Cotinine antagonizes the behavioral effects of nicotine exposure in the planarian Girardia tigrina

Abstract

Nicotine is one of the most addictive drugs abused by humans. Our laboratory and others have demonstrated that nicotine decreases motility and induces seizure-like behavior in planarians (pSLM, which are vigorous writhing and bending of the body) in a concentration-dependent manner. Nicotine also induces withdrawal-like behaviors in these worms. Cotinine is the major nicotine metabolite in humans, although it is not the final product of nicotine metabolism. Cotinine is mostly inactive in vertebrate nervous systems and is currently being explored as a molecule which possess most of nicotine’s beneficial effects and few of its undesirable ones. It is not known whether cotinine is a product of nicotine metabolism in planarians. We found that cotinine by itself does not seem to elicit any behavioral effects in planarians up to a concentration of 1 mM. We also show that cotinine antagonizes the aforementioned nicotine-induced motility decrease and also decreases the expression of nicotine-induced pSLMs in a concentration-dependent manner. Also cotinine prevents the manifestation of some of the withdrawal-like behaviors induced by nicotine in our experimental organism. Thus, we obtained evidence supporting that cotinine antagonizes nicotine in this planarian species. Possible explanations include competitive binding of both compounds at overlapping binding sites, at different nicotinic receptor subtypes, or maybe allosteric interactions.

Measuring functional brain recovery in regenerating planarians by assessing the behavioral response to the cholinergic compound cytisine

“…This behavioral response has also been referred to as a C-like hyperkinesia (Palladini et al, 1996;Pagán et al, 2008) and is expressed as a series of sudden contractions/twitches of the anterior section while the tail is usually anchored to the bottom of the container, as opposed to the passive gliding that these animals normally display (please see Supplementary Video 1). pSLMs are easily quantified visually, are concentration-dependent, and have been used to document the behavioral effects of a variety of psychoactive agents, including cocaine, nicotine, and opiates, among other compounds (Bach et al, 2016;Bezerra da Silva et al, 2016;Pagán et al, 2008Pagán et al, , 2012Pagán et al, , 2013Pagán et al, , 2015Raffa and Rawls, 2008;Ramakrishnan and Desaer, 2011;Ramakrishnan et al, 2013;Ramoz et al, 2012, Rawls et al, 2009Tallarida et al, 2014).…”

Towards High-Throughput Chemobehavioural Phenomics in Neuropsychiatric Drug Discovery

“…They also exhibit learning and memory behaviours that can be altered following exposure to drugs affecting neural transmission [38,92,104]. For instance, when exposed to different addictive substances, including psychostimulant drugs, planarians display stereotyped mammalian-like behavioural responses including abstinence-induced withdrawal and anxiogenic-like response [108,109,110]. Both planarian phototactic as well as environmental place conditioning (EPC) behaviours were shown to be successful in studies of drug-seeking or anxiolytic-type phenotypes.…”

Surprising Separation of Cannabinoid Physical Dependence and Withdrawal in an Invertebrate Model

“…Planarians also have neurotransmitter systems similar (or analogous) to higher organisms [1]. Although planarians are established as an invertebrate model in regeneration, pharmacologists have used the model to study behavioral changes elicited by abused compounds [2] [3] [4] [5] [6]. Raffa and colleagues developed a quantitative method for measuring planarian locomotor activity [7] and applying the metric to phenomena related to drug use/abuse such as the development of physical dependence and withdrawal [8] [9] [10].…”