Synaptic mechanisms underlying reward seeking and compulsive drug use

奖励寻求和强迫性药物使用的突触机制

• 批准号: 10908156
• 负责人: Veronica A Alvarez
• 金额: $ 83.99万
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10908156
• 关键词: Acute; Addictive Behavior; Affect; Agonist; Alleles; Animals; Autoreceptors; Basal Ganglia; Behavior; Behavioral; Binding; Breeding; Clinical; Cocaine; Cocaine Abuse; Cocaine use disorder; Collection; Compulsive Behavior; Consumption; Corpus striatum structure; DRD2 gene; Data; Development; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Down-Regulation; Drug usage; Ethanol; Face; Genetic; Genotype; Globus Pallidus; Goals; Impairment; In Vitro; Individual; Intake; Intravenous; Laboratories; Lateral; Ligand Binding; Locomotion; Mediating; Midbrain structure; Mus; Neurobiology; Neurons; Nucleus Accumbens; Patients; Pharmaceutical Preparations; Phenotype; Physiological; Physiology; Play; Population; Predisposition; Property; Psychological reinforcement; Publishing; Research; Rewards; Role; Stimulant; Substance Use Disorder; Synapses; Testing; Transgenic Mice; Up-Regulation; Wild Type Mouse; Work; adverse outcome; alcohol behavior; alcohol use disorder; behavioral phenotyping; behavioral response; cocaine related behaviors; cocaine seeking; cocaine self-administration; desensitization; dopaminergic neuron; drug action; drug misuse; improved; in vivo; knock-down; motivated behavior; mouse model; optogenetics; postsynaptic; receptor; response; substance misuse; substance use treatment; synergism; tool

Evidence for a key role of D2 auto-receptors rather than striatal postsynaptic D2 receptors in the susceptibility for cocaine abuse This study tested the hypothesis that low levels of D2 receptors in both striatum and midbrain neurons might synergize to give rise to a vulnerable phenotype with enhanced reinforcing properties for cocaine and impair loss of control over consumption. We developed this hypothesis based on collection of our published work that showed that D2 auto-receptors in dopamine neurons play different and sometimes complementary roles in the circuitry in comparison to D2Rs in striatal neurons. Thus, we reasoned that lowering levels of both D2 receptors in the same animals would generate a vulnerable circuitry and lead to increased reinforcing properties of cocaine, increased perseverance in cocaine seeking and intake that is insensitive to adverse outcomes. Previously we had shown that D2 auto-receptors act as negative regulators of dopamine synthesis and release and of dopamine neuron activity. Loss of D2 auto-receptors enhanced cocaine acute locomotor response and the acquisition of cocaine self-administration behavior. On the other hand, we also showed that D2 receptors in striatal neurons regulate the strength of the lateral inhibition between striatal neurons and when these receptors are expressed at low levels, the striatum is under potent inhibition. Loss of D2 auto-receptors from midbrain dopamine neurons or loss of D2 receptors on striatal neurons produce different alterations of synaptic physiology in the basal ganglia. We showed that each of the receptors contribute to selected changes in cocaine-driven behaviors. The goal of this project was to dissect out the contribution of the D2Rs in the striatum and the midbrain to the behavioral response to cocaine and the vulnerability to develop addictive behaviors. We generated transgenic mice with targeted single-allele deletion of Drd2 gene in either the medium spiny neurons (MSN) of the striatum (iMSN-D2HET), or the midbrain dopamine neurons (auto-D2HET), or both (double-D2HET). We argue that patients suffering from substance use disorders display a reduction rather than complete loss of D2 receptor availability and as such partial knockdown of D2 receptors is a more informative manipulation with improved face-validity for the clinical condition. We bred these mice such that mice of all three genotypes and wildtype were produced as littermates and tested a battery of striatal-controlled dopamine-mediated behaviors and the response to cocaine, including intravenous cocaine self-administration (IV-SA). These are the highlights of the findings: D2 auto-receptors contribute to D2/3 ligand binding in the striatum and are largely responsible for locomotor suppression produced by d2/3 agonists (via inhibition of DA release). D2 receptors in striatal neurons are responsible for mediating the acute effects of cocaine and its actions synergized with D1 receptors. Mice with low D2 receptors in striatal neurons show normal response to D2/3 agonists, display upregulation of striatal D1-like ligand binding and behavioral response, and show lower acute response but increased sensitized response to cocaine. Mice with low expression of D2 auto-receptors have reduced D2/3 binding in the striatum, have reduced D2/3 agonist responses, display downregulation of striatal D1-like ligand binding and its behavioral response, and show increased acute response to cocaine and desensitization over repeated exposure. Thus, our data shows that mice with low D2 auto-receptors and mice with low levels of striatal D2 receptors often display opposite phenotypes with regard to dopamine-related and cocaine-related behaviors. The study further shows that simultaneous reduction of both D2 auto-receptors and D2R in striatal neurons (double-D2HET mice) most often have the mildest phenotypes. Thus, contrary to our initial hypothesis that low D2Rs in both regions will synergize to produce the vulnerable phenotype, we found that balanced reduction of D2Rs led to behavioral phenotypes that most resemble the wild-type mice. We only found evidence of synergism in the acute response to cocaine. Double-D2HET resembles auto-D2HET alterations on some behaviors while they mimic the phenotype of striatum-D2HET on other behaviors. This study gives us a better understanding of the unique contributions of striatal and midbrain D2R to dopamine-dependent behaviors and the response to cocaine to better inform new treatments for substance use disorders.

