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 |
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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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