Central Cholinergic Involvement in Cocaine Addiction

可卡因成瘾中枢胆碱能的参与

• 批准号: 7493715
• 负责人: GREGORY P MARK
• 金额: $ 4.7万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7493715
• 关键词: Abstinence; Acetylcholine; Addictive Behavior; Affect; Amphetamines; Amygdaloid structure; Animal Model; Animals; Area; Behavior; Behavioral; Behavioral Model; Body Regions; Brain; Catheters; Characteristics; Cholinergic Agents; Cholinergic Antagonists; Cholinergic Receptors; Classification; Clinical Research; Cocaine; Cocaine Dependence; Complex; Condition; Cues; Daily; Development; Developmental Process; Dopamine; Dopamine Agonists; Drug Exposure; Esthesia; Exposure to; Extinction (Psychology); Health; Human; Injection of therapeutic agent; Intake; Measures; Mecamylamine; Medial; Mediating; Methods; Microdialysis; Microinjections; Modeling; Morphine; Neurobiology; Nicotine; Nicotinic Antagonists; Nicotinic Receptors; Nucleus Accumbens; Numbers; Pathway interactions; Pharmaceutical Preparations; Prefrontal Cortex; Psychophysiology; Rate; Rattus; Receptor Activation; Relapse; Relative (related person); Research; Risk; Role; Saline; Schedule; Self Administration; Self-Administered; Site; Staging; Stimulus; System; Testing; Training; Ventral Tegmental Area; Week; Work; addiction; behavior measurement; cholinergic; craving; day; desire; drug addict; drug craving; drug seeking behavior; experience; indexing; neurochemistry; neuronal cell body; paired stimuli; prevent; reinforced behavior; research study; response

The substantial health risk posed by the compulsive use of cocaine has prompted a serious research effort to identify the neurobiological substrates that underlie the development of addiction to this drug. Despite substantial progress, an understanding of the neurochemical systems that mediate the motivational aspects of drug-seeking and craving remains incomplete. To expand this understanding, this proposal will examine the involvement of four discrete cholinergicsystems in the development of compulsive cocaine intake and cocaine- seeking behaviors in rats. Experiments will focus on nicotinic acetylcholine (ACh) receptor activation in the development and expression of addictive behavior. The first specific aim is to identify the impact of escalating cocaine self-administrationon the release of ACh in amygdaloid complex (AmC), ventral tegmental area (VTA), nucleus accumbens (NAc) and prefrontal cortex (PFC). Rats will be trained to press a lever to self-administer cocaine through indwelling jugular catheters. Availability of cocaine will be increased from 1 to 6 hr per day (which has been shown to escalate daily cocaine intake) and microdialysis will measure ACh release before and after escalated cocaine intake. A second experiment will examine the impact of intracerebral microinjections of nicotine or the nicotinic antagonist mecamylamine on the escalation of cocaine intake. The second aim of this proposal is to determine if nicotine injections in VTA, NAc, PFC or AmC will prime non-reinforced lever-press behavior in cocaine addicted rats. Prior to testing, rats will receive systemic injections of nicotine or saline before self-administering cocaine for 2 weeks. On test days, rats will be given intracerebral nicotine and non- reinforced responding will be measured as an index of cocaine craving. The third aim of this research is to determine the role of AmC, VTA, NAc and PFC ACh systems in the ability of drug-associated stimuli to control non-reinforced responding. ACh will be measured during the presentation of cocaine-associated cues along with responding elicited by a cocaine-conditioned stimulus after microinjection of nicotinic drugs into AmC, VTA, NAc and PFC. Injections of nicotinic antagonists in these four areas are expected to reduce lever- press behavior in response to presentation of second-order stimuli. It is hoped that the results of these studies will further our understanding of the involvement of central cholinergic mechanisms in cocaine-reinforced behavior and drug craving and the brain site-specific influence of nicotine on cocaine addiction and relapse.

强迫性使用可卡因所造成的巨大健康风险促使一项严肃的研究努力