The effects of binge-like sucrose consumption on the mesolimbic reward pathway in the brain

Obesity is a growing epidemic worldwide. It is estimated that the annual costs arising from obesity-related illnesses exceed $56.6 billion dollars in Australia alone, with 80% of the Australian population predicted to be overweight and obese by 2025. Whilst sugar directly contributes to a significant amount of weight gain that leads to obesity, it is also as addictive as alcohol and nicotine. The present thesis firstly establishes that the nicotinic acetylcholine receptors (nAChRs) are involved in regulating sucrose consumption. Furthermore, coupled to the changes in nAChRs, this thesis also sheds light for the first time on the global morphological changes that occur in the dendrites of the neurons in the nucleus accumbens (NAc)and amygdala (AMG) reminiscent of similar changes to drugs of abuse, suggestive of a global imbalance at the level of the Nac and AMG. Together, this suggests the brain reward center should be considered in the treatment approach for obesity

The antihypertensive drug pindolol attenuates long-term but not short-term binge-like ethanol consumption in mice

Alcohol dependence is a debilitating disorder with current therapies displaying limited efficacy and/or compliance. Consequently, there is a critical need for improved pharmacotherapeutic strategies to manage alcohol use disorders (AUDs). Previous studies have shown that the development of alcohol dependence involves repeated cycles of binge-like ethanol intake and abstinence. Therefore, we used a model of binge-ethanol consumption (drinking-in-the-dark) in mice to test the effects of compounds known to modify the activity of neurotransmitters implicated in alcohol addiction. From this, we have identified the FDA-approved antihypertensive drug pindolol, as a potential candidate for the management of AUDs. We show that the efficacy of pindolol to reduce ethanol consumption is enhanced following long-term (12weeks) binge-ethanol intake, compared with short-term (4weeks) intake. Furthermore, pindolol had no effect on locomotor activity or consumption of the natural reward sucrose. Because pindolol acts as a dual beta-adrenergic antagonist and 5-HT1A/1B partial agonist, we examined its effect on spontaneous synaptic activity in the basolateral amygdala (BLA), a brain region densely innervated by serotonin and norepinephrine-containing fibres. Pindolol increased spontaneous excitatory post-synaptic current frequency of BLA principal neurons from long-term ethanol-consuming mice but not naive mice. Additionally, this effect was blocked by the 5-HT1A/1B receptor antagonist methiothepin, suggesting that altered serotonergic activity in the BLA may contribute to the efficacy of pindolol to reduce ethanol intake following long-term exposure. Although further mechanistic investigations are required, this study demonstrates the potential of pindolol as a new treatment option for AUDs that can be fast-tracked into human clinical studies