The role of endogenous serotonin in methamphetamine‐induced neurotoxicity to dopamine nerve endings of the striatum

Thomas, David M.; Pérez, Mariana Angoa; Francescutti-Verbeem, Dina M.; Shah, Mrudang M.; Kuhn, Donald M.

doi:10.1111/j.1471-4159.2010.06950.x

Cited by 51 publications

(65 citation statements)

References 70 publications

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“…As a result of the null mutation in the gene for TPH2, these mice have no measureable brain 5HT 15,16,18 . These mice show a very interesting behavioral phenotype characterized primarily by repetitive, compulsive-like digging and burying 15,16 .…”

Section: Representative Resultsmentioning

confidence: 99%

Marble Burying and Nestlet Shredding as Tests of Repetitive, Compulsive-like Behaviors in Mice

Angoa‐Pérez

Kane

Briggs

et al. 2013

JoVE

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Obsessive-compulsive disorder (OCD) and autism spectrum disorders (ASD) are serious and debilitating psychiatric conditions and each constitutes a significant public health concern, particularly in children. Both of these conditions are highlighted by the repeated expression of meaningless behaviors. Individuals with OCD often show checking, frequent hand washing, and counting. Children with ASDs also engage in repetitive tapping, arm or hand flapping, and rocking. These behaviors can vary widely in intensity and frequency of expression. More intense forms of repetitive behaviors can even result in injury (e.g. excessive grooming, hand washing, and self-stimulation). These behaviors are therefore very disruptive and make normal social discourse difficult. Treatment options for repetitive behaviors in OCD and ASDs are somewhat limited and there is great interest in developing more effective therapies for each condition. Numerous animal models for evaluating compulsivelike behaviors have been developed over the past three decades. Perhaps the animal models with the greatest validity and ease of use are the marble burying test and the nestlet shredding test. Both tests take advantage of the fact that the target behaviors occur spontaneously in mice. In the marble burying test, 20 marbles are arrayed on the surface of clean bedding. The number of marbles buried in a 30 min session is scored by investigators blind to the treatment or status of the subjects. In the nestlet shredding test, a nestlet comprised of pulped cotton fiber is preweighed and placed on top of cage bedding and the amount of the nestlet remaining intact after a 30 min test session is determined. Presently, we describe protocols for and show movie documentation of marble burying and nestlet shredding. Both tests are easily and accurately scored and each is sensitive to small changes in the expression of compulsive-like behaviors that result from genetic manipulations, disease, or head injury. Video LinkThe video component of this article can be found at

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Section: Representative Resultsmentioning

confidence: 99%

Marble Burying and Nestlet Shredding as Tests of Repetitive, Compulsive-like Behaviors in Mice

Angoa‐Pérez

Kane

Briggs

et al. 2013

JoVE

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240

229

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“…Other major elements of the 5HT neuronal system (i.e., receptors, neurons, axons, dendrites, raphe unit firing and the 5HT transporter) remain essentially intact in these mice and there appear to be few if any compensatory alterations in other neurotransmitter systems. 19,20,[23][24][25][26][27][28] In the course of characterizing the behavioral phenotype of the TPH2 −/− mouse, we and others …”

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confidence: 99%

“…19 TPH2 is the initial and rate-limiting enzyme in the biosynthesis of 5HT. Mice lacking the gene for TPH2 are viable and fertile but show some degree of developmental lag by comparison to wild-type mice.…”

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confidence: 99%

“…[20][21][22] TPH2 −/− mice have no TPH2 protein and brain tissue from these mice cannot hydroxylate tryptophan to 5-hydroxytryptophan. 19 Consequently, their central nervous systems are devoid of 5HT. Other major elements of the 5HT neuronal system (i.e., receptors, neurons, axons, dendrites, raphe unit firing and the 5HT transporter) remain essentially intact in these mice and there appear to be few if any compensatory alterations in other neurotransmitter systems.…”

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confidence: 99%

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Mice Genetically Depleted of Brain Serotonin Do Not Display a Depression-like Behavioral Phenotype

Angoa‐Pérez

Kane

Briggs

et al. 2014

ACS Chem. Neurosci.

