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

Abstract

RationaleProlinol aryl ethers and their rigidified analogues pyrrolidinyl benzodioxanes have a high affinity for mammalian a4β2 nicotinic acetylcholine receptors (nAChRs). Electrophysiological studies have shown that the former are full agonists and the latter partial agonists or antagonists of human a4β2 receptors, but their in vivo effects are unkown. Objectives and MethodsAs a4b2 nAChRs play an important role in 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. ResultsIn 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 doseresponse 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 [ 3 H]epibatidine receptors than [ 125 I]-aBungarotoxin 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 agonistinduced activities.

Modifications at C(5) of 2-(2-Pyrrolidinyl)-Substituted 1,4-Benzodioxane Elicit Potent α4β2 Nicotinic Acetylcholine Receptor Partial Agonism with High Selectivity over the α3β4 Subtype

“…Relying on these receptor architecture findings and on mutagenesis experiments aimed at defining residues governing receptor activation, we discuss here the ( S , S )/( S , R ) diastereomeric pairs 1 – 6 of pyrrolidinyl benzodioxanes, substituted at the 7-, 6-, and 5-benzodioxane positions (Chart ). We have designed them in the past few years starting from the unsubstituted lead N -methyl-2-(2-pyrrolidinyl)-1,4-benzodioxane ( S , R )- 7 , − a relatively rigid template endowed with moderate α4β2 affinity, some α4β2 versus α3β4 selectivity, and as recently reported, potent α4β2 antagonism, , in an effort to elicit α4β2 partial agonism character and to optimize α4β2/α3β4 selectivity (Chart ).…”

Nicotinic Antagonist UFR2709 Inhibits Nicotine Reward and Decreases Anxiety in Zebrafish

“…This paradigm has been successfully applied to zebrafish by other groups to study the effects of a variety of drugs of abuse, including cocaine, nicotine, ethanol, and D-amphetamine [13,[24][25][26][27]. In addition, it has been also applied to determine the effect of novel compounds/mechanisms with possible anti-addictive properties [28,29].…”

Towards Modeling Anhedonia and Its Treatment in Zebrafish

“…Indeed, as these fish display a rich behavioral repertoire with a wide range of reward-related behaviors ( Kalueff et al, 2013 ), reduced reward-seeking behavior can be readily assessed in zebrafish by quantifying their impaired reward-like behavior in CPP and hypophagia models ( Collier and Echevarria, 2013 ; Nguyen et al, 2014 a) ( Table 2 ). In both adult and larvae zebrafish, CPP models assess reward-like phenotypes ( Mathur and Guo, 2010 ; Mathur et al, 2011 ; Hinz et al, 2013 ; Collier et al, 2014 ; Braida et al, 2020 ), hence reflecting their potential to characterize experimentally induced anhedonia-like states as well. Zebrafish do develop CPP towards a wide range of reward stimuli, including food, warm temperature ( Rey et al, 2015 ), and various drugs, such as morphine, diazepam, fluoxetine, risperidone, and buspirone ( Lau et al, 2011 ; Abreu et al, 2016 ).…”

“…For example, male C57BL/6 mice exposed to chronic stress display reduced SP, a behavioral sign of anhedonia ( Strekalova et al, 2004 ). The right panel illustrates zebrafish CPP models developed to measure reward-like phenotypes, hence reflecting their potential to assess anhedonia ( Mathur and Guo, 2010 ; Mathur et al, 2011 ; Hinz et al, 2013 ; Collier et al, 2014 ; Braida et al, 2020 ). For example, zebrafish clearly prefer reward-associated CPP compartments (e.g., paired with morphine, diazepam, fluoxetine, risperidone, and buspirone) ( Lau et al, 2011 ; Abreu et al, 2016 ) and also offer several other behavioral tests assessing social phenotypes (relevant to social anhedonia) ( Pham et al, 2012 ; Ogi et al, 2021 ) as well as novelty-seeking behavior (novel object or environment exploration), also seen in rodent anhedonia models ( Strekalova et al, 2004 ), reflecting decreased exploration of novelty.…”