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The novel α7 nicotinic acetylcholine receptor agonist EVP-6124 enhances dopamine, acetylcholine, and glutamate efflux in rat cortex and nucleus accumbens

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Abstract

Background

Alpha7 and α4β2 nicotinic acetylcholine receptor (nAChR) agonists have been shown to improve cognition in various animal models of cognitive impairment and are of interest as treatments for schizophrenia, Alzheimer’s disease, and other cognitive disorders. Increased release of dopamine (DA), acetylcholine (ACh), glutamate (Glu), and γ-aminobutyric acid (GABA) in cerebral cortex, hippocampus, and nucleus accumbens (NAC) has been suggested to contribute to their beneficial effects on cognition.

Results

Using in vivo microdialysis, we found that EVP-6124 [(R)-7-chloro-N-quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide], a high-affinity α7 nAChR partial agonist, at 0.1 mg/kg, s.c., increased DA efflux in the medial prefrontal cortex (mPFC) and NAC. EVP-6124, 0.1 and 0.3 mg/kg, also increased efflux of ACh in the mPFC but not in the NAC. Similarly, EVP-6124, 0.1 mg/kg, but not 0.03 and 0.3 mg/kg, significantly increased mPFC Glu efflux. Thus, EVP-6124 produced an inverted U-shaped curve for DA and Glu release, as previously reported for other α7 nAChR agonists. The three doses of EVP-6124 did not produce a significant effect on GABA efflux in either region. Pretreatment with the selective α7 nAChR antagonist, methyllycaconitine (MLA, 1.0 mg/kg), significantly blocked cortical DA and Glu efflux induced by EVP-6124 (0.1 mg/kg), suggesting that the effects of EVP-6124 on these neurotransmitters were due to α7 nAChR agonism. MLA only partially blocked the effects of EVP-6124 on ACh efflux in the mPFC.

Conclusion

These results suggest increased cortical DA, ACh, and Glu release, which may contribute to the ability of the α7 nAChR agonist, EVP-6124, to treat cognitive impairment and possibly other dimensions of psychopathology.

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Acknowledgments

This study was supported by FORUM Pharmaceuticals, Inc. The authors thank Dr. Karu Jayathilake at Vanderbilt University, Nashville, TN for his statistics support.

Conflicts of interest

Herbert Y. Meltzer is a stockholder of ACADIA and SureGene. He is, or has been, a consultant to ACADIA, Alkermes, Astellas, Boehringer Mannheim, Bristol Myers Squibb, BioLine Rx, Cephalon, Cypress, Dainippon Sumitomo, Eli Lilly, FORUM, Janssen, Lundbeck, Merck, Novartis, Ovation, Otsuka, Pfizer, Sunovion, Teva, and Valeant (BioVail); Dorothy G. Flood, Chaya Bhuvaneswaran, Dana Hilt, and Gerhard Koenig are employees of FORUM Pharmaceutical Inc.; Mei Huang and Anna R Felix do not have any conflicts of interests.

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  1. Mei Huang & Herbert Y. Meltzer

    Present address: Department of Psychiatry and Behavioral Science, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave., Ward Building 12-104, Chicago, IL, 60611, USA

Authors and Affiliations

  1. Division of Psychopharmacology, Vanderbilt University School of Medicine, Nashville, TN, 37212, USA

    Mei Huang, Anna R. Felix & Herbert Y. Meltzer

  2. FORUM Pharmaceuticals Inc., Watertown, MA, 02472, USA

    Dorothy G. Flood, Chaya Bhuvaneswaran, Dana Hilt & Gerhard Koenig

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  1. Mei Huang
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Correspondence to Herbert Y. Meltzer.

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Huang, M., Felix, A.R., Flood, D.G. et al. The novel α7 nicotinic acetylcholine receptor agonist EVP-6124 enhances dopamine, acetylcholine, and glutamate efflux in rat cortex and nucleus accumbens. Psychopharmacology 231, 4541–4551 (2014). https://doi.org/10.1007/s00213-014-3596-0

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