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The alpha-7 nicotinic receptor partial agonist/5-HT3 antagonist RG3487 enhances cortical and hippocampal dopamine and acetylcholine release

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Abstract

Rationale

Alpha-7 nicotinic acetylcholine receptor (nAChR) agonists may ameliorate cognitive deficits in schizophrenia, in part, because of their ability to enhance dopaminergic and cholinergic neurotransmission.

Objectives

In the current study, the effects of partial nAChR agonist and 5-HT3 receptor antagonist RG3487 (previously R3487/MEM3454) on dopamine (DA) and acetylcholine (ACh) effluxes in rat prefrontal cortex (mPFC) and hippocampus (HIP) were investigated in awake, freely moving rats.

Results

R3487/MEM3454, at doses of 0.1–10 mg/kg, s.c., enhanced DA and ACh effluxes in rat mPFC and (HIP), with a peak effect at 0.3- to 0.6-mg/kg doses, producing a bell-shaped dose–response curve. Pretreatment with the selective nAChR antagonist, methyllycaconitine (1.0 mg/kg), completely blocked RG3487-induced (0.45 mg/kg) DA but not ACh efflux, while the selective 5-HT3 receptor agonist 1-(m-chlorophenyl)-biguanide (1.0 mg/kg) partially inhibited cortical ACh but not DA efflux. RG3487 (0.45 mg/kg) combined with atypical antipsychotic drug (APD) risperidone (0.1 mg/kg), but not typical APD haloperidol (0.1 mg/kg), induced a significantly greater increase in HIP ACh efflux. Their combined effect on DA efflux was additive. RG3487, combined with other atypical APDs, namely aripiprazole (0.3 mg/kg), olanzapine (1.0 mg/kg), and quetiapine (30 mg/kg), also produced additive effects on DA efflux.

Conclusions

These results suggest that RG3487 enhances DA efflux by nAChR stimulation, whereas ACh efflux is primarily mediated via 5-HT3 receptor antagonism, and that RG3487 alone or as augmentation may improve cognitive impairment in schizophrenia.

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Abbreviations

Ach:

acetylcholine

APD:

antipsychotic drug

CPBG:

1-(m-chlorophenyl)-biguanide

DA:

dopamine

HIP:

hippocampus

mPFC:

medial prefrontal cortex

MLA:

methyllycaconitine

NAC:

nucleus accumbens

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Conflict of interest

This is supported, in part, by grants from Memory/Roche Pharmaceuticals. Huang, Felix, and Kwon have no conflict of interest to declare. Lowe, Wallace, and Santarelli are employees of Roche. HYM is a consultant to Astra Zeneca, Eli Lilly, Janssen, Memory, Roche and is a grantee of Bristol Myers Squibb, Eli Lilly, Janssen, Memory, Pifzer, and Roche.

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

    Mei Huang, Sunoh Kwon & Herbert Y Meltzer

  3. Functional Neuroscience, Memory Pharmaceutical Corporation, Montvale, NJ, 07645, USA

    David Lowe, Tanya Wallace & Luca Santarelli

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  1. Mei Huang
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  2. Anna R Felix
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  3. Sunoh Kwon
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  4. David Lowe
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  5. Tanya Wallace
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  6. Luca Santarelli
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  7. Herbert Y Meltzer
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Correspondence to Herbert Y Meltzer.

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Huang, M., Felix, A.R., Kwon, S. et al. The alpha-7 nicotinic receptor partial agonist/5-HT3 antagonist RG3487 enhances cortical and hippocampal dopamine and acetylcholine release. Psychopharmacology 231, 2199–2210 (2014). https://doi.org/10.1007/s00213-013-3373-5

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