Neurobiology of Alcohol Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada.
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada.
Int J Neuropsychopharmacol. 2019 Nov 1;22(11):724-734. doi: 10.1093/ijnp/pyz049.
Stress is associated with relapse to alcohol seeking during abstinence, but the processes underlying this relationship are poorly understood. Noradrenaline is a key transmitter in stress responses and in stress-induced drug seeking. The alpha-1 adrenoceptor antagonist prazosin has been investigated as a treatment for alcoholism and for chronic stress disorders that are frequently comorbid with alcoholism. In rats, we previously showed that prazosin blocks reinstatement of alcohol seeking induced by footshock and yohimbine stressors and reduces yohimbine-induced brain activation. The role of alpha-1 adrenoceptors in reinstatement induced by other stressors is not known. Our most recent work is on the role of kappa opioid receptors in stress-induced reinstatement of alcohol seeking and have reported that the selective kappa opioid receptor agonist U50,488 induces reinstatement and neuronal activation in stress- and relapse-related brain regions. Here we determine the involvement of alpha-1 receptors in reinstatement and brain activation induced by U50,488.
We trained male Long-Evans rats to self-administer alcohol (12% w/v), extinguished alcohol-reinforced responding, and then determined the effects of prazosin (1 mg/kg) on U50,488 (2.5 mg/kg)-induced reinstatement and regional Fos expression.
Prazosin blocked U50,488-induced reinstatement and decreased U50,488-induced Fos expression in the orbitofrontal cortex, nucleus accumbens core, ventral bed nucleus of the stria terminalis, central and basolateral amygdalar nuclei and ventral tegmental area.
These findings suggest that prazosin may reduce U50,488-induced relapse by inhibiting activity in 1 or more of these brain areas.
压力与戒断期间复饮酒精寻求有关，但这种关系的潜在机制尚不清楚。去甲肾上腺素是应激反应和应激诱导药物寻求的关键递质。α1 肾上腺素受体拮抗剂特拉唑嗪已被研究用于治疗酒精中毒和慢性应激障碍，这些障碍常与酒精中毒共病。在大鼠中，我们之前的研究表明，特拉唑嗪阻断了电击和育亨宾应激诱导的酒精寻求复燃，并减少了育亨宾诱导的大脑激活。α1 肾上腺素受体在其他应激源诱导的复燃中的作用尚不清楚。我们最近的工作是研究κ阿片受体在应激诱导的酒精寻求复燃中的作用，并报告选择性 κ阿片受体激动剂 U50,488 诱导应激和与复发相关的脑区的复燃和神经元激活。在这里，我们确定 α1 受体在 U50,488 诱导的复燃和大脑激活中的参与。
我们训练雄性长耳大鼠自行摄入酒精（12%w/v），消除酒精强化反应，然后确定特拉唑嗪（1mg/kg）对 U50,488（2.5mg/kg）诱导的复燃和区域 Fos 表达的影响。
特拉唑嗪阻断了 U50,488 诱导的复燃，并减少了 U50,488 诱导的眶额皮质、伏隔核核心、终纹床核腹侧部、中央和基底杏仁核以及腹侧被盖区的 Fos 表达。
这些发现表明，特拉唑嗪可能通过抑制这些脑区中的 1 个或多个区域的活动来减少 U50,488 诱导的复燃。
