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Behavioural and pharmacological profiles of zebrafish administrated pyrrolidinyl benzodioxanes and prolinol aryl ethers with high affinity for heteromeric nicotinic acetylcholine receptors

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Abstract

Rationale

Prolinol aryl ethers and their rigidified analogues pyrrolidinyl benzodioxanes have a high affinity for mammalian α4β2 nicotinic acetylcholine receptors (nAChRs). Electrophysiological studies have shown that the former are full agonists and the latter partial agonists or antagonists of human α4β2 receptors, but their in vivo effects are unknown.

Objectives and methods

As α4β2 nAChRs play an important role in the cognition and the rewarding effects of nicotine, we tested the effects of two full agonists and one antagonist on spatial learning, memory and attention in zebrafish using a T-maze task and virtual object recognition test (VORT). The effect of a partial agonist in reducing nicotine-induced conditioned place preference (CPP) was also investigated.

Results

In comparison with the vehicle alone, the full agonists MCL-11 and MCL-28 induced a significant cognitive enhancement as measured by the reduced running time in the T-maze and increased attention as measured by the increased discrimination index in the VORT. MCL-11 was 882 times more potent than nicotine. The two compounds were characterised by an inverted U-shaped dose-response curve, and their effects were blocked by the co-administration of the antagonist MCL-117, which alone had no effect. The partial agonist MCL-54 induced CPP and had an inverted U-shaped dose-response curve similar to that of nicotine but blocked the reinforcing effect of co-administered nicotine. Binding studies showed that all of the compounds have a higher affinity for heteromeric [3H]-epibatidine receptors than [125I]-αBungarotoxin receptors. MCL-11 was the most selective of heteromeric receptors.

Conclusions

These behavioural studies indicate that full agonist prolinol aryl ethers are very active in increasing spatial learning, memory and attention in zebrafish. The benzodioxane partial agonist MCL-54 reduced nicotine-induced CPP, and the benzodioxane antagonist MCL-117 blocked all agonist-induced activities.

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Acknowledgements

We would like to thank Fondazione Zardi Gori for a grant to Luisa Ponzoni.

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Author notes

  1. Daniela Braida and Luisa Ponzoni contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy

    Daniela Braida, Milena Moretti, Paola Viani, Cecilia Gotti & Mariaelvina Sala

  2. CNR, Institute of Neuroscience, Via Vanvitelli 32, Milan, Italy

    Luisa Ponzoni, Milena Moretti, Cecilia Gotti & Mariaelvina Sala

  3. Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Milan, Italy

    Marco Pallavicini, Cristiano Bolchi, Rebecca Appiani & Francesco Bavo

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  1. Daniela Braida
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  2. Luisa Ponzoni
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  4. Paola Viani
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Correspondence to Cecilia Gotti.

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All of the experiments followed the ARRIVE guidelines and were approved by the National Ethics Committee for the care and use of laboratory animals and the National Ministry of Health (Italian Government Decree N° 513/2018PR).

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Braida, D., Ponzoni, L., Moretti, M. et al. Behavioural and pharmacological profiles of zebrafish administrated pyrrolidinyl benzodioxanes and prolinol aryl ethers with high affinity for heteromeric nicotinic acetylcholine receptors. Psychopharmacology 237, 2317–2326 (2020). https://doi.org/10.1007/s00213-020-05536-6

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