Abstract
Dopamine (DA) dysregulation is a core feature in Parkinson’s disease and in addictive disorders. DA has been also implicated in central nervous system affective and cognitive pathologies such as bipolar disorder, schizophrenia, and attention deficit and hyperactivity disorder (ADHD). The first studies of genetically engineered mice targeting components of the DA system focused on motor behavior and on the action of addictive drugs. However, in the course of the last 20 years (the first KO relevant to the DA system to be generated were those of the D1 receptors in 1994), we have seen an increasing shift in the use of these mutants: from tools to unravel the pharmacology of addiction integrated to in vivo models to study DA-related affective and cognitive disorders.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Hall B et al (2009) Overview: generation of gene knockout mice. Current protocols in cell biology/editorial board, Juan S Bonifacino [et al.] Chapter 19:Unit 19 12 19 12 11–17
Drago J et al (1994) Altered striatal function in a mutant mouse lacking D1A dopamine receptors. Proc Natl Acad Sci U S A 91(26):12564–12568
Xu M et al (1994) Dopamine D1 receptor mutant mice are deficient in striatal expression of dynorphin and in dopamine-mediated behavioral responses. Cell 79(4):729–742
Baik JH et al (1995) Parkinsonian-like locomotor impairment in mice lacking dopamine D2 receptors. Nature 377(6548):424–428
Kelly MA et al (1997) Pituitary lactotroph hyperplasia and chronic hyperprolactinemia in dopamine D2 receptor-deficient mice. Neuron 19(1):103–113
Wang Y et al (2000) Dopamine D2 long receptor-deficient mice display alterations in striatum-dependent functions. J Neurosci 20(22):8305–8314
Usiello A et al (2000) Distinct functions of the two isoforms of dopamine D2 receptors. Nature 408(6809):199–203
Accili D et al (1996) A targeted mutation of the D3 dopamine receptor gene is associated with hyperactivity in mice. Proc Natl Acad Sci U S A 93(5):1945–1949
Xu M et al (1997) Dopamine D3 receptor mutant mice exhibit increased behavioral sensitivity to concurrent stimulation of D1 and D2 receptors. Neuron 19(4):837–848
Rubinstein M et al (1997) Mice lacking dopamine D4 receptors are supersensitive to ethanol, cocaine, and methamphetamine. Cell 90(6):991–1001
Holmes A et al (2001) Behavioral characterization of dopamine D5 receptor null mutant mice. Behav Neurosci 115(5):1129–1144
Giros B et al (1996) Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 379(6566):606–612
Fon EA et al (1997) Vesicular transport regulates monoamine storage and release but is not essential for amphetamine action. Neuron 19(6):1271–1283
Wang YM et al (1997) Knockout of the vesicular monoamine transporter 2 gene results in neonatal death and supersensitivity to cocaine and amphetamine. Neuron 19(6):1285–1296
Zhou QY et al (1995) Targeted disruption of the tyrosine hydroxylase gene reveals that catecholamines are required for mouse fetal development. Nature 374(6523):640–643
Gogos JA et al (1998) Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior. Proc Natl Acad Sci U S A 95(17):9991–9996
Sarinana J et al (2014) Differential roles of the dopamine 1-class receptors, D1R and D5R, in hippocampal dependent memory. Proc Natl Acad Sci U S A 111(22):8245–8250
Anzalone A et al (2012) Dual control of dopamine synthesis and release by presynaptic and postsynaptic dopamine D2 receptors. J Neurosci 32(26):9023–9034
Bello EP et al (2011) Cocaine supersensitivity and enhanced motivation for reward in mice lacking dopamine D2 autoreceptors. Nat Neurosci 14(8):1033–1038
Narboux-Neme N et al (2011) Severe serotonin depletion after conditional deletion of the vesicular monoamine transporter 2 gene in serotonin neurons: neural and behavioral consequences. Neuropsychopharmacology 36(12):2538–2550
Crawley JN (1999) Behavioral phenotyping of transgenic and knockout mice: experimental design and evaluation of general health, sensory functions, motor abilities, and specific behavioral tests. Brain Res 835(1):18–26
Crawley JN (2008) Behavioral phenotyping strategies for mutant mice. Neuron 57(6):809–818
