Male DAT Val559 Mice Exhibit Compulsive Behavior under Devalued Reward Conditions Accompanied by Cellular and Pharmacological Changes.

Identified across multiple psychiatric disorders, the dopamine (DA) transporter (DAT) Ala559Val substitution triggers non-vesicular, anomalous DA efflux (ADE), perturbing DA neurotransmission and behavior. We have shown that DAT Val559 mice display a waiting impulsivity and changes in cognitive performance associated with enhanced reward motivation. Here, utilizing a within-subject, lever-pressing paradigm designed to bias the formation of goal-directed or habitual behavior, we demonstrate that DAT Val559 mice modulate their nose poke behavior appropriately to match context, but demonstrate a perseverative checking behavior.

Behaviorally penetrant, anomalous dopamine efflux exposes sex and circuit dependent regulation of dopamine transporters.

Virtually all neuropsychiatric disorders display sex differences in prevalence, age of onset, and/or clinical symptomology. Although altered dopamine (DA) signaling is a feature of many of these disorders, sex-dependent mechanisms uniquely responsive to DA that drive sex-dependent behaviors remain unelucidated. Previously, we established that anomalous DA efflux (ADE) is a prominent feature of the DA transporter (DAT) variant Val559, a coding substitution identified in two male-biased disorders: attention-deficit/hyperactivity disorder and autism spectrum disorder.

Valence processing alterations in SAPAP3 knockout mice and human OCD.

Abnormalities in valence processing - the processing of aversive or appetitive stimuli - may be an underrecognized component of obsessive-compulsive disorder (OCD). Preclinical rodent models have been critical in furthering pathophysiological understanding of OCD, yet there is a dearth of investigations examining whether rodent models of compulsive behavior show alterations in valence systems congruent with those seen in individuals with OCD. In this study, we sought to assess valence processing in a preclinical rodent model of compulsive behavior, the SAPAP3 knockout (KO) mouse model, and compare our preclinical findings to similar behavioral phenomena in OCD patients.

Ketamine increases activity of a fronto-striatal projection that regulates compulsive behavior in SAPAP3 knockout mice.

Obsessive-Compulsive Disorder (OCD), characterized by intrusive thoughts (obsessions) and repetitive behaviors (compulsions), is associated with dysfunction in fronto-striatal circuits. There are currently no fast-acting pharmacological treatments for OCD. However, recent clinical studies demonstrated that an intravenous infusion of ketamine rapidly reduces OCD symptoms.

Serotonin transporter inhibition and 5-HT receptor activation drive loss of cocaine-induced locomotor activation in DAT Val559 mice.

Dopamine (DA) signaling dysfunction is believed to contribute to multiple neuropsychiatric disorders including attention-deficit/hyperactivity disorder (ADHD). The rare DA transporter (DAT) coding substitution Ala559Val found in subjects with ADHD, bipolar disorder and autism, promotes anomalous DA efflux in vitro and, in DAT Val559 mice, leads to increased reactivity to imminent handling, waiting impulsivity, and enhanced motivation for reward. Here, we report that, in contrast to amphetamine and methylphenidate, which induce significant locomotor activation, cocaine administration to these mice elicits no locomotor effects, despite retention of conditioned place preference (CPP).

Region-Specific Regulation of Presynaptic Dopamine Homeostasis by D Autoreceptors Shapes the Impact of the Neuropsychiatric Disease-Associated DAT Variant Val559.

Disruptions of dopamine (DA) signaling contribute to a broad spectrum of neuropsychiatric disorders, including attention-deficit hyperactivity disorder (ADHD), addiction, bipolar disorder, and schizophrenia. Despite evidence that risk for these disorders derives from heritable variation in DA-linked genes, a better understanding is needed of the molecular and circuit context through which gene variation drives distinct disease traits. Previously, we identified the DA transporter (DAT) variant Val559 in subjects with ADHD and established that the mutation supports anomalous DAT-mediated DA efflux (ADE).

Is dopamine transporter-mediated dopaminergic signaling in the retina a noninvasive biomarker for attention-deficit/ hyperactivity disorder? A study in a novel dopamine transporter variant Val559 transgenic mouse model.

Background: Dopamine (DA) is a critical neuromodulator in the retina. Disruption of retinal DA synthesis and signaling significantly attenuates light-adapted, electroretinogram (ERG) responses, as well as contrast sensitivity and acuity. As these measures can be detected noninvasively, they may provide opportunities to detect disease processes linked to perturbed DA signaling.

Functional coding variation in the presynaptic dopamine transporter associated with neuropsychiatric disorders drives enhanced motivation and context-dependent impulsivity in mice.

Recent genetic analyses have provided evidence that clinical commonalities associated with different psychiatric diagnoses often have shared mechanistic underpinnings. The development of animal models expressing functional genetic variation attributed to multiple disorders offers a salient opportunity to capture molecular, circuit and behavioral alterations underlying this hypothesis. In keeping with studies suggesting dopaminergic contributions to attention-deficit hyperactivity disorder (ADHD), bipolar disorder (BPD) and autism spectrum disorder (ASD), subjects with these diagnoses have been found to express a rare, functional coding substitution in the dopamine (DA) transporter (DAT), Ala559Val.

The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants.

Despite the critical role of the presynaptic dopamine (DA) transporter (DAT, SLC6A3) in DA clearance and psychostimulant responses, evidence that DAT dysfunction supports risk for mental illness is indirect. Recently, we identified a rare, nonsynonymous Slc6a3 variant that produces the DAT substitution Ala559Val in two male siblings who share a diagnosis of attention-deficit hyperactivity disorder (ADHD), with other studies identifying the variant in subjects with bipolar disorder (BPD) and autism spectrum disorder (ASD). Previously, using transfected cell studies, we observed that although DAT Val559 displays normal total and surface DAT protein levels, and normal DA recognition and uptake, the variant transporter exhibits anomalous DA efflux (ADE) and lacks capacity for amphetamine (AMPH)-stimulated DA release.

Genetic targeting of the amphetamine and methylphenidate-sensitive dopamine transporter: on the path to an animal model of attention-deficit hyperactivity disorder.

Alterations in dopamine (DA) signaling underlie the most widely held theories of molecular and circuit level perturbations that lead to risk for attention-deficit hyperactivity disorder (ADHD). The DA transporter (DAT), a presynaptic reuptake protein whose activity provides critical support for DA signaling by limiting DA action at pre- and postsynaptic receptors, has been consistently associated with ADHD through pharmacological, behavioral, brain imaging and genetic studies. Currently, the animal models of ADHD exhibit significant limitations, stemming in large part from their lack of construct validity.