Imaging dopamine transmission in cannabis dependence

描述（由申请人提供）：大麻的使用非常普遍，尤其是在青少年中。与其他滥用药物相比，它的广泛使用部分与无害的概念有关。然而，大麻已被证明会导致对其他药物的依赖、敏感或耐受、精神病、焦虑、抑郁和认知障碍。临床和临床前数据表明，在青春期使用它可能会对大脑产生持久的影响，并可能影响多巴胺能的传递。尽管有许多临床和临床前数据表明这一点，但迄今为止还没有大麻使用者多巴胺传递的影像学研究。40名寻求大麻依赖的非治疗受试者（CD）和40名匹配的健康对照（HC）将在基线和给予0.3 mg/kg d-安非他明（静脉注射）后，使用D2/3受体放射性示踪剂[11 C] raclopride进行PET扫描。我们将在基线扫描[11 C]中测量raclopride结合电位（BP）和特异性-非特异性平衡分配系数（V3”），这两种受体可用性的测量指标都是纹状体整体和纹状体亚结构。在扫描2中，我们将测量与安非他明诱导的DA释放相关的V3“与基线相比，AV3”的变化。我们预测，与其他物质类似，大麻依赖将与低纹状体D2 （SA1）和低腹侧纹状体刺激多巴胺释放（SA2）有关。这项研究将首次提供长期使用大麻对人类受试者大脑中与多巴胺能相关的奖赏回路的影响的信息，并将允许将大麻（一种被认为无害的药物）与可卡因或酒精等其他药物进行比较。这可能对公共卫生和精神病学产生重大影响。在后续的资助中，我们将提出在双重诊断（共病精神分裂症和大麻依赖）患者中研究相同的参数，因为这两种情况下多巴胺能系统在中脑边缘与相关皮质纹状体-丘脑-皮质回路中可能受到不同的影响。

DESCRIPTION (provided by applicant): Cannabis use is very prevalent especially in adolescence. Its widespread use is partially related to the concept of being somewhat harmless as compared to other drugs of abuse. Yet cannabis has been shown to induce dependence, sensitization or tolerance to other drugs, psychosis, anxiety, depression and cognitive disturbances. Clinical and preclinical data suggest that its use in adolescence may have long lasting effects on the brain and may affect dopaminergic transmission. Despite much clinical and preclinical data to this effect no imaging studies of dopamine transmission in cannabis users are available to date. Forty non treatment seeking cannabis dependent subjects (CD) and 40 matched healthy controls (HC) will undergo PET scanning with the D2/3 receptor radiotracer [11 C] raclopride at baseline and after administration of 0.3 mg/kg d-amphetamine (i.v. bolus). We will measure in the baseline scan [11 C] raclopride binding potential (BP), and the specific-to-nonspecific equilibrium partition coefficient (V3"), both measures of receptor availability, in the striatum as a whole and in striatal substructures. On scans 2 we will measure the change in V3" compared to baseline, AV3", related to amphetamine induced DA release. We predict that similarly to other substances, cannabis dependence will be associated with low striatal D2 (SA1) and low ventrostriatal stimulated dopamine release (SA2). This study will provide for the first time information on the effects of chronic cannabis use on the dopaminergic related reward circuits in the brains of human subjects and will allow drawing comparisons between cannabis, a drug thought to be harmless, and other drugs such as cocaine or alcohol. This is likely to have a significant impact on public health and psychiatry. In a companion grant we will propose later to investigate the same parameters in dual diagnosis (comorbid schizophrenia and cannabis dependence) patients as dopaminergic systems may be differentially affected in the mesolimbic versus associative corticostriato-thalamo-cortical loops by these two conditions.