Cocaine self-administration in dopamine-transporter knockout mice

@article{Rocha1998CocaineSI,
  title={Cocaine self-administration in dopamine-transporter knockout mice},
  author={Beatriz A. Rocha and Fabio Fumagalli and Raul R. Gainetdinov and Sara R. Jones and Robert Ator and Bruno Giros and Gary W. Miller and Marc G. Caron},
  journal={Nature Neuroscience},
  year={1998},
  volume={1},
  pages={132-137}
}
The plasma membrane dopamine transporter (DAT) is responsible for clearing dopamine from the synapse. Cocaine blockade of DAT leads to increased extracellular dopamine, an effect widely considered to be the primary cause of the reinforcing and addictive properties of cocaine. In this study we tested whether these properties are limited to the dopaminergic system in mice lacking DAT. In the absence of DAT, these mice exhibit high levels of extracellular dopamine, but paradoxically still self… 
Role of serotonin in cocaine effects in mice with reduced dopamine transporter function
TLDR
Modulation of the serotonergic system in the ventral tegmental area, where the mesolimbic dopamine system originates, is a target of cocaine action, and the ultimate effect of this serotonin mechanism in animal models with sustained elevations of dopamine may be a feed-forward enhancement of dopamine levels in the nucleus accumbens.
Abolished cocaine reward in mice with a cocaine-insensitive dopamine transporter.
  • Rong Chen, M. Tilley, H. Gu
  • Biology, Psychology
    Proceedings of the National Academy of Sciences of the United States of America
  • 2006
TLDR
It is suggested that blockade of DAT is necessary for cocaine reward in mice with a functional DAT, and this mouse model is unique in that it is specifically designed to differentiate the role of Dat from the roles of NET and SERT in cocaine-induced biochemical and behavioral effects.
Lack of Cocaine Effect on Dopamine Clearance in the Core and Shell of the Nucleus Accumbens of Dopamine Transporter Knock-Out Mice
TLDR
It is reported that both cocaine and desipramine, a potent NET inhibitor, failed to change DA clearance or evoked release in the NAc of mutant mice, and the present findings suggest that in the DAT-KO mice, cocaine acts primarily outside theNAc to produce its effects.
Stimulant and reinforcing effects of cocaine in monoamine transporter knockout mice.
  • B. Rocha
  • Biology, Psychology
    European journal of pharmacology
  • 2003
Dramatically Decreased Cocaine Self-Administration in Dopamine But Not Serotonin Transporter Knock-Out Mice
TLDR
Findings support the notion that the DAT, but not the SERT, is critical in mediating the reinforcing effects of cocaine.
Dopamine mechanisms and cocaine reward.
Cocaine reward and locomotion stimulation in mice with reduced dopamine transporter expression
TLDR
A reduction in DAT expression and elevation of dopaminergic tone do not lead to adaptive changes that abolish the rewarding and stimulating effects of cocaine, and this study supports the conclusion that the blockade of DAT is required for cocaine reward and locomotor stimulation.
Cocaine, reward, movement and monoamine transporters
TLDR
New insights, derived from studies of knockout mice with simultaneous deletions and/or blockade of multiple transporters, provide a novel model for the rewarding action of this heavily-abused substance and implicate multiple monoamine systems in cocaine's hedonic activities.
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 47 REFERENCES
Cocaine receptors on dopamine transporters are related to self-administration of cocaine.
TLDR
It is shown here that the potencies of cocaine-like drugs in self-administration studies correlate with their potencies in inhibiting [3H]mazindol binding to the dopamine transporters in the rat striatum, but not with theirPotencies in binding to a large number of other presynaptic and postsynaptic binding sites.
Relationship between subjective effects of cocaine and dopamine transporter occupancy
TLDR
This is the first demonstration in humans that the doses used by cocaine abusers lead to significant blockade of DAT, and that this blockade is associated with the subjective effects of cocaine.
Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects
TLDR
The findings challenge the notion that addiction involves an enhanced striatal dopamine response to cocaine and/or an enhanced induction of euphoria and suggest a participation of thalamic dopamine pathways in cocaine addiction.
Increased vulnerability to cocaine in mice lacking the serotonin-1B receptor
TLDR
It is proposed that even drug-naive 5-HT1B-knockout mice are in a behavioural and biochemical state that resembles that of wild-type mice sensitized to cocaine by repeated exposure to the drug, which might be responsible for their increased vulnerability to cocaine.
Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter
TLDR
In homozygote mice, dopamine persists at least 100 times longer in the extracellular space, explaining the biochemical basis of the hyperdopaminergic phenotype and demonstrating the critical role of the transporter in regulating neurotransmission.
Serotonergic mechanisms involved in the discriminative stimulus, reinforcing and subjective effects of cocaine
TLDR
While the functional significance of 5-HT receptors has not been fully elucidated, data suggest that changes in serotonergic activity can modulate the effects of cocaine in both animals and humans under a variety of experimental conditions.
Intravenous Cocaine Self-Administration in Mice Lacking 5-HT1B Receptors
Profound neuronal plasticity in response to inactivation of the dopamine transporter.
TLDR
It is interesting to consider that the switch to a dopamine-deficient, but functionally hyperactive, mode of neurotransmission observed in mice lacking the DAT may represent an extreme example of neuronal plasticity resulting from long-term psychostimulant abuse.
...
1
2
3
4
5
...