Impaired cliff avoidance reaction in dopamine transporter knockout mice
- 1.1k Downloads
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.
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.
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.
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.
KeywordsDopamine transporter knockout mice Attention-deficit/hyperactivity disorder Cliff avoidance reaction Prepulse inhibition of acoustic startle response Behavioral inhibition Impulsivity
This study was supported by a Grant-in-Aid for Health and Labour Science Research (Research on Pharmaceutical and Medical Safety) from MHLW of Japan; by Grants-in-Aid for Core Research for Evolutional Science and Technology (CREST), Global COE Program (Basic & Translational Research Center for Global Brain Science) from MEXT of Japan and through funding from the Intramural Research Program of the National Institute on Drug Abuse, NIH/DHHS, USA (GRU and FSH). All animal experiments were performed in accordance with the guidelines of the Animal Ethics Committee at Tohoku University Graduate School of Medicine (Sendai, Japan). No authors have any other conflicts of interest or financial disclosures to make.
- Berridge CW, Devilbiss DM, Andrzejewski ME, Arnsten AF, Kelly AE, Schmeichel B, Hamilton C, Spencer RC (2006) Methylphenidate preferentially increases catecholamine neurotransmission within the prefrontal cortex at low doses that enhance cognitive function. Biol Psychiatry 60(10):1111–1120. doi: 10.1016/j.biopsych.2006.04.022 PubMedCrossRefGoogle Scholar
- Bymaster FP, Katner JS, Nelson DL, Hemrick-Luecke SK, Threlkeld PG, Heiligenstein JH, Morin SM, Gehlert DR, Perry KW (2002) Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology 27(5):699–711. doi: 10.1016/S0893-133X(02)00346-9 PubMedCrossRefGoogle Scholar
- Cyr M, Beaulieu JM, Laakso A, Sotnikova TD, Bohn LM, Gainetdinov RR, Caron MG (2003) Sustained elevation of extracellular dopamine causes motor dysfunction and selective degeneration of striatal GABAergic neurons. Proc Natl Acad Sci U S A 100(19):11035–11040. doi: 10.1073/pnas.1831768100 PubMedCrossRefGoogle Scholar
- DeVito EE, Balckwell AD, Clark L, Kent L, Dezsery AM, Turner DC, Aitken MR, Sahakian BJ (2009) Methylphenidate improves response inhibition but not reflection-impulsivity in children with attention deficit hyperactivity disorder (ADHD). Psychopharmacol (Berl) 202(1–3):531–539. doi: 10.1007/s00213-008-1337-y CrossRefGoogle Scholar
- Fernagut PO, Chalon S, Diguet E, Guilloteau D, Tison F, Jaber M (2003) Motor behaviour deficits and their histopathological and functional correlates in the nigrostriatal system of dopamine transporter knockout mice. Neuroscience 116(4):1123–1130. doi: 10.1016/S0306-4522(02)00778-9 PubMedCrossRefGoogle Scholar
- Hernandez LF, Segovia G, Mora F (2008) Chronic treatment with a dopamine uptake blocker changes dopamine and acetylcholine but not glutamate and GABA concentrations in prefrontal cortex, striatum and nucleus accumbens of the awake rat. Neurochem Int 52(3):457–469. doi: 10.1016/j.neuint.2007.08.005 PubMedCrossRefGoogle Scholar
- Koda K, Ago Y, Cong Y, Kita Y, Takuma K, Matsuda T (2010) Effects of acute and chronic administration of atomoxetine and methylphenidate on extracellular levels of noradrenaline, dopamine and serotonin in the prefrontal cortex and striatum of mice. J Neurochem 114(1):259–270. doi: 10.1111/j.1471-4159.2010.06750.x PubMedGoogle Scholar
- Kumakura K, Nomura H, Toyoda T, Hashikawa K, Noguchi T, Takeda K, Ichijo H, Tsunoda M, Funatsu T, Ikegami D, Narita M, Suzuki T, Matsuki N (2010) Hyperactivity in novel environment with increased dopamine and impaired novelty preference in apoptosis signal-regulating kinase 1 (ASK1)-deficient mice. Neurosci Res 66(3):313–320. doi: 10.1016/j.neures.2009.12.003 PubMedCrossRefGoogle Scholar
- Kuroda K, Yamada S, Tanaka M, Iizuka M, Yano H, Mori D, Tsuboi D, Nishioka T, Namba T, Iizuka Y, Kubota S, Nagai T, Ibi D, Wang R, Enomoto A, Isotani-Sakakibara M, Asai N, Kimura K, Kiyonari H, Abe T, Mizoguchi A, Sokabe M, Takahashi M, Yamada K, Kaibuchi K (2011) Behavioral alterations associated with targeted disruption of exons 2 and 3 of the Disc1 gene in the mouse. Hum Mol Genet 20(23):4666–4683. doi: 10.1093/hmg/ddr400 PubMedCrossRefGoogle Scholar
- Shen HW, Hagino Y, Kobayashi H, Shinohara-Tanaka K, Ikeda K, Yamamoto T, Lesch KP, Murphy DL, Hall FS, Uhl GR, Sora I (2004) Regional differences in extracellular dopamine and serotonin assessed by in vivo microdialysis in mice lacking dopamine and/or serotonin transporters. Neuropsychopharmacology 29(10):1790–1799. doi: 10.1038/sj.npp.1300476 PubMedCrossRefGoogle Scholar
- Wehmeier PM, Schacht A, Wolff C, Otto WR, Dittmann RW, Banaschewski T (2011) Neuropsychological outcomes across the day in children with attention-deficit/hyperactivity disorder treated with atomoxetine: results from a placebo-controlled study using a computer-based continuous performance test combined with an infra-red motion-tracking device. J Child Adolesc Psychopharmacol 21(5):433–444. doi: 10.1089/cap.2010.0142 PubMedCrossRefGoogle Scholar
- Xu TX, Sotnikova TD, Liang C, Zhang J, Jung JU, Spealman RD, Gainetdinov RR, Yao WD (2009) Hyperdopaminergic tone erodes prefrontal long-term potential via a D2 receptor-operated protein phosphatase gate. J Neurosci 29(45):14086–14099. doi: 10.1523/JNEUROSCI.0974-09.2009 PubMedCrossRefGoogle Scholar
- Yamashita M, Fukushima S, Shen HW, Hall FS, Uhl GR, Numachi Y, Kobayashi H, Sora I (2006) Norepinephrine transporter blockade can normalize the prepulse inhibition deficits found in dopamine transporter knockout mice. Neuropsychopharmacology 31(10):2132–2139. doi: 10.1038/sj.npp.1301009 PubMedGoogle Scholar
- Yoshida S, Numachi Y, Matsuoka H, Sato M (1998) Impairment of cliff avoidance reaction induced by subchronic methamphetamine administration and restraint stress: comparison between two inbred strains of rats. Prog Neuropsychopharmacol Biol Psychiatry 22(6):1023–1032. doi: 10.1016/S0278-5846(98)00050-5 PubMedCrossRefGoogle Scholar