Restoration of cocaine stimulation and reward by reintroducing wild type dopamine transporter in adult knock-in mice with a cocaine-insensitive dopamine transporter.
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.
Department of Anesthesiology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan 430071, Hubei, China; Department of Pharmacology, The Ohio State University, Columbus, OH 43210, USA.
Haiyin
H
Wu
Department of Pharmacology, The Ohio State University, Columbus, OH 43210, USA.
Brian
B
O'Neill
Department of Pharmacology, The Ohio State University, Columbus, OH 43210, USA.
Dawn D
DD
Han
Department of Pharmacology, The Ohio State University, Columbus, OH 43210, USA.
Keerthi
K
Thirtamara-Rajamani
Department of Anesthesiology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan 430071, Hubei, China. Electronic address: wyl0342@sina.com.
Yanlin
Y
Wang
Department of Pharmacology, The Ohio State University, Columbus, OH 43210, USA. Electronic address: gu.37@osu.edu.
Howard H
HH
Gu
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D003042:Cocaine / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D000229:Dependovirus / Q000235:genetics; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000502:physiology; D055786:Gene Knockout Techniques; D005822:Genetic Vectors; D007150:Immunohistochemistry; D008297:Male; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D012201:Reward; D013037:Spatial Behavior / Q000187:drug effects / Q000502:physiology
D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D003042:Cocaine
Addiction; Adeno-associated virus; Cocaine; Dopamine transporter; Locomotion; Reward