Limpens Jules H W, Damsteegt Ruth, Broekhoven Mark H, Voorn Pieter, Vanderschuren Louk J M J
Brain Center Rudolf Magnus, Dept. of Translational Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
Department of Anatomy and Neurosciences, Neuroscience Campus Amsterdam, VU University Medical Centre, Amsterdam, The Netherlands.
Brain Res. 2015 Dec 2;1628(Pt A):210-8. doi: 10.1016/j.brainres.2014.10.045. Epub 2014 Oct 31.
Drug addiction is a chronic, relapsing brain disorder characterized by compulsive drug use. Contemporary addiction theories state that loss of control over drug use is mediated by a combination of several processes, including a transition from goal-directed to habitual forms of drug seeking and taking, and a breakdown of the prefrontally-mediated cognitive control over drug intake. In recent years, substantial progress has been made in the modelling of loss of control over drug use in animal models, but the neural substrates of compulsive drug use remain largely unknown. On the basis of their involvement in goal-directed behaviour, value-based decision making, impulse control and drug seeking behaviour, we identified the prelimbic cortex (PrL) and orbitofrontal cortex (OFC) as candidate regions to be involved in compulsive drug seeking. Using a conditioned suppression model, we have previously shown that prolonged cocaine self-administration reduces the ability of a conditioned aversive stimulus to reduce drug seeking, which may reflect the unflagging pursuit of drugs in human addicts. Therefore, we tested the hypothesis that dysfunction of the PrL and OFC underlies loss of control over drug seeking behaviour, apparent as reduced conditioned suppression. Pharmacological inactivation of the PrL, using the GABA receptor agonists baclofen and muscimol, reduced conditioned suppression of cocaine and sucrose seeking in animals with limited self-administration experience. Inactivation of the OFC did not influence conditioned suppression, however. These data indicate that reduced neural activity in the PrL promotes persistent seeking behaviour, which may underlie compulsive aspects of drug use in addiction.
药物成瘾是一种慢性复发性脑部疾病，其特征为强迫性药物使用。当代成瘾理论指出，对药物使用失去控制是由多种过程共同介导的，包括从目标导向型到习惯性药物寻求和使用形式的转变，以及前额叶介导的对药物摄入的认知控制的崩溃。近年来，在动物模型中对药物使用失去控制的建模方面取得了重大进展，但强迫性药物使用的神经基础在很大程度上仍然未知。基于它们在目标导向行为、基于价值的决策、冲动控制和药物寻求行为中的作用，我们确定前边缘皮层（PrL）和眶额皮层（OFC）为参与强迫性药物寻求的候选区域。使用条件性抑制模型，我们之前已经表明，长期的可卡因自我给药会降低条件性厌恶刺激减少药物寻求的能力，这可能反映了人类成瘾者对药物的不懈追求。因此，我们测试了以下假设：PrL和OFC功能障碍是药物寻求行为失去控制的基础，表现为条件性抑制降低。使用GABA受体激动剂巴氯芬和蝇蕈醇对PrL进行药理学失活，减少了自我给药经验有限的动物对可卡因和蔗糖寻求的条件性抑制。然而，OFC的失活并未影响条件性抑制。这些数据表明，PrL中神经活动的减少促进了持续的寻求行为，这可能是成瘾中药物使用强迫性方面的基础。
