The influence of context, dose, and drug history on the neurobiological effects of amphetamine and cocaine

The psychomotor activating effects of amphetamine and cocaine are determined by many factors, including dose, prior drug experience, and the context of drug administration. Here it is examined how these factors modulate the neurobiological effects of these drugs. Experiment one shows that c-fos mRNA expression in the cortex, caudate-putamen (CPu), and nucleus accumbens is enhanced to a greater extent when amphetamine or cocaine is given in a novel environment, relative to when given at home. Experiment two indicates that environmental novelty also modulates the basal ganglia circuitry engaged by these drugs. When given at home, amphetamine and cocaine induce c-fos in substance P containing cells in the CPu (SP+ cells; a component of the “direct pathway”), but not in enkephalin containing cells in the CPu or in the subthalamic nucleus (ENK+ cells and the STN, respectively; components of the “indirect pathway”). When given in a novel environment, amphetamine and cocaine induce c- fos in SP+ cells, and in addition, induce c-fos in ENK+ cells and the STN. Experiment three shows that the ability of amphetamine to engage ENK+ cells and the STN is not only determined by environmental context, but also by dose (only one dose was examined previously). No dose at home induces c-fos in many ENK+ cells. Low and moderate doses given in the novel environment induce c-fos in many ENK+ cells, however higher doses do not. The dose-effect curve for amphetamine-induced c-fos in the STN is shifted to the left when drug is given in the novel environment, compared to at home. Experiment four shows that prior drug experience enhances cocaine-induced c-fos in the STN. Together these results suggest that ENK+ cells and the STN have specific influences on the psychomotor activating effects of stimulant drugs. ENK+ cells are engaged under conditions in which novelty enhances the psychomotor activating effects of amphetamine and cocaine, whereas the STN appears to have a more generalized role in mediating stimulant-induced psychomotor activation. Furthermore, it is concluded that the neurobiological effects of psychostimulants differ quantitatively (in the STN), as well as qualitatively (in ENK+ cells), depending on context, dose, and drug history.