Loss of autoreceptor functions in mice lacking the dopamine transporter

Gainetdinov, Raul R.; Hu, Xiu‐Ti; Cooper, Donald; Wightman, R. Mark; White, Francis J.; Caron, Marc G.

doi:10.1038/10204

Cited by 223 publications

(163 citation statements)

References 35 publications

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“…Not surprisingly, the dramatic molecular alterations of both pre-and postsynaptic homeostasis following inactivation of the DAT have been extensively described in the striatum (Giros et al, 1996;Rocha et al, 1998;Jones et al, 1999;Shen et al, 2004), whereas no data are available in these mutant mice concerning the mesencephalo-hippocampal DA projection. We show here that synaptic plasticity is clearly impaired at the Schaffer collateral CA1 synapses.…”

Section: Discussionmentioning

confidence: 99%

Parallel Loss of Hippocampal LTD and Cognitive Flexibility in a Genetic Model of Hyperdopaminergia

Morice

Billard

Denis

et al. 2007

Neuropsychopharmacol

102

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Dopamine-mediated neurotransmission has been implicated in the modulation of synaptic plasticity and in the mechanisms underlying learning and memory. In the present study, we tested different forms of activity-dependent neuronal and behavioral plasticity in knockout mice for the dopamine transporter (DAT-KO), which constitute a unique genetic model of constitutive hyperdopaminergia. We report that DAT-KO mice exhibit slightly increased long-term potentiation and severely decreased long-term depression at hippocampal CA3-CA1 excitatory synapses. Mutant mice also show impaired adaptation to environmental changes in the Morris watermaze. Both the electrophysiological and behavioral phenotypes are reversed by the dopamine antagonist haloperidol, suggesting that hyperdopaminergia is involved in these deficits. These findings support the modulation by dopamine of synaptic plasticity and cognitive flexibility. The behavioral deficits seen in DAT-KO mice are reminiscent of the deficits in executive functions observed in dopamine-related neuropsychiatric disorders, suggesting that the study of DAT-KO mice can contribute to the understanding of the molecular basis of these disorders.

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Section: Discussionmentioning

confidence: 99%

Parallel Loss of Hippocampal LTD and Cognitive Flexibility in a Genetic Model of Hyperdopaminergia

Morice

Billard

Denis

et al. 2007

Neuropsychopharmacol

102

View full text Add to dashboard Cite

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“…A similar situation may occur during early development when negative feedback mechanisms of DA neurons are not fully developed (Trent et al, 1991) and in DAT-knockout mice in which DAmediated feedback mechanisms are desensitized (Jones et al, 1999). The a1-mediated excitation may also provide part of the explanation as to why D-amphetamine remains effective in increasing DA release in DAT-knockout mice (Carboni et al, 2001), and why the drug is less effective in producing the same effect in a 1b receptor-knockout mice (Auclair et al, 2002).…”

Section: Introductionmentioning

confidence: 93%

“…However, as cited in the introduction, the inhibitory effect may weaken and the excitatory effect may become more dominant under certain conditions (Kamata and Rebec, 1984;Trent et al, 1991;Jones et al, 1999). It would be interesting to determine whether under these conditions, a psychostimulant can induce the slow oscillation without prior D2 blockade.…”

Section: Potential Significance Of the Slow Oscillationmentioning

confidence: 99%

Psychostimulants Induce Low-Frequency Oscillations in the Firing Activity of Dopamine Neurons

Shi

Pun

Zhou

2004

Neuropsychopharmacol

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The reinforcing properties of psychostimulants depend critically on their effects on dopamine (DA) neurons in the ventral tegmental area (VTA). Using in vivo single unit recording in rats and spectral analysis, this study presents evidence for a new, non-DA-mediated effect of psychostimulants on VTA DA neurons. Thus, as previously observed with D-amphetamine, all psychostimulants tested, including cocaine, methamphetamine, and methylphenidate, had two opposing effects on firing rate of DA neurons: a DA-mediated inhibition and a non-DA-mediated excitation. The latter effect was normally masked by the DA-mediated inhibition and was revealed when the inhibition was blocked by a DA antagonist. Using spectral analysis, this study further showed that during psychostimulant-induced excitation, DA cells exhibited not only an increase in firing rate and bursting but also a low-frequency rhythmic oscillation (0.5-1.5 Hz) in their firing activity. The oscillatory response was unique to psychostimulants since it was not observed with the GABA A agonist muscimol, which also increased DA cell firing, and not mimicked by the nonpsychostimulant DA agonist L-dopa. Results further suggest that the effect requires activation of adrenergic a 1 receptors and depends on intact forebrain inputs to DA neurons. Further understanding of this novel effect may provide important insights into both the mechanism of action of psychostimulants and the neuronal circuitry that controls the activity of DA neurons in the brain.

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“…One intriguing possibility is that the much lower levels of tissue dopamine (Kilts et al 1987) and dopamine overflow (Abercrombie et al 1989), coupled with the far fewer functional reuptake sites in these structures (e.g., Cass and Gerhardt 1995; Letchworth et al 2000) interact to blunt autoinhibition. Interestingly, recent studies in a mouse mutant lacking the dopamine transporter show that interfering with the transporter severely attenuates autoreceptor function (Jones et al 1999), although the mechanism for this is as yet unclear.…”

Section: Are Autoreceptors Ubiquitous Among Dopaminergic Neurons?mentioning

confidence: 99%