Grant: Operating Grant

Drug addiction is a chronic and debilitating disorder that has an immense social and financial impact on individuals and society. Substance abuse accounts for the highest number of preventable illnesses and deaths each year in Canada and places a significant social and financial toll on individuals, families and society. In 2006, the estimated cost of substance abuse in Canada was estimated to be $39.8 billion, with illegal drugs accounting for $8.2 billion. More recent Canadian health surveys have suggested that 1 in 10 Canadians report symptoms consistent with alcohol or illicit drug dependence, and 1-2% of the population report cocaine use. Despite our understanding of the primary molecular action of drugs of abuse, our comprehension of the modifications of neural circuitry underlying addiction remains far from complete. Drugs of abuse are believed to elicit changes in neural circuits that ultimately manifest themselves in a variety of self-destructive behaviors. Emerging evidence indicates that synaptic plasticity of glutamatergic inputs to key reward structures is critical for functional changes of neurons in addiction; however, the various molecular mechanisms involved are only partly understood. Inflammation is an observed part of the response to drugs of abuse, but its role in addiction is not defined. The pro-inflammatory cytokine Tumor Necrosis Factor-alpha (TNF) is a key player in the inflammatory response, and can directly regulate synaptic function. Here we investigate how TNF modifies circuit properties in reward-relevant parts of the brain. We then investigate how drugs of abuse engage the TNF signaling system, and the impact of TNF-mediated synaptic changes on the physiological and behavioural changes induced by chronic cocaine administration. Lastly, we will test if augmenting this compensatory response has potential as a therapeutic treatment.