Caveolin-1 Expression in the Dorsal Striatum Drives Methamphetamine Addiction-Like Behavior

Autor: Brian P. Head, Wulfran Trenet, Yosef Avchalumov, Alison D. Kreisler, Juan C. Piña-Crespo, Chitra D. Mandyam, Mahasweta Nayak
Rok vydání: 2021
Předmět:
Male
Long-Term Potentiation
Caveolin 1
Striatum
Pharmacology
Methamphetamine
Substance Misuse
0302 clinical medicine
Biology (General)
Spectroscopy
0303 health sciences
CaMKII
Chemistry
Long-term potentiation
General Medicine
Computer Science Applications
cannabinoid CB1 receptor
self-administration
Indirect agonist
Addiction vulnerability
medicine.drug
QH301-705.5
Amphetamine-Related Disorders
Article
Catalysis
Inorganic Chemistry
03 medical and health sciences
Dopamine receptor D1
Reward
Dopamine
Ca2+/calmodulin-dependent protein kinase
Behavioral and Social Science
Genetics
medicine
Animals
Rats
Long-Evans

dopamine D1 receptor
Physical and Theoretical Chemistry
QD1-999
Molecular Biology
long-term potentiation
030304 developmental biology
Chemical Physics
Organic Chemistry
Neurosciences
Long-Evans
Corpus Striatum
Rats
Brain Disorders
Good Health and Well Being
caveolin
Other Biological Sciences
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Drug Abuse (NIDA only)
Other Chemical Sciences
030217 neurology & neurosurgery
Zdroj: International Journal of Molecular Sciences, Vol 22, Iss 8219, p 8219 (2021)
International journal of molecular sciences, vol 22, iss 15
International Journal of Molecular Sciences
Volume 22
Issue 15
ISSN: 1422-0067
DOI: 10.3390/ijms22158219
Popis: Dopamine D1 receptor (D1R) function is regulated by membrane/lipid raft-resident protein caveolin-1 (Cav1). We examined whether altered expression of Cav1 in the dorsal striatum would affect self-administration of methamphetamine, an indirect agonist at the D1Rs. A lentiviral construct expressing Cav1 (LV-Cav1) or containing a short hairpin RNA against Cav1 (LV-shCav1) was used to overexpress or knock down Cav1 expression respectively, in the dorsal striatum. Under a fixed-ratio schedule, LV-Cav1 enhanced and LV-shCav1 reduced responding for methamphetamine in an extended access paradigm compared to LV-GFP controls. LV-Cav1 and LV-shCav1 also produced an upward and downward shift in a dose–response paradigm, generating a drug vulnerable/resistant phenotype. LV-Cav1 and LV-shCav1 did not alter responding for sucrose. Under a progressive-ratio schedule, LV-shCav1 generally reduced positive-reinforcing effects of methamphetamine and sucrose as seen by reduced breakpoints. Western blotting confirmed enhanced Cav1 expression in LV-Cav1 rats and reduced Cav1 expression in LV-shCav1 rats. Electrophysiological findings in LV-GFP rats demonstrated an absence of high-frequency stimulation (HFS)-induced long-term potentiation (LTP) in the dorsal striatum after extended access methamphetamine self-administration, indicating methamphetamine-induced occlusion of plasticity. LV-Cav1 prevented methamphetamine-induced plasticity via increasing phosphorylation of calcium calmodulin kinase II, suggesting a mechanism for addiction vulnerability. LV-shCav1 produced a marked deficit in the ability of HFS to produce LTP and, therefore, extended access methamphetamine was unable to alter striatal plasticity, indicating a mechanism for resistance to addiction-like behavior. Our results demonstrate that Cav1 expression and knockdown driven striatal plasticity assist with modulating addiction to drug and nondrug rewards, and inspire new strategies to reduce psychostimulant addiction.
Databáze: OpenAIRE
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