Compartment-specific changes in striatal neuronal activity during expression of amphetamine sensitization are the result of drug hypersensitivity

Repeated exposure to drugs of abuse induces behavioural sensitization, i.e. a persistent hypersensitivity to the psychomotor stimulant effects of these drugs. This may be the result of increased responsiveness, to drugs, of mesostriatal dopamine systems and their projections, but it has also been suggested that acute and sensitized behavioural responses to psychostimulant drugs involve activation of distinct neuronal circuits. In order to distinguish between these possibilities, we studied amphetamine-induced c-fos immunoreactivity in subregions of rat striatum (patch and matrix compartments of caudate-putamen and nucleus accumbens core and shell) in drug-naive rats, as well as during long-term expression of amphetamine sensitization. We found that, in sensitized animals, amphetamine (1.0 mg/kg) evoked an increase in the ratio of c-fos-immunopositive cells in striatal patch and matrix compartments, suggesting a preferential involvement of striatal patches in the sensitized response to amphetamine. In drug-naive rats, amphetamine (0.5-5.0 mg/kg) dose-dependently increased c-fos expression in all striatal subregions. Remarkably, the highest dose of amphetamine also evoked an increase in patch : matrix ratio of c-fos immunoreactivity. In nucleus accumbens core and shell of amphetamine- and saline-pretreated animals, amphetamine (1.0 mg/kg) evoked comparable increases in c-fos expression. These data indicate that distinct striatal compartments display a differential sensitivity to amphetamine in both drug-naive and amphetamine-sensitized animals. In addition, they suggest that the shift in amphetamine-induced c-fos expression from striatal matrix to patches in sensitized animals is the consequence of a change in the sensitivity to amphetamine, rather than a long-term circuitry reorganization that is exclusive to the sensitized state.