Division of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria di Monserrato Monserrato, Italy.
Institut du Fer à Moulin Paris, France.
Front Integr Neurosci. 2013 Dec 19;7:93. doi: 10.3389/fnint.2013.00093. eCollection 2013.
Addiction as a psychiatric disorder involves interaction of inherited predispositions and environmental factors. Similarly to humans, laboratory animals self-administer addictive drugs, whose appetitive properties result from activation and suppression of brain reward and aversive pathways, respectively. The ventral tegmental area (VTA) where dopamine (DA) cells are located is a key component of brain reward circuitry, whereas the rostromedial tegmental nucleus (RMTg) critically regulates aversive behaviors. Reduced responses to either aversive intrinsic components of addictive drugs or to negative consequences of compulsive drug taking might contribute to vulnerability to addiction. In this regard, female Lister Hooded (LH) rats are more vulnerable than male counterparts to cannabinoid self-administration. We, therefore, took advantage of sex differences displayed by LH rats, and studied VTA DA neuronal properties to unveil functional differences. Electrophysiological properties of DA cells were examined performing either single cell extracellular recordings in anesthetized rats or whole-cell patch-clamp recordings in slices. In vivo, DA cell spontaneous activity was similar, though sex differences were observed in RMTg-induced inhibition of DA neurons. In vitro, DA cells showed similar intrinsic and synaptic properties. However, females displayed larger depolarization-induced suppression of inhibition (DSI) than male LH rats. DSI, an endocannabinoid-mediated form of short term plasticity, was mediated by 2-arachidonoylglycerol (2-AG) activating type 1-cannabinoid (CB1) receptors. We found that sex-dependent differences in DSI magnitude were not ascribed to CB1 number and/or function, but rather to a tonic 2-AG signaling. We suggest that sex specific tonic 2-AG signaling might contribute to regulate responses to aversive intrinsic properties to cannabinoids, thus resulting in faster acquisition/initiation of cannabinoid taking and, eventually, in progression to addiction.
成瘾作为一种精神障碍，涉及遗传易感性和环境因素的相互作用。与人类相似，实验室动物会自行使用成瘾药物，这些药物的食欲特性分别来自大脑奖励和厌恶途径的激活和抑制。腹侧被盖区（VTA）是多巴胺（DA）细胞所在的关键组成部分，是大脑奖励回路的关键组成部分，而延髓背内侧核（RMTg）则对厌恶行为进行严格调节。对成瘾药物的厌恶内在成分或强迫性药物使用的负面后果的反应减少可能导致对成瘾的易感性。在这方面，Lister Hooded（LH）雌性大鼠比雄性大鼠更容易受到大麻素自我给药的影响。因此，我们利用 LH 大鼠表现出的性别差异，研究 VTA DA 神经元特性，以揭示功能差异。在麻醉大鼠中进行单细胞细胞外记录或在切片中进行全细胞贴片记录来检查 DA 细胞的电生理特性。在体内，DA 细胞的自发活动相似，尽管在 RMTg 诱导的 DA 神经元抑制中观察到性别差异。在体外，DA 细胞表现出相似的内在和突触特性。然而，雌性大鼠的去极化诱导抑制抑制（DSI）比雄性 LH 大鼠更大。DSI 是一种内源性大麻素介导的短期可塑性形式，由 2-花生四烯酸甘油（2-AG）激活型 1-大麻素（CB1）受体介导。我们发现，DSI 幅度的性别依赖性差异不是由于 CB1 数量和/或功能，而是由于紧张的 2-AG 信号。我们认为，性别特异性的紧张 2-AG 信号可能有助于调节对大麻素的厌恶内在特性的反应，从而导致更快地获得/启动大麻素的摄取，最终导致成瘾。
