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A murine model of hyperdopaminergic state displays altered respiratory control

Sandra G. Vincent^*,1, Andrea E. Waddell^*,1, Marc G. Caron, Julia K. L. Walker and John T. Fisher^*,,2

Departments of
^* Physiology,

Paediatrics and Medicine, Queen’s University, Kingston, Ontario, Canada; and Departments of

Medicine and

Cell Biology, Duke University, Durham, North Carolina, USA

²Correspondence: Department of Physiology, 4th floor Botterell Hall, Queen’s University, Kingston, ON K7L 3N6, Canada. E-mail: fisherjt{at}post.queensu.ca

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.—Vincent, S. G., Waddell, A. E., Caron, M. G., Walker, J. K. L., Fisher, J. T. A murine model of hyperdopaminergic state displays altered respiratory control.

Key Words: DAT • hypoxia • ADHD • chemoreception • respiration • circadian rhythm • body temperature