Norepinephrine Transporter Blockade can Normalize the Prepulse Inhibition Deficits Found in Dopamine Transporter Knockout Mice

Abstract

Dopamine transporter knockout (DAT KO) mice display deficits in sensorimotor gating that are manifested by reduced prepulse inhibition (PPI) of the acoustic startle reflex. Since PPI deficits may model some of the cognitive dysfunctions identified in certain neuropsychiatric patients, we have studied the effects of transporter blockers on PPI in wild-type and DAT KO mice. Treatments with High dose psychostimulants that block DAT as well as the norepinephrine (NET) and serotonin (SERT) transporters (60 mg/kg cocaine or methylphenidate) significantly impaired PPI in wild-type mice. By contrast, these treatments significantly ameliorated the PPI deficits observed in untreated DAT KO mice. In studies with more selective transport inhibitors, the selective NET inhibitor nisoxetine (10 or 30 mg/kg) also significantly reversed PPI deficits in DAT KO mice. By contrast, while the SERT inhibitor fluoxetine (30 mg/kg) normalized these PPI deficits in DAT KO mice, citalopram (30 or 100 mg/kg) failed to do so. The 'paradoxical' effects of cocaine and methylphenidate in DAT KO mice are thus likely to be mediated, at least in part by the ability of these drugs to block NET, although serotonin systems may also have some role. Together with recent microdialysis data, these results support the hypothesis that prefrontal cortical NET blockade and consequent enhancement of prefrontal cortical extracellular dopamine mediates the reversal of PPI deficits in DAT KO mice.

Contributions of Dopamine D1, D2, and D3 Receptor Subtypes to the Disruptive Effects of Cocaine on Prepulse Inhibition in Mice

“…Moreover, cocaine disrupted PPI in all three lines of WT mice. Our results in mice corroborate the study by Yamashita et al (2006) and extend it with behavioral data suggesting that amphetamine and cocaine exert differential effects in rodents.…”

“…In contrast, other studies have found that DA transporter KO mice display increased amphetamineinduced conditioned place preference, and cocaine-and amphetamine-stimulated increases in DA in the nucleus accumbens (Carboni et al, 2001;Budygin et al, 2004). Confounding these reports is Yamashita et al (2006), where cocaine actually increased PPI in DA transporter KO mice, presumably through norepinephrine (NE) transporter blockade. Also, Tilley et al (2007) found that DA transporter knockdown mice exhibit increased cocaine-stimulated locomotor activity.…”

“…Acute cocaine administration disrupts PPI in rats (Martinez et al, 1999;Byrnes and Hammer, 2000) and mice (our unpublished data; Yamashita et al, 2006) at high doses. Other studies, however, have failed to show an acute effect of cocaine on PPI in rats (Varty and Higgins, 1998).…”

“…All three drugs were obtained from Sigma/RBI (St Louis, MO) and injected at a volume of 5 ml/kg body weight. The doses of SCH23390, raclopride, and cocaine were chosen based on pilot studies in C57BL/6J mice from our lab, as well as Yamashita et al (2006), for cocaine.…”

Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings

“…The DAT knockout mice phenotypes resemble amphetamine-like effects, and both hyperlocomotion and PPI deficits can be reversed with either D 1 or D 2 receptor antagonists [376], the atypical antipsychotics clozapine and quetiapine [377], various antidepressant drugs, and monoamine transporter inhibitors [378]. Thus, the DAT knockout mouse may be a useful animal model for predicting the efficacy of novel drugs for disorders such as schizophrenia that are characterized by a dysregulated limbic DA system.…”