Neural Mechanisms of Propensity for Drug Taking

吸毒倾向的神经机制

• 批准号: 9301730
• 负责人: JILL B. BECKER
• 金额: $ 3.44万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9301730
• 关键词: Affect; American; Amphetamines; Appetitive Behavior; Attenuated; Automobile Driving; Behavior; Chemosensitization; Cocaine; Cocaine Abuse; Compulsive Behavior; Corpus striatum structure; DRD2 gene; Development; Dopamine; Dopamine D2 Receptor; Down-Regulation; Drug usage; Estradiol; Estrous Cycle; Estrus; Exhibits; Female; Food; Globus Pallidus; Health; Human; Individual Differences; Laboratories; Laboratory Rat; Mediating; Motivation; Neurons; Nucleus Accumbens; Pathway interactions; Pharmaceutical Preparations; Predisposition; Proestrus; Rattus; Rewards; Role; Self Administration; Series; Sex Characteristics; Signal Transduction; Stereotyped Behavior; Stream; Substantia nigra structure; System; Testing; Woman; Women' s Role; addiction; attenuation; base; cocaine use; designer receptors exclusively activated by designer drugs; drug abuse vulnerability; drug of abuse; gamma-Aminobutyric Acid; learned behavior; male; men; motivated behavior; neurochemistry; neuromechanism; overexpression; preference; relating to nervous system; repetitive behavior; research study

 DESCRIPTION (provided by applicant): When presented with food or cocaine, dopamine (DA) in the nucleus accumbens (NAc) initially signals that the item is rewarding. When behaviors, such as drug taking, become compulsive we hypothesize that this reflects a shift in neural systems maintaining the behavior. There is enhanced DA release in the dorsolateral striatum (DLS) and attenuation of NAc DA release. Furthermore, within DLS, activity in the Direct Pathway from the striatum to the substantia nigra, that is important for initiation of appetitive behaviors is enhanced, while activity in the Indirect Pathway, from the striatum to the globus pallidus, that inhibits competing repetitive or stereotyped behaviors is attenuated. Females (women and laboratory rats) exhibit more rapid escalation of drug taking than do males and estradiol (E2) enhances acquisition of drug taking and motivation for drugs of abuse. Experiments from the Becker laboratory have demonstrated that E2 inhibits GABA release, down-regulates DA D2 receptors (D2DR), and enhances cocaine- or amphetamine-stimulated DA release in DLS but not NAc. The overarching hypotheses for this proposal are: 1) An attenuated cocaine-induced DA increase in NAc combined with an enhanced DA increase to cocaine in DLS is related to the propensity to develop a preference for cocaine over palatable food pellets in both males and females; 2) Estradiol's action in DLS of females enhances the cocaine-induced dopamine (DA) increase, inhibits GABA release, and inhibits D2 DA receptors. This combined effect enhances the rate of preference formation and motivation for cocaine over pellets in females; and 3) Decreased inhibition of the indirect pathway in DLS contributes to enhanced motivation for cocaine over pellets in both males and females. In females D2DRs are down-regulated in this pathway by E2, and this contributes to the more rapid preference formation in females and greater motivation for cocaine over pellets. Determining the mechanism(s) mediating formation of preference for cocaine over a highly palatable food reward, and how individual differences and sex differences contribute to this, are important for our understanding of and treatment of addiction in both men and women.