D2 dopamine receptor subtype-mediated hyperactivity and amphetamine responses in a model of ADHD

Abstract

Low doses of psychostimulants produce beneficial behavioral effects in ADHD patients but the mechanisms underlying the response are not understood. Here we use the hyperactive mouse mutant coloboma to identify D2-like dopamine receptor subtypes that mediate the hyperactivity and response to amphetamine; we have previously demonstrated that D1-like dopamine receptors are not involved. Targeted deletion of the D2, but not the D3 or the D4, dopamine receptor in coloboma mice eliminated the hyperactivity; depleting D2 dopamine receptors also restored the excess dopamine overflow that may drive the hyperactivity to normal concentrations. Similar to its effects on ADHD patients, amphetamine reduced the hyperactivity of coloboma mice. The D2 dopamine receptor-selective antagonist L-741,626, but not D3 or D4 dopamine receptor-selective antagonists, blocked the amphetamine-induced reduction in locomotor activity. Thus, the D2 dopamine receptor subtype mediates the both the hyperactivity and response to amphetamine, suggesting a specific target for novel therapeutics in ADHD.

Forebrain overexpression of CK1δ leads to down-regulation of dopamine receptors and altered locomotor activity reminiscent of ADHD

“…These changes are very likely to affect the extent and balance in dopaminergic transmission mediated by the two dopamine receptor subtypes in striatonigral and striatopallidal neurons. Notably, in the Coloboma mouse model, the D2R has been proposed to mediate the effects linked to ADHD (38). Here we show that both D1R and D2R may be involved in the effects of CK1δ overexpression.…”

Genetic determinants of aggression and impulsivity in humans

“…Low levels of the availability of D 2 /D 3 receptors in the nucleus accumbens were found in impulsive rats (Dalley et al 2007). In the hyperactive mouse mutant coloboma, targeted depletion of the receptor D 2 resulted in the elimination of hyperactivity (Fan et al 2010). In humans, low D 2 /D 3 autoreceptor availability in the midbrain was shown to be associated with higher levels of trait impulsivity (Buckholtz et al 2010).…”

Gene-environment interactions affect long-term depression (LTD) through changes in dopamine receptor affinity in Snap25 deficient mice

“…The SNAP-25 deficient coloboma mouse mutant that displays hyperkinetic behavior, as well as behavioral deficits reflecting inattention and impulsivity (Bruno et al, 2007; Hess et al, 1992; Hess et al, 1996) has been shown to fulfill the necessary criteria for a valid model of ADHD (Fan et al, 2012). Importantly, Hess and colleagues have shown that both the hyperactivity and amelioration of that hyperactivity by amphetamine exhibited by these mutant mice is D2R-dependent (Fan and Hess, 2007; Fan et al, 2010). Additionally, using microdialysis to assay dopamine efflux in freely moving mice, these investigators have demonstrated markedly increased basal levels of extracellular dopamine in striatum of this mouse model of ADHD that is further increased by amphetamine administration (Fan and Hess, 2007).…”

“…This SNAP-25 deficient mouse, which exhibits a 50% reduction of SNAP-25 expression (Hess et al, 1992), displays certain hallmarks of ADHD including hyperactivity that is ameliorated by the psychostimulant amphetamine (Hess et al, 1996) as well as inattention and impulsivity (Bruno et al, 2007). Moreover, the hyperkinesis and amphetamine responsiveness of these mutants have been shown to be mediated through D2 dopamine receptors (Fan and Hess, 2007; Fan et al, 2010). Interestingly, the robust hyperactive behavior of this mutant appeared not to be recapitulated in heterozygote Snap25 null mutants (Washbourne et al, 2002), although it was recently reported that these mice do display more subtle behavioral deficits and a susceptibility to seizures (Corradini et al, 2012).…”