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Reductions in function within the serotonin (5HT) neuronal system have long been proposed as etiological factors in depression. Serotonin selective reuptake inhibitors (SSRIs) are the most common treatment for depression and their therapeutic effect is generally attributed to their ability to increase the synaptic levels of 5HT. Tryptophan hydroxylase 2 (TPH2) is the initial and ratelimiting enzyme in the biosynthetic pathway of 5HT in the CNS and losses in its catalytic activity lead to reductions in 5HT production and release. The time differential between the onset of 5HT reuptake inhibition by SSRIs (minutes) and onset of their anti-depressant efficacy (weeks to months), when considered with their overall poor therapeutic effectiveness, has cast some doubt on the role of 5HT in depression. Mice lacking the gene for TPH2 are genetically depleted of brain 5HT and were tested for a depression-like behavioral phenotype using a battery of valid tests for affective-like disorders in animals. The behavior of TPH2 −/− mice on the sucrose preference test, tail suspension test and forced swim test and their responses in the unpredictable chronic mild stress and learned helplessness paradigms was the same as wild-type controls. While TPH2−/− mice as a group were not responsive to SSRIs, a subset responded to treatment with SSRIs in the same manner as wild-type controls with significant reductions in immobility time on the tail suspension test, indicative of antidepressant drug effects. The behavioral phenotype of the TPH2 −/− mouse questions the role of 5HT in depression. Furthermore, the TPH2 −/− mouse may Detroit, MI 48201-1916. Phone: 313-476-4457, Fax: 313-576-1112. donald.kuhn@wayne.edu. Author Contributions MAP, MJK, DIB, NHM and CES conducted the in vivo behavioral and pharmacological experiments. DMF and MAP conducted the in vitro synaptosomal 5HT uptake experiments. MAP, MJK and DMK interpreted the data. MAP, MJK and DMK conceived of project and wrote the paper. All authors edited and approved the final version of the manuscript. NotesThe authors declare no competing financial interest. SUPPORTING INFORMATION AVAILABLEThe numbers of TPH2+/+ and TPH2−/− mice classified as responders or non-responders (specified by sex) to the SSRIs fluoxetine, citalopram and paroxetine is included in SI Table 1. The immobility time cutoff values for defining whether a subject was classified as a responder or non-responder to SSRIs is presented in SI Table 2. Information on the specific stressors used in the UCMS is included in SI Table 3. This information is available free of charge via the Internet at http://pubs.acs.org. U.S. Department of Veterans Affairs VA Author ManuscriptVA Author Manuscript VA Author Manuscriptserve as a useful model in the search for new medications that have therapeutic targets for depression that are outside of the 5HT neuronal system. Keywordsserotonin; TPH2; TPH2 knock out; depression-like behavior; SSRIs; SERT The serotonin (5HT) neuronal system innervates nearly the entire neuraxis from...

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“…• Respond to METH in the same manner as wild-type controls, despite showing enhanced drug-induced hyperthermia [22].…”

Section: Behaviormentioning

confidence: 93%

Transgenic Animal Models for Brain 5-HT Deficiency: An Editorial Summary

Lu¹

2013

J Genet Syndr Gene Ther

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The role of endogenous serotonin in methamphetamine‐induced neurotoxicity to dopamine nerve endings of the striatum

Cited by 51 publications

References 70 publications

Marble Burying and Nestlet Shredding as Tests of Repetitive, Compulsive-like Behaviors in Mice

Marble Burying and Nestlet Shredding as Tests of Repetitive, Compulsive-like Behaviors in Mice

Mice Genetically Depleted of Brain Serotonin Do Not Display a Depression-like Behavioral Phenotype

Transgenic Animal Models for Brain 5-HT Deficiency: An Editorial Summary

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