A murine model of hyperdopaminergic state displays altered respiratory control

Abstract

The dopamine transporter (DAT) protein plays an important role in the termination of dopamine signaling. We addressed the hypothesis that loss of DAT function would result in a distinctive cardiorespiratory phenotype due to the significant role of dopamine in the control of breathing, especially with respect to chemical control, metabolism, and thermoregulation. The DAT knockout mouse (DAT-/-) displays a state of functional hyperdopaminergia characterized by marked novelty driven hyperactivity. Certain behavioral and drug responses in these mice are reminiscent of endophenotypes of individuals with attention deficit hyperactivity disorders (ADHD). We performed experiments on conscious, unrestrained DAT-/- mice (KO) and littermate DAT+/+ wild-type (WT) controls. Ventilation was measured by the barometric technique during normoxia, hypoxia, or hypercapnia. We measured core body temperature and CO2 production as an index of metabolism. DAT-/- mice displayed a significantly lower respiratory frequency than WT mice, reflecting a prolonged inspiratory time. DAT-/- mice exhibited a reduced ventilatory response to hypoxia characterized by an attenuation of both the respiratory frequency and tidal volume responses. Both groups showed similar metabolic responses to hypoxia. Circadian measurements of body temperature were significantly lower in DAT-/- mice than WT mice during inactive periods. We conclude that loss of the DAT protein in this murine model of altered dopaminergic neurotransmission results in a significant respiratory and thermal phenotype that has possible implications for understanding of conditions associated with altered dopamine regulation.

Brain biomarkers for identifying excited delirium as a cause of sudden death

“…This failure of regulation leads to a hyperdopaminergic state, which causes the violent behavior, delirium, agitation, and sudden death when the neurocardiac axis is activated. A dopamine transporter murine model of hyperdopaminergic state displays a distinctive cardiorespiratory and thermal phenotype, providing further support for the altered dopamine regulation hypothesis of excited delirium [39].…”

Dopamine transporter mutant animals: a translational perspective

“…The reaction to the hypoxia condition is reduced in DAT-KO mice, compared to wild-type (WT) mice while CO2 production does not differ in mutants (Vincent et al, 2007). Also, an alteration in body temperature of DAT-KO mice was found.…”

“…Also, an alteration in body temperature of DAT-KO mice was found. Circadian measurement showed that they have lower body temperature during resting time (daylight time) (Vincent et al, 2007). The involvement of DAT in thermoregulation is also supported by studies of methylone-induced lethality that is thought to be related to body hyperthermia.…”

Endocopic approaches to the skull base

“…DA agonism in the preoptic area triggers increased heat loss, which is blocked by DA antagonists and which reduces the ability of rats to accommodate to a heat load,74 probably D2 mediated 75. DA transporter knockout mice (DAT−/−) display functional hyperdopaminergia and hyperactivity; their body temperature is significantly lower than normal mice during inactive periods 76…”