Dopamine in the Medial Prefrontal Cortex Controls Genotype-Dependent Effects of Amphetamine on Mesoaccumbens Dopamine Release and Locomotion

Abstract

Mice of background DBA/2J are hyporesponsive to the behavioral effects of D-amphetamine in comparison with the widely exploited murine background C57BL/6J. In view of the important role of dopamine (DA) release in the nucleus accumbens (NAc) regarding the behavioral effects of psychostimulants, we tested the hypothesis of an inverse relationship between mesocortical and mesoaccumbens DA functioning in the two backgrounds. Systemic D-amphetamine induces a sustained increase in DA release in the medial prefrontal cortex (mpFC) accompanied by a poor increase in the NAc in mice of the low-responsive DBA/2J background, as shown by intracerebral microdialysis in freely moving animals. The opposite occurs in C57BL/6J mice, which show low prefrontal cortical DA outflow accompanied by high accumbal extracellular DA. Moreover, the DBA/2J background showed lower locomotor activity than C57BL/6J mice following D-amphetamine challenge. Selective DA depletion in the mpFC of DBA/2J mice produced a clear-cut increase in D-amphetamine-induced DA outflow in the NAc as well as locomotor activity that reached levels similar to those observed in C57BL/6J mice. Finally, local infusion of D-amphetamine by reverse microdialysis produced a similar increase in extracellular DA in both the mpFC and the NAc of DBA/2J mice. This finding points to similar transporter-related mechanisms in the two brain areas and supports the hypothesis that low accumbal DA release induced by systemic D-amphetamine in the DBA/2J background is determined by the inhibitory action of prefrontal cortical DA. The present results indicate that genotype-dependent susceptibility to addictive properties of D-amphetamine involves unbalanced DA transmission in the mesocorticolimbic system.

Novelty Seeking and Stereotypic Activation of Behavior in Mice with Disruption of the Dat1 Gene

“…When time-dependent effects for within-subjects tests in RMANOVA were not significant, between-subjects tests were reported and are noted in the text. In cases in RMANOVA where main effects of time were significant but the interaction with genotype and/or drug was not significant, time-based changes were evaluated within genotypes or drug treatment conditions by Bonferroni pairwise comparisons (see Ventura et al, 2004). Posthoc analyses of main effects in the ANOVA and RMANOVA tests and decomposition of significant interaction terms were conducted with Bonferroni corrected pair-wise tests to control for multiple comparisons (Winer, 1971).…”

Role of netrin-1 in the organization and function of the mesocorticolimbic dopamine system

“…For example, selective lesions of the DA input to the mPFC result in increased stress-and drug-induced release of DA in the nucleus accumbens. 23 Conversely, stimulation of DA receptors in the mPFC decreases DA release in the nucleus accumbens in response to these stimuli. [24][25][26] Such an inverse functional relationship between the mPFC and nucleus accumbens DA systems suggests that alterations in the development, organization and/or rewiring of one of these DA systems could affect the normal functioning of the other.…”

Dopamine β-Hydroxylase Knockout Mice have Alterations in Dopamine Signaling and are Hypersensitive to Cocaine

“…However, accumbal DA release following systemic amphetamine appears to be primarily impulse-dependent in some mouse strains, and NE is critical for this aspect of DA outflow (Ventura et al, 2004). Amphetamine-induced burst firing of DA neurons is dependent on a 1 AR signaling, and amphetamine-induced DA release in the NAc is attenuated in a 1B AR knockout mice, mice with depletion of NE in the PFC, and by a 1 AR antagonists (Darracq et al, 1998;Shi et al, 2000;Paladini et al, 2001;Auclair et al, 2002;Ventura et al, 2003).…”

“…Although the density of both highaffinity state D 1 and D 2 receptors was increased in the striatum, DbhÀ/À mice were hypersensitive to the behavioral effects of a D 2 agonist, but not a D 1 agonist; in fact, DbhÀ/À mice are relatively insensitive to D 1 agonistinduced locomotion (Weinshenker et al, 2002). As D 1 signaling in the PFC opposes DA release in the NAc and locomotor activation (Vezina et al, 1991;Ventura et al, 2004), PFC D 1 receptors may be preferentially activated by D 1 agonists in DbhÀ/À mice, although other explanations are possible.…”