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The dopamine transporter: genetic mouse models, psychostimulant addiction and neuropsychiatric disorders (358.3)
Author(s) -
Gether Ulrik
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.358.3
Subject(s) - dopamine transporter , dopamine , dopamine plasma membrane transport proteins , amphetamine , neurotransmitter , reuptake , postsynaptic potential , neuroscience , pharmacology , dopamine uptake inhibitors , dopamine receptor d3 , chemistry , dopamine receptor d1 , transporter , dopaminergic , receptor , biology , biochemistry , serotonin , gene
The rewarding effects of cocaine and amphetamine result primarily from their molecular interaction with the dopamine transporter (DAT). DAT belongs to the family of neurotransmitter:sodium symporters and it is a major goal of our laboratory to gain insight into molecular and cellular mechanisms underlying the effects of drugs targeting this class of transporters. The DAT C‐terminus binds the PDZ domain of the scaffolding protein PICK1 but the functional importance of this interaction is uncertain. A detailed analysis of PICK1 knock‐out (KO) mice provided no evidence for a role of PICK1 in DAT regulation. Compared to WT mice, we found no change in synaptosomal dopamine uptake, in high affinity binding of the cocaine analogue [125I]RTI‐55 and in DAT protein expression. We also did not see a change in DAT distribution and membrane raft association. Nonetheless, PICK1‐KO mice were characterized by markedly reduced locomotor response to cocaine and amphetamine. Moreover, we observed significant impairment of behavioral sensitization to both drugs as well as decreased self‐administration of cocaine. Preliminary experiments with dopamine receptor agonists suggest that the reduced response to psychostimulants is caused by impaired postsynaptic dopamine D1 receptor signaling. Summarized, our data suggest a hitherto unknown role of PICK1 in regulating downstream signaling in dopamine D1 receptor positive neurons.