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Restoration of cocaine stimulation and reward by reintroducing wild type dopamine transporter in adult knock-in mice with a cocaine-insensitive dopamine transporter.
- Source :
-
Neuropharmacology [Neuropharmacology] 2014 Nov; Vol. 86, pp. 31-7. Date of Electronic Publication: 2014 May 13. - Publication Year :
- 2014
-
Abstract
- In previous studies, we generated knock-in mice with a cocaine-insensitive dopamine transporter (DAT-CI mice) and found cocaine does not stimulate locomotion or produce reward in these mice, indicating DAT inhibition is necessary for cocaine stimulation and reward. However, DAT uptake is reduced in DAT-CI mice and thus the lack of cocaine responses could be due to adaptive changes. To test this, we used adeno-associated virus (AAV) to reintroduce the cocaine-sensitive wild type DAT (AAV-DATwt) back into adult DAT-CI mice, which restores cocaine inhibition of DAT in affected brain regions but does not reverse the adaptive changes. In an earlier study we showed that AAV-DATwt injections in regions covering the lateral nucleus accumbens (NAc) and lateral caudate-putamen (CPu) restored cocaine stimulation but not cocaine reward. In the current study, we expanded the AAV-DATwt infected areas to cover the olfactory tubercle (Tu) and the ventral midbrain (vMB) containing the ventral tegmental area (VTA) and substantia nigra (SN) in addition to CPu and NAc with multiple injections. These mice displayed the restoration of both locomotor stimulation and cocaine reward. We further found that AAV-DATwt injection in the vMB alone was sufficient to restore both cocaine stimulation and reward in DAT-CI mice. AAV injected in the VTA and SN resulted in DATwt expression and distribution to the DA terminal regions. In summary, cocaine induced locomotion and reward can be restored in fully developed DAT-CI mice, and cocaine inhibition of DAT expressed in dopaminergic neurons originated from the ventral midbrain mediates cocaine reward and stimulation.<br /> (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Brain pathology
Brain physiopathology
Conditioning, Psychological drug effects
Conditioning, Psychological physiology
Dependovirus genetics
Dopamine Plasma Membrane Transport Proteins genetics
Dopamine Plasma Membrane Transport Proteins metabolism
Dopaminergic Neurons drug effects
Dopaminergic Neurons physiology
Gene Knockout Techniques
Genetic Vectors
Immunohistochemistry
Male
Mice, Transgenic
Motor Activity physiology
Spatial Behavior drug effects
Spatial Behavior physiology
Brain drug effects
Cocaine pharmacology
Dopamine Plasma Membrane Transport Proteins antagonists & inhibitors
Dopamine Uptake Inhibitors pharmacology
Motor Activity drug effects
Reward
Subjects
Details
- Language :
- English
- ISSN :
- 1873-7064
- Volume :
- 86
- Database :
- MEDLINE
- Journal :
- Neuropharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 24835281
- Full Text :
- https://doi.org/10.1016/j.neuropharm.2014.04.022