Effects of rate of drug delivery on brain and behaviour: Implications for addiction.

Increasing the rate at which drugs of abuse reach the brain is thought to promote the transition to addiction. This may be one reason, for example, why cocaine and nicotine are more addictive when they are smoked than when they are taken by other routes. However, the mechanisms underlying the relationship between rate of drug administration and the transition to addiction remain unknown. The ability of drugs to alter brain reward systems and to produce psychomotor sensitization is thought to contribute to addiction. As such, increasing the rate of cocaine and nicotine delivery may enhance their ability to elicit this form of plasticity. To evaluate this hypothesis the influence of rate (5--100 sec) of intravenous cocaine or nicotine infusion on the development of psychomotor sensitization was examined. Rapid (5 sec) infusions of cocaine or nicotine enhanced susceptibility to locomotor sensitization. To investigate possible mechanisms, immediate early genes (IEGs) were used to examine the brain regions engaged by cocaine and nicotine as a function of infusion rate. When delivered rapidly, cocaine and nicotine evoked greater levels of IEG expression in the medial prefrontal cortex, the nucleus accumbens, and the caudate-putamen. The ability of cocaine to evoke IEG expression and to produce sensitization is dependent on its ability to inhibit the reuptake of dopamine (DA). Therefore, in vivo voltammetry was used to examine DA uptake in the nucleus accumbens core as a function of cocaine infusion rate. Rapid infusions enhanced both the kinetics and the amplitude of DA reuptake inhibition by cocaine. Thus, the ability of cocaine and nicotine to regulate gene expression, particularly in the mesocorticolimbic system, and to produce behavioural sensitization is enhanced when they are delivered rapidly. These observations suggest that rapidly administered drugs may increase the propensity to addiction because they more readily induce forms of neurobehavioural plasticity that promote the compulsive pursuit of drugs, and the enduring vulnerability to relapse that characterize addiction.Ph.D.PsychobiologyPsychologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/124551/2/3150081.pd