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The rise in obesity prevalence has been linked to overconsumption of high-sugar containing food and beverages. Recent evidence suggests that chronic sucrose consumption leads to changes in serotonergic neuroplasticity within the neural circuits involved in feeding control. Although there is a relationship between serotonin signalling in the brain and diet-induced obesity, the specific serotonin (5-HT) receptors or pathways involved remain unknown. The 5-HT1A receptor subtype plays a role in regulating mood, anxiety, and appetite, and has been associated with reversing addiction to substances of abuse. However, the respective role of 5-HT1A auto- vs heteroreceptors in sucrose consumption has not been examined. Mice were given controlled access to either 5%, 10% or 25% w/v sucrose, or water as a control, for 12 weeks using the well-established “drinking in the dark” protocol (n = 6–8 mice per group). Ligands selectively targeting 5-HT1A auto- and/or heteroreceptors (NLX-112, unbiased 5-HT1A receptor agonist; NLX-101, preferential heteroreceptor agonist; F13714, preferential autoreceptor agonist) were administered i.p. acutely after 6 and 12 weeks of sucrose consumption. The specific involvement of 5-HT1A receptors in these effects was verified by blockade with the selective 5-HT1A receptors antagonist WAY-100,635. The specific subpopulation of 5-HT1A receptors involved in sucrose consumption was dependent on the concentration of sucrose solution and the duration of exposure to sucrose (6 weeks vs 12 weeks). Long-term sucrose consumption leads to accentuated 5-HT1A autoreceptor function. Thus, targeting 5-HT1A autoreceptors might represent an effective therapeutic strategy to combat the rise in obesity resulting from the overconsumption of high-sugar diet.

Serotonin plays an important role in the regulation of various physiological functions, including mood, social and sexual behaviors, appetite, digestion, sleep, and memory. Therefore, the extracellular levels of serotonin must be finely controlled and regulated. Indeed, imbalance in serotonin homeostasis produces various physiological alterations, including anxiety, depression, anxiety, poor mood, sexual dysfunction, compulsivity, or cognitive deficits. One of the main actors of this regulation is the serotonin transporter (5-HTT), which reuptakes the extracellular serotonin back in serotonin neurons for further recycling and storage into the synaptic vesicles. This allows for a rapid termination of serotonin signaling and ensures constant levels of serotonin in subsequent vesicular releases. The 5-HTT is a solute carrier family 6 member 4 protein that is primarily located in the enterochromaffin cells of the intestines, the serotonergic neurons of the brain, and the blood platelets. This chapter describes the anatomical expression, distribution, and subcellular localization of the 5-HTT along the serotonin innervation of both the central and peripheral nervous system, and in nonserotonergic neurons, as well as its transient expression during the development. Finally, the segregation of the 5-HTT within different subsets of serotonin axons is discussed in the context of the functional heterogeneity of serotonin neurons.

While it is widely known that alcohol and nicotine addictions commonly co-occur, no pharmacotherapies are yet marketed for codependent individuals. This is a striking observation given the broad implications and detrimental impacts that arise from this drug combination. Over the past decade, clinical and research efforts have exposed a common effector-neuronal nicotinic acetylcholine receptors (nAChRs). In this chapter, we describe alcohol's actions as a powerful reinforcer. Through neuronal nAChRs, alcohol hijacks the natural reward circuitry and creates conditioned drug associations. This endows it with the power to sustain, prolong, and reinstate further alcohol and nicotine-seeking behaviors. The narrative is based on experience and considerations made in the course of our research, and it highlights key cholinergic receptors indicated in alcohol's modulation of addiction, tolerance, withdrawal, and relapse. We believe that the delineation of these cholinergic receptors is the key to creating targeted therapeutics for alcohol use disorders and reducing the comorbidity of nicotine addiction.

Background Naltrexone, a compound with high affinity for the μ opioid receptor (MOP-R) reduces alcohol consumption. SoRI-9409 is a derivative of naltrexone that has highest affinity at δ opioid receptors (DOP-Rs). We have investigated the effects of SoRI-9409 on ethanol consumption to determine the consequences of altering the naltrexone compound to a form with increased efficacy at DOP-Rs. Methods Effects of the opioid receptor antagonists, SoRI-9409 (0–30 mg/kg, IP), naltrexone (0–30 mg/kg, IP), or naltrindole (0–10 mg/kg, IP) on ethanol consumption was measured in high- and low-ethanol–consuming rats with two different drinking paradigms. SoRI-9409-, naltrexone-, and naltrindole-mediated inhibition of DOP-R–stimulated [ 35 S]GTPγS binding was measured in brain membranes prepared from high-ethanol–consuming rats. The effects of SoRI-9409 on morphine-mediated analgesia, conditioned place preference, and anxiety were also examined. Results In high- but not low-ethanol–consuming animals, SoRI-9409 is threefold more effective and selective at reducing ethanol consumption when compared with naltrexone or naltrindole for up to 24 hours. SoRI-9409 administered daily for 28 days continuously reduced ethanol consumption, and when the administration of SoRI-9409 was terminated, the amount of ethanol consumed remained lower compared with vehicle-treated animals. Furthermore, SoRI-9409 inhibits DOP-R–stimulated [ 35 S]GTPγS binding in brain membranes of high-ethanol–consuming rats. Conclusions SoRI-9409 causes selective and long-lasting reductions of ethanol consumption. This suggests that compounds that have high affinity for DOP-Rs such as SoRI-9409 might be promising candidates for development as a novel therapeutic for the treatment of alcoholism.