D2-like dopamine receptors mediate the response to amphetamine in a mouse model of ADHD

Abstract

The mechanisms underlying the effects of psychostimulants in attention deficit hyperactivity disorder (ADHD) are not well understood, but indirect evidence implicates D2 dopamine receptors. Here we dissect the components of dopaminergic neurotransmission in the hyperactive mouse mutant coloboma to identify pre-and postsynaptic elements essential for the effects of amphetamine in these mice. Amphetamine treatment reduced locomotor activity in coloboma mice, but induced a robust increase in dopamine overflow suggesting that abnormal regulation of dopamine efflux does not account for the behavioral effect. However, the D2-like dopamine receptor antagonists haloperidol and raclopride, but not the D1-like dopamine receptor antagonist SCH23390, blocked the amphetamine-induced reduction in locomotor activity in coloboma mice, providing direct evidence that D2-like dopamine receptors mediate the effect of amphetamine in these mice. With the precedent established that it is possible to directly antagonize this response, this strategy should prove useful for identifying novel therapeutics in ADHD.

A Novel Mechanism and Treatment Target for Presynaptic Abnormalities in Specific Striatal Regions in Schizophrenia

“…The subregional distribution of abnormalities of dopamine release in schizophrenia is unknown. Basal-and amphetamine-stimulated dopamine release is higher than normal in the striatum of coloboma mice, where SNAP-25 is low (Fan and Hess, 2007). The low levels of SNAP-25 observed in VMC in our samples could implicate SNAP-25 in the abnormalities of release in patients with schizophrenia.…”

“…The consequences of greater SNARE complex formation/ stability for neurotransmission may include reduced vesicular release, as shown for glutamatergic terminals in the blind-drunk mouse (Jeans et al, 2007). A greater amount of dopamine release in schizophrenia would be consistent with lower levels of SNAP-25, as observed in coloboma mice (Fan and Hess, 2007). The observed increased SNARE complex formation in VMC in schizophrenia could represent a compensatory mechanism, attempting to dampen overactive dopamine release directly, or indirectly through reduced glutamate release (which normally facilitates striatal dopamine release) (West et al, 2003).…”

“…Hyperactivity in these animals responds to amphetamine treatment (Hess et al, 1996). Microdialysis studies indicate that coloboma mice have high basal levels of synaptic dopamine in the striatum, and increased dopamine release after amphetamine challenge (Fan and Hess, 2007); both these features are similar to schizophrenia (Lyon et al, 2009). Another mutant mouse helps understand the implications of functional changes in SNARE proteins, rather than differences in amount.…”

Imaging apomorphine stimulation of brain arachidonic acid signaling via D2-like receptors in unanesthetized rats

“…We also reported that Damphetamine, which stimulates dopamine receptors by increasing dopamine concentration in the synaptic cleft, increased k* for AA in a dose-dependent manner in comparable regions (Bhattacharjee et al 2006). Damphetamine's effects could be prevented by pretreatment with raclopride, a D 2 -D 3 receptor antagonist with negligible affinity for D 4 receptors (Bhattacharjee et al 2006;Fan and Hess 2007;Kohler et al 1985), indicating that they were mediated specifically by D 2 -like receptors.…”

“…To begin doing this, we have developed an in vivo method to image brain AA signaling via PLA 2 in terms of a regional brain AA incorporation coefficient k*-brain radioactivity divided by integrated plasma radioactivitymeasured by quantitative autoradiography following the intravenous injection of radiolabeled AA (Bhattacharjee et al 2005;DeGeorge et al 1991;Hayakawa et al 2001;Rapoport 2003;Robinson et al 1992). Using this method, we showed in unanesthetized rats that acute administration of quinpirole, a selective D 2 -like receptor agonist, increased k* for AA in brain regions with high densities of D 2 -like receptors and in functionally connected regions, and that the increases could be blocked by pretreatment with the preferential D 2 -like receptor antagonist, butaclamol (Bhattacharjee et al 2005;Bristow et al 1998;Fan and Hess 2007;Hayakawa et al 2001). We also reported that Damphetamine, which stimulates dopamine receptors by increasing dopamine concentration in the synaptic cleft, increased k* for AA in a dose-dependent manner in comparable regions (Bhattacharjee et al 2006).…”