Lost in translation? A critical look at the role that animal models of obsessive compulsive disorder play in current drug discovery strategies

Hoffman, Kurt L.; Cano-Ramírez, Hugo

doi:10.1080/17460441.2018.1417379

Cited by 13 publications

(3 citation statements)

References 89 publications

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“…Personality associations are variable in human studies; there are only a few mouse models with substantial validation. There are a number of face‐valid models for features of OCD, but relatively few of these models have been validated pharmacologically and none have been applied to PTPRD, to our knowledge. These associations thus merit efforts for replication in humans and generalization to mouse models.…”

Section: Ptprd Variation and Brain Phenotypes: Current Supportmentioning

confidence: 99%

PTPRD: neurobiology, genetics, and initial pharmacology of a pleiotropic contributor to brain phenotypes

Uhl

Martínez

2019

Annals of the New York Academy of Sciences

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Receptor‐type protein tyrosine phosphatase, receptor type D (PTPRD) has likely roles as a neuronal cell adhesion molecule and synaptic specifier. Interest in its neurobiology and genomics has been stimulated by results from human genetics and mouse models for phenotypes related to addiction, restless leg syndrome, neurofibrillary pathology in Alzheimer's disease, cognitive impairment/intellectual disability, mood lability, and obsessive‐compulsive disorder. We review PTPRD's discovery, gene family, candidate homomeric and heteromeric binding partners, phosphatase activities, brain distribution, human genetic associations with nervous system phenotypes, and mouse model data relevant to these phenotypes. We discuss the recently reported discovery of the first small molecule inhibitor of PTPRD phosphatase, the identification of its addiction‐related effects, and the implications of these findings for the PTPRD‐associated brain phenotypes. In assembling PTPRD neurobiology, human genetics, and mouse genetic and pharmacological datasets, we provide a compelling picture of the roles played by PTPRD, its variation, and its potential as a target for novel therapeutics.

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Section: Ptprd Variation and Brain Phenotypes: Current Supportmentioning

confidence: 99%

PTPRD: neurobiology, genetics, and initial pharmacology of a pleiotropic contributor to brain phenotypes

Uhl

Martínez

2019

Annals of the New York Academy of Sciences

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“…The validity of OCD behavioral models (face, predictive, and construct validity) has been reviewed extensively ( 13 , 22 , 88 ). Concisely, face validity gauges how well the animal’s behavior recapitulates pathological human behavior.…”

Section: Discussionmentioning

confidence: 99%

EPD1504: a novel μ-opioid receptor partial agonist attenuates obsessive–compulsive disorder (OCD)-like behaviors

Youngblood¹,

Medina

Gehlert³

et al. 2023

Front. Psychiatry

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Low doses of μ-opioid receptor (MOR) agonists rapidly ameliorate symptoms in treatment-resistant obsessive–compulsive disorder (OCD) patients (10–50% of OCD patients). However, the utility of MOR agonists is limited by their safety liabilities. We developed a novel MOR partial agonist (EPD1540) that has an improved respiratory safety profile when compared to buprenorphine. Buprenorphine is a MOR partial agonist primarily used in the treatment of opiate-use disorder, which in investigator-led trials, has been shown to rapidly ameliorate symptoms in treatment-resistant OCD patients. In this study, we show that doses of EPD1504 and buprenorphine that occupy small fractions of MORs in the CNS (approximately 20%) are as effective as fluoxetine at ameliorating OCD-like behaviors in two different rat models (an operant probabilistic reversal task and marble burying). Importantly, effective doses of EPD1504 did not impair either locomotor activity, or respiration under normoxic or hypercapnic conditions. Additionally, EPD1504 had effects comparable to buprenorphine in the conditioned place preference assay. These results indicate that EPD1504 may provide a safer alternative to buprenorphine for the treatment of OCD patients.

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“…Marble burying represents persistent, repetitive behavior that is resistant to habituation and is proposed to model obsessive/compulsive behavior 45,47 . This behavior is used to screen pharmacotherapeutics for OCD 48 . Genetic variance in marble burying among inbred mouse strains is heritable but is genetically uncorrelated with anxiety-like behaviors and is thus, mediated by distinct genetic factors 45 .…”

Section: Premorbid Anxiety-and Compulsive-like Behavioral Batterymentioning

confidence: 99%

Cyfip1 haploinsufficiency increases compulsive-like behavior and modulates palatable food intake: Implications for Prader-Willi Syndrome

Babbs

Ruan

Kelliher

et al. 2018

Preprint

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Binge eating (BE) is a heritable trait associated with eating disorders and involves consumption of a large quantity of food in a short time. We identified cytoplasmic FMRP-interacting protein 2 (Cyfip2) as a major genetic factor underlying BE and concomitant compulsive-like behaviors in mice. CYFIP2 is a gene homolog of CYFIP1 -one of four paternally deleted genes in patients with the more severe Type I Prader-Willi Syndrome (PWS). PWS is a neurodevelopmental genetic disorder where 70% of cases involve paternal deletion of 15q11-q13. PWS is defined phenotypically by the emergence of hyperphagia and obesity during childhood as well as cognitive deficits and obsessive-compulsive behaviors. We tested the hypothesis that Cyfip1 haploinsufficiency would enhance premorbid compulsive-like behavior and palatable food (PF) consumption in a parent-of-origin-selective manner.Additionally, because our initial studies involved mice on a C57BL/6N background that possess the BEassociated missense mutation in Cyfip2, we tested mice on a mixed background where mice were homozygous for the C57BL/6J (B6J) allele at the Cyfip2 locus. Cyfip1 haploinsufficiency increased compulsive-like behavior on both backgrounds and PF consumption was greater with paternal inheritance. Gene expression in the hypothalamus revealed a paternal effect of Cyfip1 deletion on transcription of Cyfip1 but not Cyfip2 or Magel2. To summarize, the selective increased compulsive-like behavior and PF consumption in paternally deleted Cyfip1 +/-mice could translate to enhancing hyperphagia in a subset of individuals with neurodevelopmental disorders involving reduced expression or haploinsufficiency of CYFIP1, including PWS but also Fragile X Syndrome and 15q11.2 Microdeletion Syndrome.

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Lost in translation? A critical look at the role that animal models of obsessive compulsive disorder play in current drug discovery strategies

Cited by 13 publications

References 89 publications

PTPRD: neurobiology, genetics, and initial pharmacology of a pleiotropic contributor to brain phenotypes

PTPRD: neurobiology, genetics, and initial pharmacology of a pleiotropic contributor to brain phenotypes

EPD1504: a novel μ-opioid receptor partial agonist attenuates obsessive–compulsive disorder (OCD)-like behaviors

Cyfip1 haploinsufficiency increases compulsive-like behavior and modulates palatable food intake: Implications for Prader-Willi Syndrome

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