Grant: Operating Grant

The faster drugs reach the brain, the more addictive they are. As such, drug addiction is more likely and more severe in individuals who use routes that rapidly deliver drugs to the brain (e.g., smoking or intravenous injection). However, it is not known why this is. We have found recently that when drugs like cocaine and nicotine are delivered rapidly, they more readily activate neurons within the medial prefrontal cortex (mPFC) and within a region that receives glutamate-containing inputs from the mPFC, the nucleus accumbens (NACC). This is significant because drug-induced activation of the mPFC-NACC circuit plays a critical role in the development and maintenance of drug addiction. Our goal is to determine whether rapidly delivered drugs promote addiction because they more readily engage the mPFC-NACC pathway. To this end, we will allow rats to voluntarily self-administer rapid or slower intravenous cocaine or nicotine injections and we will determine (1) whether disrupting function within the mPFC with a chemical lesion suppresses the voluntary intake of rapid drug injections, (2) whether the intake of rapidly delivered drugs is regulated by glutamate receptors in the NACC, (3) whether the intake of rapidly delivered drugs increases glutamate levels in the NACC, and (4) whether the intake of rapidly delivered drugs alters the expression of glutamate receptors within the NACC. This research could provide unique information on the brain mechanisms by which the rate of drug delivery influences the potential for addiction. Such findings could help to reduce the burden of drug addiction in two major ways. First, the mechanisms identified can aid in the development of new anti-addiction treatments designed specifically for addicts who use "rapid" routes of drug administration. Second, the mechanisms identified can contribute to the design of new formulations for potentially addictive medications (e.g., Ritalin) in order to reduce non-medical use.