Awathale Sanjay N, Choudhary Amit G, Subhedar Nishikant K, Kokare Dadasaheb M
Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, India.
Indian Institute of Science Education and Research (IISER), Pune, India.
J Neurochem. 2021 Sep;158(5):1172-1185. doi: 10.1111/jnc.15479. Epub 2021 Aug 6.
Neuropeptide cocaine- and amphetamine-regulated transcript (CART) is known to influence the activity of the canonical mesolimbic dopaminergic pathway and modulate reward seeking behaviour. CART neurons of the lateral hypothalamus (LH) send afferents to the ventral tegmental area (VTA) and paraventricular thalamic nucleus (PVT) and these nuclei, in turn, send secondary projections to nucleus accumbens. We try to dissect the precise sites of CART's action in these circuits in promoting reward. Rats were implanted with bipolar electrode targeted at the lateral hypothalamus-medial forebrain bundle (LH-MFB) and trained to press the lever through intracranial self-stimulation (ICSS) protocol. CART (55-102) administered directly into posterior VTA (pVTA) or PVT of the conditioned rats significantly increased the number of lever presses, indicating reward-promoting activity of the peptide. Concomitant increase in dopamine (DA) and 3, 4-dihydroxyphenylacetic acid (DOPAC) efflux was noted in the microdialysate collected from the nucleus accumbens shell (AcbSh). On the other hand, immunoneutralization of endogenous CART with CART antibodies injected directly in the pVTA or PVT reduced the lever press activity as well as DA and DOPAC efflux in the AcbSh. Injection of CART (1-39) in pVTA or PVT was ineffective. We suggest that CART cells in the LH-MFB area send afferents to (a) pVTA and influence dopaminergic neurons projecting to AcbSh and (b) PVT, from where the secondary neurons may feed into the AcbSh. Excitation of the CARTergic pathway to the pVTA as well as the PVT seems to promote DA release in the AcbSh and contribute to the generation of reward.
已知神经肽可卡因和苯丙胺调节转录物（CART）会影响经典中脑边缘多巴胺能通路的活性，并调节奖赏寻求行为。下丘脑外侧区（LH）的CART神经元将传入神经投射到腹侧被盖区（VTA）和丘脑室旁核（PVT），而这些核反过来又向伏隔核发出二级投射。我们试图剖析CART在这些促进奖赏的回路中的精确作用位点。将大鼠植入靶向下丘脑外侧区-内侧前脑束（LH-MFB）的双极电极，并通过颅内自我刺激（ICSS）方案训练其按压杠杆。将CART（55-102）直接注入条件大鼠的后VTA（pVTA）或PVT中，显著增加了杠杆按压次数，表明该肽具有促进奖赏的活性。从伏隔核壳（AcbSh）收集的微透析液中，多巴胺（DA）和3,4-二羟基苯乙酸（DOPAC）外流同时增加。另一方面，将CART抗体直接注射到pVTA或PVT中对内源性CART进行免疫中和，降低了AcbSh中的杠杆按压活动以及DA和DOPAC外流。在pVTA或PVT中注射CART（1-39）无效。我们认为，LH-MFB区域的CART细胞将传入神经投射到（a）pVTA，并影响投射到AcbSh的多巴胺能神经元，以及（b）PVT，二级神经元可能从这里进入AcbSh。刺激通向pVTA和PVT的CART能通路似乎会促进AcbSh中DA的释放，并有助于产生奖赏。
