Department of Psychology, University of Wisconsin, Madison, WI 53706, USA.
Int J Neuropsychopharmacol. 2014 Jan;17(1):63-75. doi: 10.1017/S1461145713000734. Epub 2013 Jul 29.
Psychostimulants, including amphetamine (AMPH), exert robust arousal-enhancing, reinforcing and locomotor-activating effects. These behavioural actions involve drug-induced elevations in extracellular norepinephrine (NE) and dopamine (DA) within a variety of cortical and subcortical regions. The lateral hypothalamic area (LHA), including the lateral hypothalamus proper, perifornical area and adjacent dorsomedial hypothalamus, is implicated in appetitive- and arousal-related processes. The LHA is innervated by both NE and DA projections and systemically administered AMPH has been demonstrated to activate LHA neurons. Combined, these and other observations suggest the LHA may be a site of action in the behavioural effects of psychostimulants. To test this hypothesis, we examined the degree to which AMPH (10 nmol, 25 nmol) acts within the LHA to exert arousing, locomotor-activating and reinforcing actions in quietly resting/sleeping rats. Although intra-LHA AMPH robustly increased time spent awake, this occurred in the absence of pronounced locomotor activation or reinforcing actions, as measured in a conditioned place preference (CPP) paradigm. Arousing and stressful conditions or drug re-exposure can elicit relapse in humans and reinstate drug-seeking in animals. Given the LHA is also implicated in the reinstatement of drug-seeking behaviour, additional studies examined whether AMPH acts within the LHA to reinstate an extinguished CPP produced with systemic AMPH administration. Our results demonstrate that AMPH action within the LHA is sufficient to reinstate drug-seeking behaviour, as measured in this paradigm. Collectively, these observations demonstrate that psychostimulants act within the LHA to elicit affectively neutral arousal and reinstate drug-seeking behaviour.
兴奋剂,包括安非他命(AMPH),具有强大的兴奋增强、强化和运动激活作用。这些行为作用涉及各种皮质和皮质下区域内的药物诱导的去甲肾上腺素(NE)和多巴胺(DA)的升高。外侧下丘脑区域(LHA),包括外侧下丘脑本身、peri 穹窿区和相邻的背内侧下丘脑,与食欲和觉醒相关的过程有关。LHA 被 NE 和 DA 投射支配,系统给予的 AMPH 已被证明可以激活 LHA 神经元。综合这些和其他观察结果表明,LHA 可能是兴奋剂行为作用的作用部位。为了检验这一假设,我们研究了 AMPH(10 nmol,25 nmol)在 LHA 内的作用程度,以在安静休息/睡眠的大鼠中发挥兴奋、运动激活和强化作用。尽管 LHA 内的 AMPH 强烈增加了清醒时间,但这是在没有明显运动激活或强化作用的情况下发生的,如在条件性位置偏好(CPP)范式中测量的那样。唤醒和应激条件或药物再暴露可在人类中引发复发,并在动物中恢复药物寻求。鉴于 LHA 也与药物寻求行为的恢复有关,进一步的研究还检查了 AMPH 是否在 LHA 内作用以恢复由系统 AMPH 给药产生的已消除的 CPP。我们的结果表明,LHA 内的 AMPH 作用足以恢复在该范式中测量的药物寻求行为。总的来说,这些观察结果表明,兴奋剂在 LHA 内作用以引起情感中立的觉醒并恢复药物寻求行为。