Addiction

One of the more intractable characteristics of drugs of abuse is their ability to subvert the reward system of the individual such that long after contact with the drug the drug-addicted subjects can experience intense drug craving, triggering compulsive drug use. This phenomenon, called cue-induced craving, where exposure to places where the drug-addict may have taken the drug, to people with whom prior drug use occurred, or to paraphernalia used to administer the drug leads to drug relapse, is clinically relevant and is a major contributor in the cycle of relapse in addiction. The neurotransmitter dopamine (DA) is thought to be the major contributor to cue-elicited drug craving. Indeed, in laboratory animals when neutral stimuli are paired with a rewarding drug there is an increase of DA in the nucleus accumbens (NAc) and in the dorsal striatum, and these neurochemical responses are associated with drug-seeking behavior. In the brain, reward involves widespread neurocircuitry, but the most sensitive sites involve the trajectory of the medial forebrain bundle that connects the ventral tegmental area (VTA) to the basal forebrain. DA is involved with reward and with the prediction of reward. All drugs of abuse activate the mesolimbic dopamine system. In fact, within the mesolimbic system the release of DA into the NAc is an absolute requirement for the induction of the abnormal cellular and behavioural response that leads to addictive behaviour. DA release is controlled by various input signals in the form of peptides and small molecules released into the VTA of the brain where they are sensed by the dopaminergic neurons that project to the NAc. Within these neurons are various receptors of the G-protein-coupled receptors (GPCRs) family that translate input signals into dopamine release modulation. Traditional approaches to control drug addiction have focused on targeting neuronal receptors as single entities. Our hypothesis, based on our preliminary results, is that many of these receptors may interact in the form of receptor heteromers and these receptor heteromers confer novel functions that modulate addictive behaviours. We identify and characterize these receptor heteromers to understand the molecular mechanisms behind their function and how they can lead to addiction.

Schematic of how cocaine leads to an imbalance of Dopamine inputs.