McIlwain KL et al (2001) The use of behavioral test batteries: effects of training history. Physiol Behav 73(5):705–717
Doetschman TC et al (1985) The in vitro development of blastocyst-derived embryonic stem cell lines: formation of visceral yolk sac, blood islands and myocardium. J Embryol Exp Morphol 87:27–45
Li E et al (1992) Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69(6):915–926
Nagy A et al (1993) Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. Proc Natl Acad Sci U S A 90(18):8424–8428
Crawley JN et al (1997) Behavioral phenotypes of inbred mouse strains: implications and recommendations for molecular studies. Psychopharmacology (Berl) 132(2):107–124
Silva AJ et al (1997) Mutant mice and neuroscience: recommendations concerning genetic background. Banbury conference on genetic background in mice. Neuron 19(4):755–759
Farley S et al (2012) Increased expression of the Vesicular Glutamate Transporter-1 (VGLUT1) in the prefrontal cortex correlates with differential vulnerability to chronic stress in various mouse strains: effects of fluoxetine and MK-801. Neuropharmacology 62(1):503–517
Holmes A et al (2003) Abnormal anxiety-related behavior in serotonin transporter null mutant mice: the influence of genetic background. Genes Brain Behav 2(6):365–380
Kelly MA et al (1998) Locomotor activity in D2 dopamine receptor-deficient mice is determined by gene dosage, genetic background, and developmental adaptations. J Neurosci 18(9):3470–3479
Morice E et al (2004) Phenotypic expression of the targeted null-mutation in the dopamine transporter gene varies as a function of the genetic background. Eur J Neurosci 20(1):120–126
Karasinska JM et al (2005) Deletion of dopamine D1 and D3 receptors differentially affects spontaneous behaviour and cocaine-induced locomotor activity, reward and CREB phosphorylation. Eur J Neurosci 22(7):1741–1750
Bales KR et al (2006) Cholinergic dysfunction in a mouse model of Alzheimer disease is reversed by an anti-A beta antibody. J Clin Invest 116(3):825–832
Tzavara ET et al (2003) Dysregulated hippocampal acetylcholine neurotransmission and impaired cognition in M2, M4 and M2/M4 muscarinic receptor knockout mice. Mol Psychiatry 8(7):673–679
Viggiano D et al (2003) Dopamine phenotype and behaviour in animal models: in relation to attention deficit hyperactivity disorder. Neurosci Biobehav Rev 27(7):623–637
Jung MY et al (1999) Potentiation of the D2 mutant motor phenotype in mice lacking dopamine D2 and D3 receptors. Neuroscience 91(3):911–924
Dulawa SC et al (1999) Dopamine D4 receptor-knock-out mice exhibit reduced exploration of novel stimuli. J Neurosci 19(21):9550–9556
Kruzich PJ et al (2004) Dopamine D4 receptor-deficient mice, congenic on the C57BL/6J background, are hypersensitive to amphetamine. Synapse 53(2):131–139
Ralph RJ et al (2001) Prepulse inhibition deficits and perseverative motor patterns in dopamine transporter knock-out mice: differential effects of D1 and D2 receptor antagonists. J Neurosci 21(1):305–313
Gainetdinov RR, Caron MG (2003) Monoamine transporters: from genes to behavior. Annu Rev Pharmacol Toxicol 43:261–284
Gainetdinov RR et al (1999) Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity. Science 283(5400):397–401
Yamashita M et al (2013) Impaired cliff avoidance reaction in dopamine transporter knockout mice. Psychopharmacology (Berl) 227(4):741–749
Barth V et al (2013) In vivo occupancy of dopamine D3 receptors by antagonists produces neurochemical and behavioral effects of potential relevance to attention-deficit-hyperactivity disorder. J Pharmacol Exp Ther 344(2):501–510
Napolitano F et al (2010) Role of aberrant striatal dopamine D1 receptor/cAMP/protein kinase A/DARPP32 signaling in the paradoxical calming effect of amphetamine. J Neurosci 30(33):11043–11056
Tzavara ET et al (2006) Endocannabinoids activate transient receptor potential vanilloid 1 receptors to reduce hyperdopaminergia-related hyperactivity: therapeutic implications. Biol Psychiatry 59(6):508–515
El Khoury MA et al (2012) Interactions between the cannabinoid and dopaminergic systems: evidence from animal studies. Prog Neuropsychopharmacol Biol Psychiatry 38(1):36–50
