<i>Tmod2</i> is a regulator of cocaine responses through control of striatal and cortical excitability, and drug-induced plasticity

Mitra, Arojit; Deats, Sean P.; Dickson, Price E.; Zhu, Jin; Gardin, Justin; Nieman, Brian J.; Henkelman, R. Mark; Tsai, Nien Pei; Chesler, Elissa J.; Zhang, Zhongwei; Kumar, Vivek

doi:10.1101/648295

Cited by 2 publications

(4 citation statements)

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“…The Tmod2 strain had similar preference levels to the initial concentration as controls but had a peak for MA preference at the 40 mg/L concentration (40.9 ± 6.4%) (Figure 5B). Further studies will be needed to determine to what drives the increased preference for methamphetamine 59 …”

Section: Resultsmentioning

confidence: 99%

“…Further studies will be needed to determine to what drives the increased preference for methamphetamine. 59 …”

Section: Resultsmentioning

confidence: 99%

“…Further studies will be needed to determine to what drives the increased preference for methamphetamine. 59 In our initial prioritization of the KO strains tested by the MA main effects of strain or strain Â concentration (FDR <0.05). Sex had no significant main or interaction effect on either MA consumption or preference phenotypes.…”

Section: Two-bottle Choice Assay To Determine Methamphetamine-use Phe...mentioning

confidence: 99%

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Discovery and validation of genes driving drug‐intake and related behavioral traits in mice

Roy,

Bubier,

Dickson

et al. 2024

Genes Brain and Behavior

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Substance use disorders are heritable disorders characterized by compulsive drug use, the biological mechanisms for which remain largely unknown. Genetic correlations reveal that predisposing drug‐naïve phenotypes, including anxiety, depression, novelty preference and sensation seeking, are predictive of drug‐use phenotypes, thereby implicating shared genetic mechanisms. High‐throughput behavioral screening in knockout (KO) mice allows efficient discovery of the function of genes. We used this strategy in two rounds of candidate prioritization in which we identified 33 drug‐use candidate genes based upon predisposing drug‐naïve phenotypes and ultimately validated the perturbation of 22 genes as causal drivers of substance intake. We selected 19/221 KO strains (8.5%) that had a difference from control on at least one drug‐naïve predictive behavioral phenotype and determined that 15/19 (~80%) affected the consumption or preference for alcohol, methamphetamine or both. No mutant exhibited a difference in nicotine consumption or preference which was possibly confounded with saccharin. In the second round of prioritization, we employed a multivariate approach to identify outliers and performed validation using methamphetamine two‐bottle choice and ethanol drinking‐in‐the‐dark protocols. We identified 15/401 KO strains (3.7%, which included one gene from the first cohort) that differed most from controls for the predisposing phenotypes. 8 of 15 gene deletions (53%) affected intake or preference for alcohol, methamphetamine or both. Using multivariate and bioinformatic analyses, we observed multiple relations between predisposing behaviors and drug intake, revealing many distinct biobehavioral processes underlying these relationships. The set of mouse models identified in this study can be used to characterize these addiction‐related processes further.

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Section: Resultsmentioning

confidence: 99%

“…Further studies will be needed to determine to what drives the increased preference for methamphetamine. 59 …”

Section: Resultsmentioning

confidence: 99%

Section: Two-bottle Choice Assay To Determine Methamphetamine-use Phe...mentioning

confidence: 99%

See 1 more Smart Citation

Discovery and validation of genes driving drug‐intake and related behavioral traits in mice

Roy,

Bubier,

Dickson

et al. 2024

Genes Brain and Behavior

Self Cite

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show abstract

“…5B). Further studies will be needed to determine to what drives the increased preference for sensitivity to methamphetamine 58 .…”

Section: │ Two-bottle Choice Assay To Determine Methamphetamine-use P...mentioning

confidence: 99%

Discovery and Validation of Genes Driving Drug-Intake and Related Behavioral Traits in Mice

Roy

Bubier

Dickson

et al. 2023

Preprint

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Substance use disorders (SUDs) are heritable disorders characterized by compulsive drug use, but the biological mechanisms driving addiction remain largely unknown. Genetic correlations reveal that predisposing drug-naïve phenotypes, including anxiety, depression, novelty preference, and sensation seeking, are predictive of drug-use phenotypes, implicating shared genetic mechanisms. Because of this relationship, high-throughput behavioral screening of predictive phenotypes in knockout (KO) mice allows efficient discovery of genes likely to be involved in drug use. We used this strategy in two rounds of screening in which we identified 33 drug-use candidate genes and ultimately validated the perturbation of 22 of these genes as causal drivers of substance intake. In our initial round of screening, we employed the two-bottle-choice paradigms to assess alcohol, methamphetamine, and nicotine intake. We identified 19 KO strains that were extreme responders on at least one predictive phenotype. Thirteen of the 19 gene deletions (68%) significantly affected alcohol use three methamphetamine use, and two both. In the second round of screening, we employed a multivariate approach to identify outliers and performed validation using methamphetamine two-bottle choice and ethanol drinking-in-the-dark protocols. We identified 15 KO strains that were extreme responders across the predisposing drug-naïve phenotypes. Eight of the 15 gene deletions (53%) significantly affected intake or preference for three alcohol, eight methamphetamine or three both (3). We observed multiple relations between predisposing behaviors and drug intake, revealing many distinct biobehavioral processes underlying these relationships. The set of mouse models identified in this study can be used to characterize these addiction-related processes further.

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Tmod2 is a regulator of cocaine responses through control of striatal and cortical excitability, and drug-induced plasticity

Cited by 2 publications

References 118 publications

Discovery and validation of genes driving drug‐intake and related behavioral traits in mice

Discovery and validation of genes driving drug‐intake and related behavioral traits in mice

Discovery and Validation of Genes Driving Drug-Intake and Related Behavioral Traits in Mice

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