Results show that the amphetamine-sensitized state impairs prefrontally mediated attentional set shifting. This is consistent with cognitive deficits in schizophrenia and addiction, and with the evidence that amphetamine sensitization is accompanied by functional changes in the mPFC. These results further add to a growing literature showing that activating D(1) receptors in the mPFC improves aspects of cognition.

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While a range of dopamine D(2)-related behaviors are exaggerated in amphetamine-sensitized animals, studies of the dopamine D(2) receptor have reported either no change or a decrease in dopamine D(2) receptor density--especially when measured using radioraclopride. We hypothesized that a decrease in D(2) receptors may actually be "apparent" and that these receptors may still be present, but are noncompetitively "occupied" by endogenous dopamine. Animals sensitized to amphetamine (and their saline controls) were examined 4 weeks after their last injection. We first measured the [(3)H]raclopride binding in vivo, and observed that sensitized animals showed a 29% lower level of raclopride binding in vivo, suggesting an apparently lower level of dopamine D(2) receptors. To assess the reason for this we examined the density of receptors (using Scatchard analysis in vitro) measured by [(3)H]raclopride in the presence and absence of guanilylimidodiphosphate. This guanine nucleotide converts the dopamine-bound high-affinity state of D(2) receptors into low-affinity states, thereby making measurable the absolute density of the sites. As previously reported, the amphetamine-sensitized animals showed a 31% lower number of D(2) receptors in conventional binding (B(max) 15.6 vs. 22.7 pmol/g). However, with the addition of guanilylimidodiphosphate there was an equalization of both groups (B(max) 25.9 vs. 25.6 pmol/g), revealing an additional 10.3 pmol/g in the sensitized animals, but only 2.9 pmol/g in saline controls. There were no changes in the dissociation constant of [(3)H]raclopride for the receptors. The nearly four-fold increase of dopamine D(2) receptors in the high-affinity state occupied by dopamine may explain why amphetamine-sensitized animals show almost an order of magnitude greater response to dopamine-releasing challenges or dopamine agonists, even though the absolute receptor number is unchanged and the "apparent" receptor number is decreased.

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