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Molecular vibrations and quantum tunneling may link ligand binding to the function of pharmacological receptors. The well‐established lock‐and‐key model explains a ligand's binding and recognition by a receptor; however, a general mechanism by which receptors translate binding into activation, inactivation, or modulation remains elusive. The Vibration Theory of Olfaction was proposed in the 1930s to explain this subset of receptor‐mediated phenomena by correlating odorant molecular vibrations to smell, but a mechanism was lacking. In the 1990s, inelastic electron tunneling was proposed as a plausible mechanism for translating molecular vibration to odorant physiology. More recently, studies of ligands' vibrational spectra and the use of deuterated ligand analogs have provided helpful information to study this admittedly controversial hypothesis in metabotropic receptors other than olfactory receptors. In the present work, based in part on published experiments from our laboratory using planarians as an experimental organism, I will present a rationale and possible experimental approach for extending this idea to ligand‐gated ion channels. [ABSTRACT FROM AUTHOR]

One of the most important aspects of the scientific endeavour is the definition of specific concepts as precisely as possible. However, it is also important not to lose sight of two facts: (i) we divide the study of nature into manageable parts in order to better understand it owing to our limited cognitive capacities and (ii) definitions are inherently arbitrary and heavily influenced by cultural norms, language, the current political climate, and even personal preferences, among many other factors. As a consequence of these facts, clear-cut definitions, despite their evident importance, are oftentimes quite difficult to formulate. One of the most illustrative examples about the difficulty of articulating precise scientific definitions is trying to define the concept of a brain. Even though the current thinking about the brain is beginning to take into account a variety of organisms, a vertebrocentric bias still tends to dominate the scientific discourse about this concept. Here I will briefly explore the evolution of our 'thoughts about the brain', highlighting the difficulty of constructing a universally (or even a generally) accepted formal definition of it and using planarians as one of the earliest examples of organisms proposed to possess a 'traditional', vertebrate-style brain. I also suggest that the time is right to attempt to expand our view of what a brain is, going beyond exclusively structural and taxa-specific criteria. Thus, I propose a classification that could represent a starting point in an effort to expand our current definitions of the brain, hopefully to help initiate conversations leading to changes of perspective on how we think about this concept. This article is part of the theme issue 'Liquid brains, solid brains: How distributed cognitive architectures process information'. [ABSTRACT FROM AUTHOR]

Combinatorially synthesized nucleotide polymers have been used during the last decade to find ligands that bind to specific sites on biological molecules, including membrane-bound proteins such as the nicotinic acetylcholine receptors (nAChRs). The neurotransmitter receptors belong to a group of four structurally related proteins that regulate signal transmission between ~10(11) neurons of the mammalian nervous system. The nAChRs are inhibited by compounds such as the anticonvulsant MK-801 [(+)-dizocilpine] and abused drugs such as cocaine. Based on predictions arising from the mechanism of receptor inhibition by MK-801 and cocaine, we developed two classes of RNA aptamers: class I members, which inhibit the nAChR, and class II members, which alleviate inhibition of the receptor by MK-801 and cocaine. The systematic evolution of ligands by the exponential enrichment (SELEX) method was used to obtain these compounds. Here, we report that we have truncated RNA aptamers in each class to determine the minimal nucleic acid sequence that retains the characteristic function for which the aptamer was originally selected. We demonstrate that a truncated class I aptamer containing a sequence of seven nucleotides inhibits the nAChR and that a truncated class II aptamer containing a sequence of only four nucleotides can alleviate MK-801 inhibition. [ABSTRACT FROM AUTHOR]

Abstract: Nicotinic acetylcholine receptors (AChRs) are pentameric proteins that form agonist-gated cation channels through the plasma membrane. AChR agonists and antagonists are potential candidates for the treatment of neurodegenerative diseases. Cembranoids are naturally occurring diterpenoids that contain a 14-carbon ring. These diterpenoids interact with AChRs in complex ways: as irreversible inhibitors at the agonist sites, as noncompetitive inhibitors, or as positive modulators, but no cembranoid was ever shown to have agonistic activity on AChRs. The cembranoid eupalmerin acetate displays positive modulation of agonist-induced currents in the muscle-type AChR and in the related gamma-aminobutyric acid (GABA) type A receptor. Moreover, cembranoids display important biological effects, many of them mediated by nicotinic receptors. Cembranoids from tobacco are neuroprotective through a nicotinic anti-apoptotic mechanism preventing excitotoxic neuronal death which in part could result from anti-inflammatory properties of cembranoids. Moreover, tobacco cembranoids also have anti-inflammatory properties which could enhance their neuroprotective properties. Cembranoids from tobacco affect nicotine-related behavior: they increase the transient initial ataxia caused by first nicotine injection into naive rats and inhibit the expression of locomotor sensitization to repeated injections of nicotine. In addition, cembranoids are known to act as anti-tumor compounds. In conclusion, cembranoids provide a promising source of lead drugs for many clinical areas, including neuroprotection, smoking-cessation, and anti-cancer therapies. [Copyright &y& Elsevier]

