Lau B, Bretaud S, Huang Y, Lin E, Guo S
Department of Biopharmaceutical Sciences, Programs in Human Genetics and Biological Sciences, Neuroscience, Wheeler Center for the Neurobiology of Addiction, University of California, San Francisco, CA 94143-0446, USA.
Genes Brain Behav. 2006 Oct;5(7):497-505. doi: 10.1111/j.1601-183X.2005.00185.x.
Both natural rewards and addictive substances have the ability to reinforce behaviors. It has been unclear whether identical neural pathways mediate the actions of both. In addition, little is known about these behaviors and the underlying neural mechanisms in a genetically tractable vertebrate, the zebrafish Danio rerio. Using a conditioned place preference paradigm, we demonstrate that wildtype zebrafish exhibit a robust preference for food as well as the opiate drug morphine that can be blocked by the opioid receptor antagonist naloxone. Moreover, we show that the too few mutant, which disrupts a conserved zinc finger-containing gene and exhibits a reduction of selective groups of dopaminergic and serotonergic neurons in the basal diencephalon, displays normal food preference but shows no preference for morphine. Pretreatment with dopamine receptor antagonists abolishes morphine preference in the wildtype. These studies demonstrate that zebrafish display measurable preference behavior for reward and show that the preference for natural reward and addictive drug is dissociable by a single-gene mutation that alters subregions of brain monoamine neurotransmitter systems. Future genetic analysis in zebrafish shall uncover further molecular and cellular mechanisms underlying the formation and function of neural circuitry that regulate opiate and food preference behavior.
天然奖赏和成瘾性物质都具有强化行为的能力。目前尚不清楚是否相同的神经通路介导了两者的作用。此外，对于一种具有遗传易处理性的脊椎动物——斑马鱼（Danio rerio）的这些行为及其潜在的神经机制，人们了解甚少。利用条件性位置偏爱范式，我们证明野生型斑马鱼对食物以及阿片类药物吗啡表现出强烈的偏爱，而这种偏爱可被阿片受体拮抗剂纳洛酮阻断。此外，我们发现too few突变体（该突变体破坏了一个保守的含锌指基因，并表现出基底间脑多巴胺能和5-羟色胺能神经元的选择性群体减少）对食物表现出正常的偏爱，但对吗啡没有偏爱。用多巴胺受体拮抗剂预处理可消除野生型对吗啡的偏爱。这些研究表明斑马鱼对奖赏表现出可测量的偏爱行为，并且表明对天然奖赏和成瘾性药物的偏爱可通过一个单基因突变而分离，该突变改变了脑单胺神经递质系统的亚区域。未来对斑马鱼的遗传分析将揭示调节阿片类和食物偏爱行为的神经回路形成和功能的进一步分子和细胞机制。
