An increasing body of evidence indicates that psychostimulants increase dopamine transmission in the nucleus accumbens, the sub-cortical area that mediates their stimulant/reinforcing effects, through complex neural network involving a number of brain areas and neurotransmitters

Comparative studies of central neurotransmitter activity and behavioral response to amphetamine in different genotypes represent a major strategy for investigating the neural basis of drug effects.

Mice of the inbred strain C57BL/6J and DBA/2J have been extensively characterized for their differential sensitivity to behavioral effects of drugs of abuse. Mice of the C57BL/6J background are highly responsive to the stimulatory effects of amphetamine on behavior and on dopamine (DA) release within the nucleus accumbens (NAc) while DBA/2J mice are low responders. In view of the hypothesis of an inverse relationship between mesocortical and mesoaccumbens DA functioning, we assessed if amphetamine produces genotype-dependent effects on prefrontal DA release opposite to those reported for the accumbens.

DA outflow within the prefrontal cortex (pFC) and in the NAc were evaluated by intra-cerebral microdialysis in freely moving mice of the C57BL/6J and DBA/2J strains. The effects of amphetamine on prefrontal DA outflow were observable up to 120 min post-injection. At all time-points, DBA/2J mice showed significantly higher DA responses than C57BL/6J mice. By contrast, the psychostimulant produced higher DA outflow in the NAc of C57BL/6J than in that of DBA/2J mice.

Bilateral selective DA depletion in the pFC of DBA/2J mice produced a clear-cut increase in amphetamine-induced DA outflow in the NAc as well as in locomotor activity that reached levels similar to those observed in C57BL/6J mice. Immunohistochemical results showed differences in tyrosine-hydroxylase (TH) and dopamine transporter (DAT) distribution patterns between the two backgrounds that provide morphological support to the neurochemical and behavioral strain differences.