Wickham R J, Solecki W B, Nunes E J, Addy N A
Interdepartmental Neuroscience Program, Yale Graduate School of Arts and Sciences, New Haven, CT 06520, USA.
Interdepartmental Neuroscience Program, Yale Graduate School of Arts and Sciences, New Haven, CT 06520, USA; Department of Psychiatry, Yale School of Medicine, New Haven, CT 06511, USA; Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT 06511, USA.
Neuroscience. 2015 Aug 20;301:384-94. doi: 10.1016/j.neuroscience.2015.06.021. Epub 2015 Jun 17.
Stimuli paired with rewards acquire reinforcing properties to promote reward-seeking behavior. Previous work supports the role of ventral tegmental area (VTA) nicotinic acetylcholine receptors (nAChRs) in mediating conditioned reinforcement elicited by drug-associated cues. However, it is not known whether these cholinergic mechanisms are specific to drug-associated cues or whether VTA cholinergic mechanisms also underlie the ability of cues paired with natural rewards to act as conditioned reinforcers. Burst firing of VTA dopamine (DA) neurons and the subsequent phasic DA release in the nucleus accumbens (NAc) plays an important role in cue-mediated behavior and in the ability of cues to acquire reinforcing properties. In the VTA, both AChRs and N-methyl-d-aspartate receptors (NMDARs) regulate DA burst firing and phasic DA release. Here, we tested the role of VTA nAChRs, muscarinic AChRs (mAChRs), and NMDARs in the conditioned reinforcement elicited by a food-associated, natural reward cue. Subjects received 10 consecutive days of Pavlovian conditioning training where lever extension served as a predictive cue for food availability. On day 11, rats received bilateral VTA infusion of saline, AP-5 (0.1 or 1μg), mecamylamine (MEC: 3 or 30μg) or scopolamine (SCOP: 3 or 66.7μg) immediately prior to the conditioned reinforcement test. During the test, nosepoking into the active (conditioned reinforced, CR) noseport produced a lever cue while nosepoking on the inactive (non-conditioned reinforced, NCR) noseport had no consequence. AP-5 robustly attenuated conditioned reinforcement and blocked discrimination between CR and NCR noseports at the 1-μg dose. MEC infusion decreased responding for both CR and NCR while 66.7-μg SCOP disrupted the subject's ability to discriminate between CR and NCR. Together, our data suggest that VTA NMDARs and mAChRs, but not nAChRs, play a role in the ability of natural reward-associated cues to act as conditioned reinforcers.
与奖励配对的刺激会获得强化特性，以促进寻求奖励的行为。先前的研究支持腹侧被盖区（VTA）烟碱型乙酰胆碱受体（nAChRs）在介导由药物相关线索引发的条件性强化中的作用。然而，尚不清楚这些胆碱能机制是否特定于药物相关线索，或者VTA胆碱能机制是否也构成与自然奖励配对的线索作为条件性强化物的能力的基础。VTA多巴胺（DA）神经元的爆发式放电以及随后伏隔核（NAc）中的阶段性DA释放，在线索介导的行为以及线索获得强化特性的能力中起着重要作用。在VTA中，AChRs和N-甲基-D-天冬氨酸受体（NMDARs）均调节DA爆发式放电和阶段性DA释放。在此，我们测试了VTA nAChRs、毒蕈碱型AChRs（mAChRs）和NMDARs在由食物相关的自然奖励线索引发的条件性强化中的作用。实验对象接受了连续10天的经典条件反射训练，其中杠杆伸展作为食物可得性的预测线索。在第11天，大鼠在条件性强化测试前立即接受双侧VTA注射生理盐水、AP-5（0.1或1μg）、美加明（MEC：3或30μg）或东莨菪碱（SCOP：3或66.7μg）。在测试期间，将鼻子探入活动（条件性强化，CR）鼻端口会产生杠杆线索，而将鼻子探入非活动（非条件性强化，NCR）鼻端口则没有任何结果。AP-5在1μg剂量时强烈减弱了条件性强化，并阻断了CR和NCR鼻端口之间的辨别。MEC注射降低了对CR和NCR的反应，而66.7μg的SCOP破坏了实验对象区分CR和NCR的能力。总之，我们的数据表明，VTA NMDARs和mAChRs而非nAChRs，在与自然奖励相关的线索作为条件性强化物的能力中发挥作用。
