Neurobiology, pharmacokinetics and pharmacodynamics of drug abuse

ABSTRACT

All drugs of abuse, like neural rewarding behaviors such as sex and eating, increase extra-cellular dopamine (DA) levels in the nucleus accumbens (NA), which is a part of the common reward mesolimbic pathway from the ventral tegmental area (VTA) to the NA. As addiction progresses from initial use to obsessive compulsive use, the neurobiology shifts from a DA-based behavioral system to a predominantly glutamate-based one, still relying on DA. A DA release in the prefrontal cortex (PFC) and amygdala in the relapse stimulates glutamate transmission between the PFC and amygdala and glutamate release in the pathway from the PFC to the NA core, constituting a "final common pathway" for drug-seeking behavior. Dysfunction of critical PFC structures results in drug craving and impaired decision making. Inhalation and smoking are the routes of administration that allow the most rapid delivery of drugs to the brain, while intravenous injection maximizes the bioavailability of a drug. The pharmacokinetic properties of a drug that dispose the user to increased self-administration include rapid absorption, rapid entry into the central nervous system, high bioavailability, short half-life, small volume of distribution, and high free drug clearance. The pharmacokinetic properties associated with drug dependence are a long half-life, low free drug clearance, and presence of the drug at high enough concentrations and for a sufficient time to permit tolerance to develop. Pharmacokinetics and pharmacodynamics play an important role in predicting the dependence and abuse potential of drugs.