D2自身受体而不是纹状体突触后D2受体在可卡因滥用易感性中的关键作用的证据 这项研究测试的假设，低水平的D2受体在纹状体和中脑神经元可能会协同产生一个脆弱的表型与可卡因增强增强性能和损害失去控制的消费。我们基于我们已发表的工作的集合提出了这一假设，这些工作表明，与纹状体神经元中的D2受体相比，多巴胺神经元中的D2自受体在回路中发挥着不同的、有时是互补的作用。因此，我们推断，降低同一动物中两种D2受体的水平将产生脆弱的回路，并导致可卡因的增强特性增加，可卡因寻求和摄入的毅力增加，对不良结果不敏感。 以前我们已经表明，D2自身受体作为多巴胺合成和释放以及多巴胺神经元活动的负调节剂。D2自身受体的丧失增强了可卡因急性运动反应和可卡因自我给药行为的获得。 另一方面，我们还表明，纹状体神经元中的D2受体调节纹状体神经元之间的侧抑制的强度，当这些受体以低水平表达时，纹状体处于有效抑制下。中脑多巴胺神经元的D2自身受体的丧失或纹状体神经元上D2受体的丧失在基底神经节中产生突触生理学的不同改变。我们发现，每种受体都有助于可卡因驱动行为的选择性变化。该项目的目标是剖析纹状体和中脑中D2 R对可卡因行为反应的贡献以及发展成瘾行为的脆弱性。 我们产生了在纹状体的中棘神经元（MSN）（iMSN-D2 HET）或中脑多巴胺神经元（auto-D2 HET）或两者（双D2 HET）中具有Drd 2基因的靶向单等位基因缺失的转基因小鼠。我们认为，患有物质使用障碍的患者显示减少，而不是完全丧失D2受体的可用性，因此部分敲除D2受体是一个更翔实的操作，改善了临床条件的面子。我们繁殖这些小鼠，使所有三种基因型和野生型的小鼠作为同窝出生，并测试了一系列纹状体控制的多巴胺介导的行为和对可卡因的反应，包括静脉内可卡因自我给药（IV-SA）。这些是研究结果的亮点：D2自身受体有助于纹状体中的D2/3配体结合，并且主要负责d2/3激动剂产生的运动抑制（通过抑制DA释放）。纹状体神经元中的D2受体负责介导可卡因的急性效应，并且其作用与D1受体协同。 纹状体神经元中D2受体较低的小鼠对D2/3激动剂表现出正常反应，显示出纹状体D1样配体结合和行为反应的上调，并表现出较低的急性反应，但对可卡因的致敏反应增加。 D2自身受体低表达的小鼠纹状体中的D2/3结合减少，D2/3激动剂反应减少，显示纹状体D1样配体结合及其行为反应下调，并显示对可卡因的急性反应增加和重复暴露的脱敏。 因此，我们的数据表明，低D2自身受体的小鼠和纹状体D2受体水平低的小鼠在多巴胺相关和可卡因相关行为方面往往表现出相反的表型。该研究进一步表明，纹状体神经元（双D2 HET小鼠）中D2自身受体和D2 R的同时减少通常具有最温和的表型。因此，与我们最初的假设相反，即两个区域中的低D2 Rs将协同产生脆弱表型，我们发现D2 Rs的平衡减少导致最类似于野生型小鼠的行为表型。我们只在可卡因的急性反应中发现了协同作用的证据。双D2 HET在某些行为上类似于自身D2 HET改变，而在其他行为上它们模仿纹状体D2 HET的表型。这项研究使我们更好地了解纹状体和中脑D2 R对多巴胺依赖性行为的独特贡献以及对可卡因的反应，以更好地为物质使用障碍的新治疗提供信息。

