Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania.
Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania.
Biol Psychiatry. 2022 Dec 1;92(11):880-894. doi: 10.1016/j.biopsych.2022.06.006. Epub 2022 Jun 13.
Persistent sleep disruptions following withdrawal from abused drugs may hold keys to battle drug relapse. It is posited that there may be sleep signatures that predict relapse propensity, identifying which may open new avenues for treating substance use disorders.
We trained male rats (approximately postnatal day 56) to self-administer cocaine. After long-term drug withdrawal (approximately postnatal day 100), we examined the correlations between the intensity of cocaine seeking and key sleep features. To test for causal relationships, we then used behavioral, chemogenetic, or optogenetic methods to selectively increase rapid eye movement sleep (REMS) and measured behavioral and electrophysiological outcomes to probe for cellular and circuit mechanisms underlying REMS-mediated regulation of cocaine seeking.
A selective set of REMS features was preferentially associated with the intensity of cue-induced cocaine seeking after drug withdrawal. Moreover, selectively increasing REMS time and continuity by environmental warming attenuated a withdrawal time-dependent intensification of cocaine seeking, or incubation of cocaine craving, suggesting that REMS may benefit withdrawal. Warming increased the activity of lateral hypothalamic melanin-concentrating hormone (MCH) neurons selectively during prolonged REMS episodes and counteracted cocaine-induced synaptic accumulation of calcium-permeable AMPA receptors in the nucleus accumbens-a critical substrate for incubation. Finally, the warming effects were partly mimicked by chemogenetic or optogenetic stimulations of MCH neurons during sleep, or intra-accumbens infusions of MCH peptide during the rat's inactive phase.
REMS may encode individual vulnerability to relapse, and MCH neuron activities can be selectively targeted during REMS to reduce drug relapse.
滥用药物戒断后持续的睡眠中断可能是与对抗药物复吸有关的关键因素。据推测，可能存在预测复吸倾向的睡眠特征，可以识别这些特征，为治疗物质使用障碍开辟新途径。
我们训练雄性大鼠（大约在出生后第 56 天）自行注射可卡因。在长期药物戒断（大约在出生后第 100 天）后，我们检查了可卡因寻求的强度与关键睡眠特征之间的相关性。为了测试因果关系，我们随后使用行为、化学遗传学或光遗传学方法选择性地增加快速眼动睡眠（REMS），并测量行为和电生理结果，以探究 REMS 调节可卡因寻求的细胞和电路机制。
一组选择性的 REMS 特征与药物戒断后线索诱导的可卡因寻求的强度优先相关。此外，通过环境升温选择性地增加 REMS 时间和连续性，减弱了戒断时间依赖性可卡因寻求的强化，或可卡因渴求的潜伏期，表明 REMS 可能有益于戒断。升温选择性地增加了长时 REMS 期间外侧下丘脑黑色素浓缩激素（MCH）神经元的活性，并抵消了可卡因诱导的伏隔核中钙通透性 AMPA 受体的突触积累——这是潜伏期的一个关键底物。最后，在睡眠期间化学遗传学或光遗传学刺激 MCH 神经元，或在大鼠非活动期内内侧伏隔核内注射 MCH 肽，部分模拟了升温的效果。
REMS 可能编码个体对复吸的易感性，并且可以在 REMS 期间选择性地靶向 MCH 神经元活动，以减少药物复吸。
