Impaired cliff avoidance reaction in dopamine transporter knockout mice

• Published in: Psychopharmacology Vol. 227; no. 4; pp. 741 - 749
• Main Authors: Yamashita, Motoyasu, Sakakibara, Yasufumi, Hall, F. Scott, Numachi, Yohtaro, Yoshida, Sumiko, Kobayashi, Hideaki, Uchiumi, Osamu, Uhl, George R., Kasahara, Yoshiyuki, Sora, Ichiro
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.06.2013; Springer; Springer Nature B.V
• Subjects: Animal behavior; Animals; Attention Deficit Disorder with Hyperactivity - physiopathology; Attention-deficit hyperactivity disorder; Avoidance Learning - drug effects; Avoidance Learning - physiology; Behavior, Animal - drug effects; Biomedical and Life Sciences; Biomedicine; Disease Models, Animal; Dopamine; Dopamine Plasma Membrane Transport Proteins - genetics; Fluoxetine - analogs & derivatives; Fluoxetine - pharmacology; Impulse; Impulsive Behavior - physiopathology; Male; Methylphenidate - pharmacology; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurosciences; Norepinephrine Plasma Membrane Transport Proteins - metabolism; Original Investigation; Pharmacology/Toxicology; Physiological aspects; Psychiatry; Reflex, Startle - drug effects; Rodents; Sensory Gating - drug effects; Sensory Gating - physiology; Japan; Behavioral inhibition; Impulsivity; Attention-deficit/hyperactivity disorder; Cliff avoidance reaction; Dopamine transporter knockout mice; Prepulse inhibition of acoustic startle response
• ISSN: 0033-3158; 1432-2072; 1432-2072
• DOI: 10.1007/s00213-013-3009-9

Rationale Impulsivity is a key feature of disorders that include attention-deficit/hyperactivity disorder (ADHD). The cliff avoidance reaction (CAR) assesses maladaptive impulsive rodent behavior. Dopamine transporter knockout (DAT-KO) mice display features of ADHD and are candidates in which to test other impulsive phenotypes. Objectives Impulsivity of DAT-KO mice was assessed in the CAR paradigm. For comparison, attentional deficits were also assessed in prepulse inhibition (PPI) in which DAT-KO mice have been shown to exhibit impaired sensorimotor gating. Results DAT-KO mice exhibited a profound CAR impairment compared to wild-type (WT) mice. As expected, DAT-KO mice showed PPI deficits compared to WT mice. Furthermore, the DAT-KO mice with the most impaired CAR exhibited the most severe PPI deficits. Treatment with methylphenidate or nisoxetine ameliorated CAR impairments in DAT-KO mice. Conclusion These results suggest that DAT-KO mice exhibit impulsive CAR behavior that correlates with their PPI deficits. Blockade of monoamine transporters, especially the norepinephrine transporter (NET) in the prefrontal cortex (PFC), may contribute to pharmacological improvement of impulsivity in these mice.