The Effects of Binge-Like Sucrose Consumption on the Mesolimbic Reward Pathway in the Brain

Abstract

Obesity is becoming a worldwide epidemic (WHO, 2000, Leigh and Morris, 2016, Lifshitz and Lifshitz, 2014, James, 2004. Pharmacotherapeutics that attempt to stem overweight and obesity have largely been ineffective and often are accompanied by adverse side effects (Glazer, 2001). It is therefore imperative to develop effective strategies to combat obesity. A paradigm that has gained momentum relatively recently is the development of addiction to fat and sweet food (Fortuna, 2012, Smith and Robbins, 2013, Volkow et al., 2013a. While drugs of abuse affect various brain subregions, they have been shown to act on three major areas of the brain, namely the brain stem, the limbic system and the cerebral cortex (NIDA, 2010).The limbic system is an interconnected collection of brain structures such as the nucleus accumbens (NAc) and the basolateral amygdala (BLA), whose neural connectivities encode emotional states such as anticipation of reward and motivation (Berridge, 2012). At the molecular level, in addition to the various dysregulatory outcomes in relation to neurotransmitters, it is the dysregulation of balance between dopamine (DA) and acetylcholine (ACh) in the limbic system, especially in the NAc that has been found to drive and maintain behaviours that perpetuate addiction to substances of abuse (Hoebel et al., 2007, Aosaki et al., 2010. Interestingly, sucrose, a potent contributor to the development of obesity (Lakhan and Kirchgessner, 2013, Tappy et al., 2010), has been shown, albeit indirectly, to affect the release of DA in the NAc via the nAChRs (Avena et al., 2008). The role of specific subtypes of nAChRs in the NAc has yet to be elucidated in relation to sucrose consumption.Firstly, this study establishes that the nAChRs are involved in regulating sucrose consumption. Based on the various nAChRs agonists/partial agonists and antagonists tested systemically, it is surmised that *nAChRs are involved in mediating sucrose consumption.Furthermore, coupled to the changes in nAChRs, this study also sheds light for the first time ii on the global morphological changes that occur in the dendrites of the neurons in the NAc and BLA reminiscent of similar changes due to drugs of abuse, suggestive of a global imbalance at the level of the NAc and amygdala. Further studies are warranted to determine the precise functional significance of the morphological changes that are reported in this study, and to discover potential newer pharmacotherapies that target the nAChRs. At the present time, however, varenicline, an FDA approved pharmacotherapeutic, appears to be an attractive agent in reducing sucrose intake. Varenicline may hold potential benefits in lowering weight gain thus concomitantly lowering the global burden of obesity-related disease.iii