项目成果

Correction: Genetic inhibition of neurotransmission reveals role of glutamatergic input to dopamine neurons in high-effort behavior.

纠正：神经传递的基因抑制揭示了谷氨酸能输入多巴胺神经元在高努力行为中的作用。

• DOI: 10.1038/mp.2018.3
• 发表时间: 2018
• 期刊: Molecular psychiatry
• 影响因子: 11
• 作者: Hutchison,MA;Gu,X;Adrover,MF;Lee,MR;Hnasko,TS;Alvarez,VA;Lu,W
• 通讯作者: Lu,W

Strengthening the accumbal indirect pathway promotes resilience to compulsive cocaine use.

• DOI: 10.1038/nn.3369
• 发表时间: 2013-05
• 期刊: NATURE NEUROSCIENCE
• 影响因子: 25
• 作者: Bock, Roland;Shin, J. Hoon;Kaplan, Alanna R.;Dobi, Alice;Markey, Eric;Kramer, Paul F.;Gremel, Christina M.;Christensen, Christine H.;Adrover, Martin F.;Alvarez, Veronica A.
• 通讯作者: Alvarez, Veronica A.

Association of mouse Dlg4 (PSD-95) gene deletion and human DLG4 gene variation with phenotypes relevant to autism spectrum disorders and Williams' syndrome.

• DOI: 10.1176/appi.ajp.2010.10040484
• 发表时间: 2010-12
• 期刊: The American journal of psychiatry
• 作者: Feyder M;Karlsson RM;Mathur P;Lyman M;Bock R;Momenan R;Munasinghe J;Scattoni ML;Ihne J;Camp M;Graybeal C;Strathdee D;Begg A;Alvarez VA;Kirsch P;Rietschel M;Cichon S;Walter H;Meyer-Lindenberg A;Grant SG;Holmes A
• 通讯作者: Holmes A

Cocaine-induced plasticity in the nucleus accumbens is cell specific and develops without prolonged withdrawal.

• DOI: 10.1523/jneurosci.5375-10.2011
• 发表时间: 2011-02-02
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Dobi A;Seabold GK;Christensen CH;Bock R;Alvarez VA
• 通讯作者: Alvarez VA

Alcohol and basal ganglia circuitry: Animal models.

• DOI: 10.1016/j.neuropharm.2017.03.023
• 发表时间: 2017-08-01
• 期刊: Neuropharmacology
• 影响因子: 4.7
• 作者: Lovinger DM;Alvarez VA
• 通讯作者: Alvarez VA