Genetic basis and mechanisms underlying binge-level methamphetamine intake

暴食水平甲基苯丙胺摄入的遗传基础和机制

• 批准号: 10427124
• 负责人: TAMARA J. RICHARDS
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10427124
• 关键词: Abstinence; Address; Alleles; Amines; Animal Genetics; Animal Model; Animals; Attenuated; Auditory Hallucination; Behavior; Behavioral; Body Temperature; Body Temperature Changes; Brain; Caring; Cessation of life; Chemicals; Chronic; Code; Consumption; Data; Diagnosis; Disease; Dose; Drug Controls; Drug Exposure; Elderly; Euphoria; Exhibits; Frequencies; Funding; Genes; Genetic; Genetic Models; Genetic Risk; Genetic study; Genotype; Goals; Heroin; Human; Illicit Drugs; Individual; Intake; Judgment; Knock-in; Laboratories; Lead; Measures; Medical; Medical center; Metabolic Clearance Rate; Methamphetamine; Methamphetamine use disorder; Modeling; Mood Disorders; Moods; Mus; Mutation; Neurotoxins; New York; Oregon; Other Genetics; Overdose; Paranoia; Pattern; Persons; Phenotype; Physiological; Policies; Population; Post-Traumatic Stress Disorders; Prevention; Production; Relapse; Research; Resistance; Rewards; Risk; Role; Saline; Single Nucleotide Polymorphism; Stimulant; Temperature; Time; Tissues; Toxic effect; United States; United States Department of Veterans Affairs; Variant; Veterans; Violence; Visual Hallucination; affective disturbance; alcohol use disorder; attenuation; drinking; effective intervention; effective therapy; gene network; genetic risk factor; high risk; inpatient service; insight; methamphetamine abuse; methamphetamine effect; methamphetamine exposure; methamphetamine use; mouse model; neurotoxic; neurotoxicity; post-traumatic stress; preference; programs; protective allele; protective factors; receptor; receptor function; relating to nervous system; response; risk variant; stimulant use; trait; transcriptome; transcriptome sequencing; young adult

Methamphetamine (MA) use can alter judgment, increase unsafe behaviors and violence, and cause mood disturbances. Chronic use is associated with paranoia, as well as visual and auditory hallucinations. A number of indicators point to increasing availability and abuse of MA in the United States, especially in the southern and western regions, among both young and older adults. MA is often taken in repeated binge- level doses, and individuals who become addicted to MA suffer high rates of relapse, even after prolonged periods of abstinence. MA is a neurotoxin when higher amounts are taken. Risk as a population measure can be assessed in animal models in the absence of drug exposure through a number of strategies, including the use of selectively bred animal lines. The Richards laboratory has developed an animal model of binge-like MA intake to study genetic risk, neurotoxicity, and changes in behavioral effects of MA associated with this high level of intake. That model, in concert with a genetic model of resistance to MA intake that was also developed in the Richards lab, was used to identify trace amine-associated receptor 1 (Taar1) as a gene that accounts for >50% of the genetic variance in MA intake. The high risk allele codes for a non-functional version of the receptor. However, whereas on an isogenic background, Taar1 allele type accounts for 92% of the phenotypic variance, it accounts for only 68% of the phenotypic variance on a mixed genetic background. Furthermore, some individuals that are homozygous for the high risk Taar1 allele retain a low MA intake profile. In addition to examining neurotoxicity associated with binge-level MA exposure and with differential Taar1 genotype, a focus of this research program will be on the identification of mechanisms, through transcriptome analyses, that protect against binge-level MA intake in individuals known to possess a high-risk Taar1 genotype; in other words to identify genetic modifiers. In Aim 1, controlled binge-level MA dosing and voluntary binge-level MA intake will be compared for their neurotoxic effects in a high MA intake selected mouse line and in mice of the high MA intake line in which the Taar1 allele that promotes high MA intake has been replaced with the protective allele, a genetic knock-in approach. In Aim 2, the impact of voluntary binge-level MA intake on conditioned-reward and a reliable physiological response to MA – body temperature change – will be examined. In Aim 3, a new genetic model will be developed comprised of bidirectionally selected lines derived from individuals that are all homozygous for the Taar1 MA risk allele, but are bred for high vs. low MA intake. Although listed as Aim 3, the production of these lines will begin early in the research program so that they are available for use by year 3. These lines will also be characterized for MA reward, temperature change, tastant preference and MA clearance rate. Finally, in Aim 4, analyses will be conducted using tissues from the selected lines to identify differences in the transcriptome that predict an attenuation of the Taar1 allele effect on MA intake. Tissues from saline- and MA-treated animals will be used. Because there is evidence for human TAAR1 allelic differences that impact receptor function, this is an exciting research direction that could lead to the identification of protective factors that alleviate genetic risk for binge-level MA intake and ultimately to new and more effective treatments.

甲基苯丙胺（MA）的使用会改变判断，增加不安全行为和暴力，并引起情绪波动

项目成果

Methamphetamine Consumption Inhibits Pair Bonding and Hypothalamic Oxytocin in Prairie Voles.

• DOI: 10.1371/journal.pone.0158178
• 发表时间: 2016
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Hostetler CM;Phillips TJ;Ryabinin AE
• 通讯作者: Ryabinin AE

Peri-adolescent exposure to (meth)amphetamine in animal models.

• DOI: 10.1016/bs.irn.2021.06.011
• 发表时间: 2022
• 期刊: INTERNATIONAL REVIEW OF NEUROBIOLOGY
• 作者: Phillips, T. J.;Aldrich, S. J.
• 通讯作者: Aldrich, S. J.

Prefrontal glutamate correlates of methamphetamine sensitization and preference.

• DOI: 10.1111/ejn.13159
• 发表时间: 2016-03
• 期刊: The European journal of neuroscience
• 作者: Lominac KD;Quadir SG;Barrett HM;McKenna CL;Schwartz LM;Ruiz PN;Wroten MG;Campbell RR;Miller BW;Holloway JJ;Travis KO;Rajasekar G;Maliniak D;Thompson AB;Urman LE;Kippin TE;Phillips TJ;Szumlinski KK
• 通讯作者: Szumlinski KK

Long-term effects of exposure to methamphetamine in adolescent rats.

青少年大鼠暴露于甲基苯丙胺的长期影响。

• DOI: 10.1016/j.drugalcdep.2014.02.021
• 发表时间: 2014
• 期刊: Drug and alcohol dependence
• 影响因子: 4.2
• 作者: Ye,Tony;Pozos,Hilda;Phillips,TamaraJ;Izquierdo,Alicia
• 通讯作者: Izquierdo,Alicia

Mesocorticolimbic monoamine correlates of methamphetamine sensitization and motivation.

• DOI: 10.3389/fnsys.2014.00070
• 发表时间: 2014
• 期刊: Frontiers in systems neuroscience
• 影响因子: 3
• 作者: Lominac KD;McKenna CL;Schwartz LM;Ruiz PN;Wroten MG;Miller BW;Holloway JJ;Travis KO;Rajasekar G;Maliniak D;Thompson AB;Urman LE;Phillips TJ;Szumlinski KK
• 通讯作者: Szumlinski KK