Polter Abigail M, Bishop Rachel A, Briand Lisa A, Graziane Nicholas M, Pierce R Christopher, Kauer Julie A
Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, Rhode Island.
Center for Neurobiology and Behavior, Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
Biol Psychiatry. 2014 Nov 15;76(10):785-93. doi: 10.1016/j.biopsych.2014.04.019. Epub 2014 May 21.
Dopaminergic neurons in the ventral tegmental area of the brain are an important site of convergence of drugs and stress. We previously identified a form of long-term potentiation of gamma-aminobutyric acid (GABA)ergic synapses on these neurons (LTPGABA). Our studies have shown that exposure to acute stress blocks this LTP and that reversal of the block of LTPGABA is correlated with prevention of stress-induced reinstatement of cocaine-seeking behavior.
Sprague-Dawley rats were subjected to cold-water swim stress. Midbrain slices were prepared following stress, and whole-cell patch clamp recordings of inhibitory postsynaptic currents were performed from ventral tegmental area dopamine neurons. Antagonists of glucocorticoid receptors and kappa opioid receptors (κORs) were administered at varying time points after stress. Additionally, the ability of a kappa antagonist administered following stress to block forced swim stress-induced reinstatement of cocaine self-administration was tested.
We found that an acute stressor blocks LTPGABA for 5 days after stress through a transient activation of glucocorticoid receptors and more lasting contribution of κORs. Even pharmacological block of κORs beginning 4 days after stress has occurred reversed the block of LTPGABA. Administration of a κORs antagonist following stress prevents reinstatement of cocaine-seeking behavior.
A brief stressor produces changes in the reward circuitry lasting several days. Our findings reveal roles for glucocorticoid receptors and κORs as mediators of the lasting effects of stress on synaptic plasticity. κORs antagonists reverse the neuroadaptations underlying stress-induced drug-seeking behavior and may be useful in the treatment of cocaine addiction.
大脑腹侧被盖区的多巴胺能神经元是药物和应激汇聚的重要部位。我们之前在这些神经元上发现了一种γ-氨基丁酸（GABA）能突触的长期增强形式（LTPGABA）。我们的研究表明，急性应激暴露会阻断这种LTP，并且LTPGABA阻断的逆转与预防应激诱导的可卡因觅药行为的复燃相关。
将Sprague-Dawley大鼠置于冷水游泳应激中。应激后制备中脑切片，并从腹侧被盖区多巴胺能神经元进行抑制性突触后电流的全细胞膜片钳记录。在应激后的不同时间点给予糖皮质激素受体拮抗剂和κ阿片受体（κORs）拮抗剂。此外，还测试了应激后给予κ拮抗剂阻断强迫游泳应激诱导的可卡因自我给药复燃的能力。
我们发现，急性应激源通过糖皮质激素受体的短暂激活和κORs更持久的作用，在应激后5天阻断LTPGABA。即使在应激发生4天后开始对κORs进行药理学阻断也能逆转LTPGABA的阻断。应激后给予κORs拮抗剂可预防可卡因觅药行为的复燃。
短暂的应激源会在奖励回路中产生持续数天的变化。我们的研究结果揭示了糖皮质激素受体和κORs作为应激对突触可塑性长期影响的介质的作用。κORs拮抗剂可逆转应激诱导的药物觅药行为背后的神经适应性变化，可能对可卡因成瘾的治疗有用。
