Abstract

Addiction can be defined as a chronic relapsing disorder that is characterized by a loss of control over drug consumption. One of the major obstacles in the treatment of drug addiction is relapse, with the majority of individuals relapsing within the first year of drug abstinence. In humans, restricted food intake can modulate the main triggers of relapse thereby increasing drug craving and relapse. In animal models of relapse, caloric restriction will also increase drug seeking. The experiments presented in this thesis investigated the neuronal mechanisms that mediate the augmentation of heroin seeking induced by chronic food restriction in the rat. The mesolimbic dopamine pathway is heavily implicated in reward and motivation. Therefore, the experiments presented in Chapter 3 explored the role of dopamine in the mesolimbic pathway, specifically the nucleus accumbens, in the augmentation of heroin seeking induced by chronic food restriction. Extracellular dopamine in the nucleus accumbens core and shell subregions was differentially altered during the heroin-seeking test in chronically food restricted rats. Blockade of dopamine D1-like receptors in the nucleus accumbens shell decreased heroin seeking, whereas blockade of D1-like receptors in the nucleus accumbens core selectively reduced heroin seeking in the food restricted rats.
Hormones involved in energy balance and food intake, such as leptin and ghrelin are implicated in drug-related behaviors. Thus, the experiments in Chapter 4 investigated the role of leptin and ghrelin in heroin seeking induced by chronic food restriction. As expected, chronic food restriction decreased plasma levels of leptin and increased plasma levels of ghrelin. Furthermore, administration of leptin or a ghrelin receptor antagonist into the ventral tegmental area exclusively decreased heroin seeking in the food restricted rats. These results suggest that leptin and ghrelin may modulate drug seeking by acting upstream from the mesolimbic dopamine pathway.
Finally, in addition to the dense innervations from dopamine projections, the nucleus accumbens also receives a multitude of glutamatergic innervations from a variety of brain regions. Hence, in Chapter 5 we investigated the role of glutamate in the nucleus accumbens on the augmentation of heroin seeking induced by chronic food restriction. Contrary to our predictions, there were no changes in extracellular glutamate in the nucleus accumbens during ongoing heroin seeking. Moreover, administration of a glutamate receptor antagonist had no effect on heroin seeking induced by chronic food restriction. Taken together, these findings demonstrate that the augmentation of heroin seeking induced by chronic food restriction is mediated by dopamine transmission in the nucleus accumbens and can be modulated by hormones involved in metabolic processes, such as leptin and ghrelin.