Behavioral characterization of serotonergic activation in the flatworm Planaria

Farrell, Martilias S.; Gilmore, Kirsti; Raffa, Robert B.; Walker, Ellen A.

doi:10.1097/fbp.0b013e3282fe885e

Cited by 16 publications

(10 citation statements)

References 20 publications

(35 reference statements)

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“…Considering that previous works in planarians showed an effect of serotonergic drugs on both spontaneous locomotor velocity and behavior [26], one could suppose that sertraline effect could be related to the behavioral alterations here described. In this case, bearing in mind the sertraline's classic mechanism of action, the inhibition of serotonin reuptake might increase the neurotransmitter level and consequently mediate an endogenous activation of their receptors.…”

Section: Discussionmentioning

confidence: 71%

“…In this case, bearing in mind the sertraline's classic mechanism of action, the inhibition of serotonin reuptake might increase the neurotransmitter level and consequently mediate an endogenous activation of their receptors. However, it is important to consider that, in these studies where behavioral effects of serotonin-addition were observed, the concentration of the neurotransmitter added was high, around 100–1000 µ M [26, 43]. Another additional possibility to be considered might be an indirect effect of sertraline on other neurotransmission systems, such as the glutamatergic system.…”

Section: Discussionmentioning

confidence: 99%

“…Planarians also possess several neurotransmitter-receptor systems and are widely used as an animal model in neuropharmacological studies [25]. For instance, they present a serotonergic system that share some similarities with those found in vertebrates [25] and where serotonergic drugs showed effect on both spontaneous locomotor velocity and behavior [26]. …”

Section: Introductionmentioning

confidence: 99%

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Sertraline Induces Toxicity and Behavioral Alterations in Planarians

Thumé

Frizzo

2017

BioMed Research International

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Toxicity attributed to sertraline has been demonstrated recently in different cell types and also in some organisms. We investigated the effect of sertraline on planarians, which are considered suitable for investigations in neurotoxicology and currently are widely used as an animal model in neuropharmacological studies. Planarians treated with 10 µM sertraline showed a rapid reduction in their spontaneous movement until they became completely motionless and then showed a series of asynchronous paroxysms (seizures) followed by progressive tissue damage, beginning 48 h after the sertraline treatment, and died approximately 72 h later. Our data showed that sertraline does not cause planarian death within the range of therapeutic concentrations; however, behavioral alterations were observed with concentrations that can be considered compatible with therapeutic ones, such as a significant reduction in planarian locomotory activity at 0.4 µM. Treatment with 4 µM sertraline had a significant effect, reducing planarian locomotory activity and increasing the number of asynchronous paroxysms; both effects were significantly maintained even 24 h after the sertraline was withdrawn. These behavioral changes observed at low micromolar concentrations suggest that sertraline might have residual biological consequences for planarians, even after it is withdrawn.

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sertraline Induces Toxicity and Behavioral Alterations in Planarians

Thumé

Frizzo

2017

BioMed Research International

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“…DtSER-1 responds to 5-HT and is coupled to the G pathway. Serotonin receptors are implicated in motility and regeneration due to the phenotypic effects of serotonin in this phylum [39], [40]. Given that this receptor mediates significant increases in cAMP levels in response to serotonin, it is likely involved in these or other important physiological processes.…”

Section: Resultsmentioning

confidence: 99%

Novel RNAi-Mediated Approach to G Protein-Coupled Receptor Deorphanization: Proof of Principle and Characterization of a Planarian 5-HT Receptor

et al. 2012

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G protein-coupled receptors (GPCRs) represent the largest known superfamily of membrane proteins extending throughout the Metazoa. There exists ample motivation to elucidate the functional properties of GPCRs given their role in signal transduction and their prominence as drug targets. In many target organisms, these efforts are hampered by the unreliable nature of heterologous receptor expression platforms. We validate and describe an alternative loss-of-function approach for ascertaining the ligand and G protein coupling properties of GPCRs in their native cell membrane environment. Our efforts are focused on the phylum Platyhelminthes, given the heavy health burden exacted by pathogenic flatworms, as well as the role of free-living flatworms as model organisms for the study of developmental biology. RNA interference (RNAi) was used in conjunction with a biochemical endpoint assay to monitor cAMP modulation in response to the translational suppression of individual receptors. As proof of principle, this approach was used to confirm the neuropeptide GYIRFamide as the cognate ligand for the planarian neuropeptide receptor GtNPR-1, while revealing its endogenous coupling to Gαi/o. The method was then extended to deorphanize a novel Gαs-coupled planarian serotonin receptor, DtSER-1. A bioinformatics protocol guided the selection of receptor candidates mediating 5-HT-evoked responses. These results provide functional data on a neurotransmitter central to flatworm biology, while establishing the great potential of an RNAi-based deorphanization protocol. Future work can help optimize and adapt this protocol for higher-throughput platforms as well as other phyla.

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“…Planarians were then placed for 5 min into one of the following: 5-HT (0.001 – 100 µM); 8-OH-DPAT (0.1 – 20 µM); WAY 100635 (0.001 – 1 µM); or m-CPZ (0.1 – 20 µM). The concentration of methamphetamine used to induce abstinence-induced withdrawal, as well as concentrations of 5-HT and 5-HT agonists/antagonists that do not affect planarian movement when given alone, were selected on the basis of prior studies [5, 30–31]. Data were expressed as the mean (± S.E.M.)…”

Section: Methodsmentioning

confidence: 99%

5-HT1A-like receptor activation inhibits abstinence-induced methamphetamine withdrawal in planarians

Shah

Ayoub

Raffa

2010

Neuroscience Letters

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No pharmacological therapy is approved to treat methamphetamine physical dependence, but it has been hypothesized that serotonin (5-HT)-enhancing drugs might limit the severity of withdrawal symptoms. To test this hypothesis, we used a planarian model of physical dependence that quantifies withdrawal as a reduction in planarian movement. Planarians exposed to methamphetamine (10 µM) for 60 min, and then placed (tested) into drug-free water for 5 min, displayed less movement (i.e., withdrawal) than either methamphetamine-naïve planarians tested in water or methamphetamine-exposed planarians tested in methamphetamine. A concentration-related inhibition of withdrawal was observed when methamphetamine-exposed planarians were placed into a solution containing either methamphetamine and 5-HT (0.1 – 100 µM) or methamphetamine and the 5-HT1A receptor agonist 8-Hydroxy-N,N-dipropyl-2-aminotetralin (8-OH-DPAT) (10, 20 µM). Planarians with prior methamphetamine exposure displayed enhanced withdrawal when tested in a solution of the 5-HT1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]- N-(2-pyridyl)cyclohexanecarboxamide (WAY 100635) (1 µM). Methamphetamine-induced withdrawal was not affected by the 5-HT2B/2C receptor agonist meta-chlorophenylpiperazine (m-CPZ) (0.1 – 20 µM). These results provide pharmacological evidence that serotonin-enhancing drugs inhibit expression of methamphetamine physical dependence in an invertebrate model of withdrawal, possibly through a 5-HT1A-like receptor-dependent mechanism.

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Behavioral characterization of serotonergic activation in the flatworm Planaria

Cited by 16 publications

References 20 publications

Sertraline Induces Toxicity and Behavioral Alterations in Planarians

Sertraline Induces Toxicity and Behavioral Alterations in Planarians

Novel RNAi-Mediated Approach to G Protein-Coupled Receptor Deorphanization: Proof of Principle and Characterization of a Planarian 5-HT Receptor

5-HT1A-like receptor activation inhibits abstinence-induced methamphetamine withdrawal in planarians

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