Incubated drug-craving and neurochemical interactions

潜伏的药物渴望和神经化学相互作用

• 批准号: 10543817
• 负责人: Karen Kathleen Szumlinski
• 金额: $ 33.13万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10543817
• 关键词: AMPA Receptors; Abstinence; Address; Animal Experimentation; Animal Model; Animals; Automobile Driving; Behavior; Behavioral; Biochemical; Biochemistry; Biological Assay; Brain region; Chronic; Clinical; Cocaine; Cognitive; Cues; Data; Disease; Disease Management; Disease Progression; Disease model; Dopamine; Dopamine D1 Receptor; Dopamine Receptor; Down-Regulation; Epidemic; Exhibits; Experimental Designs; Extinction; GRM1 gene; GRM5 gene; Glutamate Receptor; Glutamates; Human; Hyperactivity; Impaired cognition; Incubated; Intake; Laboratory Animals; Learning; Link; Mediating; Mediator; Metabolic; Metabotropic Glutamate Receptors; Methamphetamine; Microdialysis; Modeling; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nature; Neurobiology; Neurotransmitters; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Predisposition; Prefrontal Cortex; Process; Psychological reinforcement; Rattus; Recording of previous events; Regulation; Relapse; Reporting; Research; Role; Scaffolding Protein; Series; Signal Transduction; Specificity; Stimulant; Sucrose; Testing; Therapeutic; Time; Treatment Efficacy; Withdrawal; Work; addiction; antagonist; base; biobehavior; cocaine craving; cocaine exposure; cocaine seeking; craving; diagnostic criteria; drug craving; drug seeking behavior; effective intervention; experience; extracellular; gamma-Aminobutyric Acid; in vivo; innovation; insight; kainate; neurochemistry; neuropathology; non-drug; novel; pharmacologic; postsynaptic; pre-clinical; psychostimulant; receptor; receptor function; reinforcer; stimulant use disorder; theories; transmission process; treatment strategy

Psychomotor-stimulant Use Disorder (PUD) is a chronic relapsing disorder, characterized by a high propensity for relapse even during protracted abstinence. In both humans with PUD & animal models, the intensity of cue- elicited drug craving & drug-seeking behavior increases or “incubates” during protracted withdrawal. The neurochemical underpinnings of drug craving & its incubation are not well understood. Drug cue-induced increase in metabolic hyperactivity within the prefrontal cortex (PFC) is correlated with the intensity of drug- craving in humans. Consistent with this, we have reported a link between the magnitude of drug-seeking in a rat model of cocaine-taking & a number of abnormalities in glutamate (GLU) transmission within the ventromedial aspect of the PFC (vmPFC). Notably, incubated cocaine-seeking is associated with a time-dependent increase in the capacity of drug-predictive cues to increase GLU levels, primarily within the prelimbic (PL) subregion. We theorize this cue-elicited rise in GLU might underpin cue-elicited increases in metabolic hyperactivity observed within PFC of PUD patients. Importantly: (1) the increased GLU responsiveness to drug-predictive cues is selective for rats with a cocaine-taking history; (2) the magnitude of the GLU increase predicts the vigor of cocaine-seeking behavior; & (3) neuropharmacological inhibition of GLU transmission within the PL eliminates cocaine-incubated responding. Intriguingly, the incubated cue-responsiveness of vmPFC GLU is inversely related to cue-elicited changes in vmPFC dopamine (DA). This inverse neurochemical relation has led to the over-arching hypothesis to be tested in this proposal: the incubation of cue-elicited drug-seeking behavior results from dysregulated GLU-DA interactions w ithin the PL subregion of the vmPFC . Aim 1 of this proposal employs neuropharmacological approaches to systematically target & dissect the relative contribution of postsynaptic AMPA & NMDA GLU receptor subtypes to the manifestation of incubated cocaine-seeking & examine for the generalization of pharmacological effects to a highly prevalent psychomotor-stimulant, methamphetamine (MA), as well as the non-drug reinforcer, sucrose. It is hypothesized in Aim 1 that the incubation of COC craving is driven by GLU-mediated activation of ionotropic GLU receptors within vmPFC. Aim 2 will employ a combination of in vivo microdialysis & neuropharmacological approaches to examine the role for D1- & D3-type DA receptors & their regulation of GLU, DA & GABA release within the vmPFC in incubated cocaine-, MA- & sucrose-seeking. It is hypothesized in Aim 2 that the incubation of cue- elicited GLU release, cellular hyperactivity & drug-seeking reflect time-dependent anomalies in DA signaling within PL. The proposal presents a series of theoretically innovative experiments designed to address the biobehavioral underpinnings of incubated craving, which will advance our basic understanding of the neurobiology of relapse.

精神运动兴奋剂使用障碍（PUD）是一种慢性复发性障碍，其特点是高倾向性