Meltzer HY et al (2004) Placebo-controlled evaluation of four novel compounds for the treatment of schizophrenia and schizoaffective disorder. Am J Psychiatry 161(6):975–984
Geyer MA et al (2001) Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psychopharmacology (Berl) 156(2–3):117–154
Swerdlow NR et al (2008) A novel rat strain with enhanced sensitivity to the effects of dopamine agonists on startle gating. Pharmacol Biochem Behav 88(3):280–290
Svenningsson P et al (2003) Diverse psychotomimetics act through a common signaling pathway. Science 302(5649):1412–1415
van den Buuse M (2010) Modeling the positive symptoms of schizophrenia in genetically modified mice: pharmacology and methodology aspects. Schizophr Bull 36(2):246–270
Ralph RJ et al (1999) The dopamine D2, but not D3 or D4, receptor subtype is essential for the disruption of prepulse inhibition produced by amphetamine in mice. J Neurosci 19(11):4627–4633
Barr AM et al (2004) The selective serotonin-2A receptor antagonist M100907 reverses behavioral deficits in dopamine transporter knockout mice. Neuropsychopharmacology 29(2):221–228
Sora I et al (1998) Cocaine reward models: conditioned place preference can be established in dopamine- and in serotonin-transporter knockout mice. Proc Natl Acad Sci U S A 95(13):7699–7704
Yamashita M et al (2006) Norepinephrine transporter blockade can normalize the prepulse inhibition deficits found in dopamine transporter knockout mice. Neuropsychopharmacology 31(10):2132–2139
Arime Y et al (2012) Cortico-subcortical neuromodulation involved in the amelioration of prepulse inhibition deficits in dopamine transporter knockout mice. Neuropsychopharmacology 37(11):2522–2530
Young JW et al (2009) Using the MATRICS to guide development of a preclinical cognitive test battery for research in schizophrenia. Pharmacol Ther 122(2):150–202
Young JW et al (2011) The effect of reduced dopamine D4 receptor expression in the 5-choice continuous performance task: Separating response inhibition from premature responding. Behav Brain Res 222(1):183–192
El-Ghundi M et al (1999) Spatial learning deficit in dopamine D(1) receptor knockout mice. Eur J Pharmacol 383(2):95–106
Karasinska JM et al (2000) Modification of dopamine D(1) receptor knockout phenotype in mice lacking both dopamine D(1) and D(3) receptors. Eur J Pharmacol 399(2–3):171–181
Rocchetti J et al (2014) Presynaptic D2 dopamine receptors control long-term depression expression and memory processes in the temporal hippocampus. Biol Psychiatry pii: S0006-3223(14)00166–8. doi: 10.1016/j.biopsych.2014.03.013.
Ortiz O et al (2010) Associative learning and CA3-CA1 synaptic plasticity are impaired in D1R null, Drd1a−/− mice and in hippocampal siRNA silenced Drd1a mice. J Neurosci 30(37):12288–12300
Morice E et al (2007) Parallel loss of hippocampal LTD and cognitive flexibility in a genetic model of hyperdopaminergia. Neuropsycho-pharmacology 32(10):2108–2116
Kellendonk C et al (2006) Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent abnormalities in prefrontal cortex functioning. Neuron 49(4):603–615
Tzavara ET et al (2003) Biphasic effects of cannabinoids on acetylcholine release in the hippocampus: site and mechanism of action. J Neurosci 23(28):9374–9384
Rodriguiz RM, Wetsel WC (2006) Assessments of cognitive deficits in mutant mice. In: Levin ED, Buccafusco JJ (eds) Animal models of cognitive impairment. CRC, Boca Raton, FL, Chapter 12
Terry AV Jr (2009) Spatial navigation (water maze) tasks. In: Buccafusco JJ (ed) Methods of behavior analysis in neuroscience, 2nd edn. CRC, Boca Raton, FL, Chapter 13
Glickstein SB et al (2002) Mice lacking dopamine D2 and D3 receptors have spatial working memory deficits. J Neurosci 22(13):5619–5629
Papaleo F et al (2008) Genetic dissection of the role of catechol-O-methyltransferase in cognition and stress reactivity in mice. J Neurosci 28(35):8709–8723
Birrell JM, Brown VJ (2000) Medial frontal cortex mediates perceptual attentional set shifting in the rat. J Neurosci 20(11):4320–4324
Floresco SB et al (2006) Multiple dopamine receptor subtypes in the medial prefrontal cortex of the rat regulate set-shifting. Neuropsychopharmacology 31(2):297–309