Abstract: Using an adaptation of published behavioral protocols, we determined that acute exposure to the cholinergic compounds nicotine and carbamylcholine decreased planarian motility in a concentration-dependent manner. A tobacco cembranoid (1S,2E,4R,6R,7E,11E)-cembra-2,7,11-triene-4,6-diol (4R-cembranoid), also decreased planarian motility. Experiments in the presence of 1 µM 4R-cembranoid did increase the IC50 for nicotine- but not carbamylcholine-induced decrease in planarian motility. When planarians were exposed for 24 h to either nicotine or carbamylcholine at concentrations near their respective IC50 values and then transferred to plain media, nicotine-exposed, but not carbamylcholine- or cembranoid-exposed worms displayed withdrawal-like distress behaviors. In experiments where planarians were pre-exposed to 100 µM nicotine for 24 h in the presence of 1 µM 4R-cembranoid, the withdrawal-like effects were significantly reduced. These results indicate that the 4R-cembranoid might have valuable applications for tobacco abuse research. This experimental approach using planarians is useful for the initial screening of compounds relevant to drug abuse and dependence. [Copyright &y& Elsevier]

Abstract: Here we report the prevention and reversal of cocaine-induced behaviors in planarian worms by parthenolide and two related cyclic sesquiterpene lactones (SL), costunolide and santonin. Using established protocols, we studied two cocaine-induced behavioral effects in planaria; the induction of motility decrease and the induction of C-like hyperkinesia. Cocaine, parthenolide, costunolide, santonin, and a lactone-less cyclic sesquiterpene, β-eudesmol, decreased planarian motility in a concentration-dependent manner. Only cocaine induced C-like hyperkinesia. At concentrations that did not show any motility decrease, partenolide, costunolide and santonin, but not β-eudesmol, significantly reduced the cocaine-induced motility decrease and C-like hyperkinesia, in a concentration-dependent manner. Furthermore, partenolide, costunolide and santonin were able to rescue planaria from C-like hyperkinesia, after the worms were exposed to cocaine. Conversely, cocaine at a concentration that did not show any measurable effects (10 µM), was able to alleviate the SL-, but not the β-eudesmol-induced motility decrease. Liquid Chromatography/Mass Spectrometry experiments demonstrated that cocaine does not interact directly with any of the cyclic sesquiterpenoids, which suggests specific biochemical targets for these compounds in planarians. Our data suggests a common binding site for cocaine and the sesquiterpene lactones in planarians. [Copyright &y& Elsevier]

Abstract: In this work, we describe aspects of the toxicity and behavioral effects of dimethylsulfoxide (DMSO) in planaria. Planarian worms have traditionally been a favored animal model in developmental biology. More recently, this organism is being recognized as an animal model in neuropharmacology research. DMSO is often used in cell and tissue culture as a cryoprotectant agent and is also commonly used to enhance the solubility of hydrophobic drugs in aqueous solutions. This compound can elicit various physiological effects in both vertebrates and invertebrates. Many drugs and drug candidates are hydrophobic, needing solvents like DMSO to be able to reach their physiological targets. As planaria becomes increasingly popular in neuropharmacology research, a description of the DMSO effects in this organism is essential. We found that DMSO is toxic to planarians at concentrations above 5% (705mM), with an LD50 of 10% (1.4M) at exposure times above 5min. At sub-toxic concentrations, DMSO decreases planarian exploratory behavior in a concentration-dependent manner. This reduction in locomotor behavior is reversible and preincubation-independent. DMSO at a concentration of 0.1% (14.1mM), which is usually enough to solubilize hydrophobic substances in aqueous solutions, did not display any toxic or behavioral effects in planaria. Therefore, in this animal model, DMSO concentrations above 0.1% should be avoided in order to be able to reliably observe any behavioral or toxic effects of hydrophobic drugs. [Copyright &y& Elsevier]

Abstract: We recently reported that parthenolide and related sesquiterpene lactones are able to prevent and reverse behavioral responses in planarian worms induced by acute cocaine exposure. Previous reports indicate that when planarians are chronically exposed to µM concentrations of cocaine, they display stereotypical withdrawal-like behaviors when the cocaine is removed. Here we report that parthenolide prevents this cocaine-induced expression of planarian withdrawal-like behaviors. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Abstract: We recently reported that the natural cyclic lactone, parthenolide, and related analogs prevent the expression of behavioral effects induced by cocaine in planarians and that parthenolide''s γ-lactone ring is required for this effect. In the present work, we tested a series of alkyl γ-lactones with varying chain length (1–8 carbons) to determine their ability to antagonize the planarian motility decrease induced by 200μM cocaine. Alkyl lactones with up to a 4-carbon alkyl chain did not affect planarian motility or antagonized the cocaine-induced motility decrease; only the compound γ-nonalactone (a γ-lactone with a 5-carbon chain) was able to prevent the cocaine-induced behavioral patterns, while alkyl lactones with longer carbon chains failed to prevent the cocaine-induced effects. Thus, we conclude that the optimal structural features of this family of compounds to antagonize cocaine''s effect in this experimental system is a γ-lactone ring with at a 5-carbon long functional group. [Copyright &y& Elsevier]