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Characterization and reversal of neurocognitive dysfunction produced by long-term synthetic cathinone use

长期使用合成卡西酮引起的神经认知功能障碍的特征和逆转

基本信息

批准号：
9978792
负责人：
M. FOSTER OLIVE
金额：
$ 37.96万
依托单位：
ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9978792
关键词：
Abstinence Address Alcohol or Other Drugs use Alkaloids Amphetamines Animals Antioxidants Brain Brain region Catha edulis Cocaine Cognition Cognitive Dependence Development Dose Drug Costs Exhibits Female Functional disorder Goals Histologic Home environment Hour Impaired cognition Impairment Individual Intake Ketoprofen Lead Legal Long-Term Effects Measures Mediating Medical Methamphetamine Modeling Nerve Degeneration Neurocognitive Neurocognitive Deficit Non-Steroidal Anti-Inflammatory Agents Oxidative Stress Pattern Performance Pharmaceutical Preparations Pharmacologic Actions Pharmacology Procedures Property Public Health Rattus Resistance Reversal Learning Risk Rodent Rodent Model Saline Self Administration Societies Testing Therapeutic Intervention Time bath salts brain tissue cognitive function cognitive testing flexibility high risk histopathological examination improved inhibitor/antagonist khat male memory recognition monoamine mortality neural circuit neuroinflammation neuropsychiatry neurotoxicity novel object recognition psychostimulant public health relevance reuptake sex socioeconomics synthetic drug systemic toxicity tempol therapeutic development

项目摘要

ABSTRACT Synthetic cathinones are novel psychoactive substances used for their euphorigenic and psychostimulant properties, but carry a significant risk of inducing adverse psychiatric complications, systemic toxicity, and patterns of abuse and dependence. We recently demonstrated that the synthetic cathinone 3,4- methylenedioxypyrovalerone (MDPV), a potent and long-lasting monoamine reuptake inhibitor, is readily self- administered by rodents under limited access conditions. However, synthetic cathinone users frequently engage in repeated binge-like patterns of drug intake across several consecutive days, which have not yet been modeled in rodents to determine potential detrimental effects on cognition and brain function. To address this, we recently conducted preliminary studies in which rats were allowed to self-administer MDPV or saline for 96 consecutive hrs (4 days), followed by 72 hrs (3 days) of abstinence in the home cage. This procedure was repeated to allow for a total of 5 weeks of prolonged drug self-administration alternating with periods of abstinence. Next, animals underwent assessment of cognitive function using object placement and recognition tasks, followed by analysis of brain tissue for potential evidence of neurodegeneration, neuroinflammation, or oxidative stress. Animals self- administering MDPV displayed high levels of drug intake (>100 mg/kg per 96-hr session), and compared to animals self-administering saline, showed performance deficits in object recognition but not object placement. We also observed evidence of MDPV-induced neurodegeneration, neuroinflammation, and oxidative stress in the recognition memory circuit. However, additional studies are needed to further examine the dose and sex- dependency of these effects, whether they extend to measures of cognitive flexibility, and to investigate potential underlying mechanisms and approaches for mitigating these effects. The overarching hypothesis of the studies proposed in this application is that MDPV-induced neurocognitive dysfunction is highly influenced by sex, dose, and neuroinflammatory mechanisms. To test this hypothesis, we propose three independent yet inter-related aims. In Specific Aim 1, we will examine the influence of sex and dose on MDPV-induced neurocognitive dysfunction. In Specific Aim 2, we will examine the effects of repeated binge-like MDPV intake on cognitive flexibility. Finally, in Specific Aim 3, we will pharmacologically investigate potential mechanisms (neuroinflammation or oxidative stress) underlying MDPV-induced neurocognitive dysfunction. Together, these studies will assist in the development of therapeutic interventions to counteract the detrimental effects of synthetic cathinones on cognition and brain function.

摘要