Ragozzino ME (2007) The contribution of the medial prefrontal cortex, orbitofrontal cortex, and dorsomedial striatum to behavioral flexibility. Ann N Y Acad Sci 1121:355–375
Grant DA, Berg EA (1948) A behavioral analysis of degree of reinforcement and ease of shifting to new responses in a Weigl-type card-sorting problem. J Exp Psychol 38(4):404–411
Glickstein SB et al (2005) Mice lacking dopamine D2 and D3 receptors exhibit differential activation of prefrontal cortical neurons during tasks requiring attention. Cereb Cortex 15(7):1016–1024
De Steno DA, Schmauss C (2009) A role for dopamine D2 receptors in reversal learning. Neuroscience 162(1):118–127
Smith JW et al (2002) Dopamine D2L receptor knockout mice display deficits in positive and negative reinforcing properties of morphine and in avoidance learning. Neuroscience 113(4):755–765
Floresco SB (2013) Prefrontal dopamine and behavioral flexibility: shifting from an “inverted-U” toward a family of functions. Front Neurosci 7:62
Doherty JM et al (2008) Contributions of dopamine D1, D2, and D3 receptor subtypes to the disruptive effects of cocaine on prepulse inhibition in mice. Neuropsychopharmacology 33(11):2648–2656
Ralph-Williams RJ et al (2002) Differential effects of direct and indirect dopamine agonists on prepulse inhibition: a study in D1 and D2 receptor knock-out mice. J Neurosci 22(21):9604–9611
Xing B et al (2010) Dopamine D1 but not D3 receptor is critical for spatial learning and related signaling in the hippocampus. Neuroscience 169(4):1511–1519
Hranilovic D et al (2008) Emotional response in dopamine D2L receptor-deficient mice. Behav Brain Res 195(2):246–250
Xing B et al (2012) The dopamine D1 but not D3 receptor plays a fundamental role in spatial working memory and BDNF expression in prefrontal cortex of mice. Behav Brain Res 235(1):36–41
Helms CM et al (2008) D4 receptor deficiency in mice has limited effects on impulsivity and novelty seeking. Pharmacol Biochem Behav 90(3):387–393
Jones SR et al (1999) Loss of autoreceptor functions in mice lacking the dopamine transporter. Nat Neurosci 2(7):649–655
Jones SR et al (1998) Profound neuronal plasticity in response to inactivation of the dopamine transporter. Proc Natl Acad Sci U S A 95(7):4029–4034
Spielewoy C et al (2000) Increased rewarding properties of morphine in dopamine-transporter knockout mice. Eur J Neurosci 12(5):1827–1837
Spielewoy C et al (2000) Behavioural disturbances associated with hyperdopaminergia in dopamine-transporter knockout mice. Behav Pharmacol 11(3–4):279–290
Zhuang X et al (2001) Hyperactivity and impaired response habituation in hyperdopaminergic mice. Proc Natl Acad Sci U S A 98(4):1982–1987
Chen R et al (2006) Abolished cocaine reward in mice with a cocaine-insensitive dopamine transporter. Proc Natl Acad Sci U S A 103(24):9333–9338
Ghisi V et al (2009) Reduced D2-mediated signaling activity and trans-synaptic upregulation of D1 and D2 dopamine receptors in mice overexpressing the dopamine transporter. Cell Signal 21(1):87–94
Salahpour A et al (2008) Increased amphetamine-induced hyperactivity and reward in mice overexpressing the dopamine transporter. Proc Natl Acad Sci U S A 105(11):4405–4410
Huotari M et al (2002) Brain catecholamine metabolism in catechol-O-methyltransferase (COMT)-deficient mice. Eur J Neurosci 15(2):246–256
Huotari M et al (2002) Effect of dopamine uptake inhibition on brain catecholamine levels and locomotion in catechol-O-methyltransferase-disrupted mice. J Pharmacol Exp Ther 303(3):1309–1316
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2015 Springer Science+Business Media New York
About this protocol
Cite this protocol
Gorgievski, V., Tzavara, E.T., Giros, B. (2015). Study of Dopamine Receptor and Dopamine Transporter Networks in Mice. In: Tiberi, M. (eds) Dopamine Receptor Technologies. Neuromethods, vol 96. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-2196-6_17
Download citation
DOI: https://doi.org/10.1007/978-1-4939-2196-6_17
Published:
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-2195-9
Online ISBN: 978-1-4939-2196-6
eBook Packages: Springer Protocols