An immunohistochemical examination of the effects of sensitisation on the mesotelencephalic dopaminergic response to d-amphetamine

Abstract

The dopaminergic response to d-amphetamine with or without prior repeated experience with the drug was investigated immunohistochemically in key target regions of the mesotelencephalic dopamine system using antibodies raised against glutaraldehyde-conjugated dopamine. This methodology permitted the unambiguous determination of dopaminergic activity within specific subregions of structures implicated in the behavioural effects of psychomotor stimulants drugs, and in the expression of behavioural sensitisation. Experiment 1 examined dopamine immunoreactivity in central or basolateral amygdala, shell or core of the nucleus accumbens, medial and lateral caudate-putamen and medial prefrontal cortex following the administration of various doses of d-amphetamine to drug-naïve rats. Whilst dose-related increases in dopaminergic activity were detected in all regions examined, a regional heterogeneity was clearly evident. For example, d-amphetamine enhanced dopaminergic activity preferentially within the shell subregion of the nucleus accumbens both with respect to the core subregion and to other striatal and non-striatal areas. Experiment 2 examined changes in dopaminergic activity following the administration of a low dose of d-amphetamine to d-amphetamine-sensitised rats and saline-pretreated control animals. Regional heterogeneity both between and within terminal areas was again detected. Thus, there was evidence of a preferential increase in dopaminergic activity within the shell of the nucleus accumbens of sensitised rats. Moreover, sensitisation to d-amphetamine increased the dopaminergic response to acute administration of d-amphetamine within all striatal and non-striatal areas examined. Comparison of this effect across subterritories of the areas under investigation revealed that in sensitised rats, acute administration of d-amphetamine elevated dopaminergic activity within the shell of the nucleus accumbens to a greater extent than within the core. These data therefore indicate that systemic administration of d-amphetamine is associated with regionally heterogeneous changes in dopaminergic activity within terminal regions of the mesotelencephalic dopamine system in both sensitised and unsensitised rats. Moreover, the present methodology permitted resolution of these changes at an anatomical level beyond that of conventional approaches.