The rewarding effects of stimulant drugs such as methylphenidate (MP) depend crucially on how fast they raise dopamine in the brain. Yet how the rate of drug-induced dopamine increases impacts brain network communication remains unresolved. We manipulated route of MP administration to generate fast versus slow dopamine increases. We hypothesized that fast versus slow dopamine increases would result in a differential pattern of global brain connectivity (GBC) in association with regional levels of dopamine D1 receptors, which are critical for drug reward. Twenty healthy adults received MP intravenously (0.5 mg/kg; fast dopamine increases) and orally (60 mg; slow dopamine increases) during simultaneous [¹¹C]raclopride PET-fMRI scans (double-blind, placebo-controlled). We tested how GBC was temporally associated with slow and fast dopamine increases on a minute-to-minute basis. Connectivity patterns were strikingly different for slow versus fast dopamine increases, and whole-brain spatial patterns were negatively correlated with one another (rho = −0.54, p_spin < 0.001). GBC showed “fast>slow” associations in dorsal prefrontal cortex, insula, posterior thalamus and brainstem, caudate and precuneus; and “slow>fast” associations in ventral striatum, orbitofrontal cortex, and frontopolar cortex (p_FDR < 0.05). “Fast>slow” GBC patterns showed significant spatial correspondence with D1 receptor availability (estimated via normative maps of [¹¹C]SCH23390 binding; rho = 0.22, p_spin < 0.05). Further, hippocampal GBC to fast dopamine increases was significantly negatively correlated with self-reported ‘high’ ratings to intravenous MP across individuals (r₍₁₉₎ = −0.68, p_bonferroni = 0.015). Different routes of MP administration produce divergent patterns of brain connectivity. Fast dopamine increases are uniquely associated with connectivity patterns that have relevance for the subjective experience of drug reward.

哌醋甲酯 (MP) 等兴奋剂药物的奖励作用很大程度上取决于它们在大脑中提高多巴胺的速度。然而，药物引起的多巴胺增加率如何影响大脑网络通讯仍然悬而未决。我们操纵 MP 给药途径来产生快速与缓慢的多巴胺增加。我们假设，快速与缓慢的多巴胺增加将导致与区域多巴胺 D1 受体水平相关的全球大脑连接 (GBC) 的差异模式，这对于药物奖励至关重要。 20 名健康成年人在同步[ ¹¹ C]雷氯必利 PET-fMRI 扫描（双盲，安慰剂对照）期间接受静脉注射（0.5 mg/kg；多巴胺快速增加）和口服（60 mg；多巴胺缓慢增加）MP。我们测试了 GBC 如何在时间上与每分钟缓慢和快速多巴胺增加相关。多巴胺缓慢增加与快速增加的连接模式显着不同，全脑空间模式彼此呈负相关（rho = -0.54， p _spin < 0.001）。 GBC在背侧前额皮质、岛叶、丘脑后部和脑干、尾状核和楔前叶中表现出“快>慢”的关联；腹侧纹状体、眶额皮质和额极皮质中的“慢>快”关联（ p _FDR < 0.05）。 “快>慢”GBC 模式显示出与 D1 受体可用性的显着空间对应关系（通过 [ ¹¹ C]SCH23390 结合的规范图估计；rho = 0.22， p_自旋< 0.05）。 此外，海马 GBC 对快速多巴胺增加的影响与个体自我报告的静脉 MP 的“高”评级显着负相关（ r _{( 19)} = -0.68， p _bonferroni = 0.015）。不同的 MP 给药途径会产生不同的大脑连接模式。多巴胺的快速增加与连接模式独特相关，而连接模式与药物奖励的主观体验相关。