What Have We Learned (or Expect to) From Analysis of Murine Genetic Models Related to Substance Use Disorders?

Peltz, Gary; Tan, Yalun

doi:10.3389/fpsyt.2021.793961

Cited by 2 publications

(4 citation statements)

References 125 publications

(148 reference statements)

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“…Inbred mouse strains have been analyzed to identify genetic factors affecting addiction-related behaviors and their responses to drugs with high abuse potential 4 – 8 . While we do not expect that murine studies will be likely to identify the same genetic factors that are operative in humans, the neurobiological mechanisms that underlie SUD risk are likely to converge in mice and humans 3 . Hence, characterizing genetic factors that affect the responses of inbred mouse strains to these drugs could (i) increase our understanding of the neurobiological pathways that are impacted by them; (ii) reveal how addiction-related behaviors are generated; and (iii) could help to generate new approaches for preventing drug addiction in humans 9 .…”

Section: Introductionmentioning

confidence: 96%

“…While a substantial proportion of the risk for developing a SUD is genetic 1 , 2 , the genes and alleles that influence susceptibility to a SUD remain largely unknown. Just as in the human population, inbred mouse strains exhibit substantial and heritable differences in their responses to commonly abused drugs, which has enabled murine models for many human SUD behaviors to be generated 3 . Inbred mouse strains have been analyzed to identify genetic factors affecting addiction-related behaviors and their responses to drugs with high abuse potential 4 – 8 .…”

Section: Introductionmentioning

confidence: 99%

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Neuron Navigator 1 (Nav1) regulates the response to cocaine in mice

Bagley,

Tan,

Zhu

et al. 2023

Commun Biol

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Genetic variation accounts for much of the risk for developing a substance use disorder, but the underlying genetic factors and their genetic effector mechanisms are mostly unknown. Inbred mouse strains exhibit substantial and heritable differences in the extent of voluntary cocaine self-administration. Computational genetic analysis of cocaine self-administration data obtained from twenty-one inbred strains identified Nav1, a member of the neuron navigator family that regulates dendrite formation and axonal guidance, as a candidate gene. To test this genetic hypothesis, we generated and characterized Nav1 knockout mice. Consistent with the genetic prediction, Nav1 knockout mice exhibited increased voluntary cocaine intake and had increased motivation for cocaine consumption. Immunohistochemistry, electrophysiology, and transcriptomic studies were performed as a starting point for investigating the mechanism for the Nav1 knockout effect. Nav1 knockout mice had a reduced inhibitory synapse density in their cortex, increased excitatory synaptic transmission in their cortex and hippocampus, and increased excitatory neurons in a deep cortical layer. Collectively, our results indicate that Nav1 regulates the response to cocaine, and we identified Nav1 knockout induced changes in the excitatory and inhibitory synaptic balance in the cortex and hippocampus that could contribute to this effect.

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Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Neuron Navigator 1 (Nav1) regulates the response to cocaine in mice

Bagley,

Tan,

Zhu

et al. 2023

Commun Biol

Self Cite

View full text Add to dashboard Cite

show abstract

“…Inbred mouse strains have been analyzed to identify genetic factors affecting addiction-related behaviors and responses to multiple types of drugs with high abuse potential ( 4-8 ). While we do not expect that murine studies will be likely to identify the same genetic factors that are operative in humans, the neurobiological mechanisms that underlie the risk for a SUD are likely to converge in mice and humans ( 3 ). Hence, characterizing genetic factors that affect the responses of inbred mouse strains to these drugs could (i) increase our understanding of the neurobiological pathways that are impacted by them; (ii) reveal how addiction-related behaviors are generated; and (iii) could help to generate new approaches for preventing drug addiction in humans ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

“…While a substantial proportion of the risk for developing a substance use disorder is genetic ( 1, 2 ), the genes and alleles that influence susceptibility to drug addiction remain largely unknown. Just as in the human population, inbred mouse strains exhibit substantial and heritable differences in their responses to commonly used drugs with high abuse potential, which has enabled murine models for many of the behaviors observed in those with a SUD to be generated ( 3 ). Inbred mouse strains have been analyzed to identify genetic factors affecting addiction-related behaviors and responses to multiple types of drugs with high abuse potential ( 4-8 ).…”

Section: Introductionmentioning

confidence: 99%

Neuron Navigator 1Regulates Learning, Memory, and the Response to Multiple Potentially Addictive Drugs

Bagley

Tan

et al. 2022

Preprint

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Genetic variation accounts for much of the risk for developing a substance use disorder (SUD). Inbred mouse strains exhibit substantial and heritable differences in the extent of voluntary cocaine intravenous self-administration (IVSA). Computational genetic analysis of IVSA data obtained from an inbred strain panel identified Nav1, a member of the neuron navigator family that regulates dendrite formation and axonal guidance, as a candidate gene. To test this hypothesis, we generated and characterized Nav1 knockout (KO) mice. Nav1 KO mice exhibited increased cocaine intake during IVSA testing. Surprisingly, Nav1 KO mice also displayed a reduced susceptibility to become opioid dependent or develop opioid-induced hyperalgesia after chronic morphine administration, and had impaired spatial learning/memory. Immunohistochemistry and electrophysiology studies revealed that inhibitory synapse density in the cortex of Nav1 KO mice was reduced, and excitatory synaptic transmission was increased in the Nav1 KO cortex and hippocampus. Transcriptomic analysis revealed that Nav1 KO mice had a marked increase in excitatory neurons in a deep cortical layer. Collectively, our results indicate that Nav1 regulates learning, memory, and the response to multiple addictive drugs, and that changes in the excitatory and inhibitory synaptic balance in the cortex and hippocampus could possibly mediate its phenotypic effects.

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What Have We Learned (or Expect to) From Analysis of Murine Genetic Models Related to Substance Use Disorders?

Cited by 2 publications

References 125 publications

Neuron Navigator 1 (Nav1) regulates the response to cocaine in mice

Neuron Navigator 1 (Nav1) regulates the response to cocaine in mice

Neuron Navigator 1Regulates Learning, Memory, and the Response to Multiple Potentially Addictive Drugs

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