronic) blocked cue-induced reinstatement of nicotine- and food-seeking behavior.

Conclusions

These findings indicate an important role for mGlu2 receptors in the reinforcing properties of self-administered nicotine and the motivational impact of cues that were previously associated with nicotine administration (i.e., cue-induced reinstatement of nicotine-seeking behavior). Thus, mGlu2 PAMs may be useful medications to assist people to quit tobacco smoking and prevent relapse.

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Acknowledgments

The authors would like to thank Mr. Michael Arends for his outstanding editorial assistance. This work was funded by a research contract from AstraZeneca to AM and grant R56DA011946 from the National Institute on Drug Abuse to AM.

Conflict of interest

Athina Markou has received contract research support from AstraZeneca and Forest Laboratories and an honorarium from AbbVie, Germany, during the last 3 years. Alan Cross is an employee of AstraZeneca. James Doherty was an employee of AstraZeneca and is an employee of Sage Therapeutics. Dr. Markou has a patent on the use of metabotropic glutamate compounds for the treatment of nicotine dependence. The remaining authors report no financial conflicts of interest.

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Correspondence to Athina Markou.

Additional information

Xia Li, Manoranjan S. D’Souza and Ana M. Niño contributed equally to this work.

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Li, X., D’Souza, M.S., Niño, A.M. et al. Attenuation of nicotine-taking and nicotine-seeking behavior by the mGlu2 receptor positive allosteric modulators AZD8418 and AZD8529 in rats. Psychopharmacology 233, 1801–1814 (2016). https://doi.org/10.1007/s00213-016-4220-2

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  • DOI: https://doi.org/10.1007/s00213-016-4220-2

Keywords

  • Metabotropic glutamate receptor
  • Nicotine
  • Self-administration
  • Reinstatement
  • Chronic treatment