Dopamine and Leptin Interactions in Rodent Models of Obesity and Cocaine Abuse

Abstract

Dopamine (DA) is a catecholamine neurotransmitter and along with its receptors plays a well-documented role in motivation and goal-directed behavior. Clinical studies have previously documented striatal DA D2 receptor (D2R) deficits in obese individuals and chronic cocaine users. These studies suggest that impaired DA-D2R signaling in the striatum may underlie deficits in goal-directed behaviors that can ultimately lead to obesity and drug addiction. However, such studies have not addressed the question of whether D2R deficits precede obesity and cocaine abuse or whether D2R decline in response to repeated overeating and cocaine use.This thesis aims to answer this question by further investigating the involvement of D2R in obesity and cocaine abuse in rodents. In particular, this thesis documents striatal D2R deficits in genetic and environmentally-induced obese as well as cocaine-exposed rodents using small animal positron emission tomography (æPET) and receptor autoradiography. Furthermore, a functional role for D2R in mediating cocaine use is demonstrated by genetically upregulating D2R in the striatum by way of an adenoviral viral vector expressing the D2R gene, which attenuated operant responding for intravenous cocaine in rats. Using æPET, this thesis also shows that D2R can serve as a biomarker that predicts susceptibility to weight gain and cocaine abuse since D2R levels negatively correlated with both future weight gain and cocaine preference in rats. Finally, using æPET evidence is presented that peripheral leptin signaling affects DA-D2R interactions in the striatum and that these effects are dependent upon individual susceptibility to weight gain and cocaine preference.The central premise is that leptin is an adiposity signal whose effects are not limited to homeostatic mechanisms as originally thought, but also to goal-directed behavior and that this behavior is modulated in part via leptin's action on striatal D2R. This work leads to a better understanding of peripheral and central nervous system interactions involved in energy regulation and motivation and highlights the involvement of such interactions in obesity and cocaine abuse.