Yosef Avchalumov,1 Alison D. Kreisler,1 Wulfran Trenet,1 Mahasweta Nayak,1 Brian P. Head,1,2 Juan C. Piña-Crespo,3 and Chitra D. Mandyam1,2,*


1Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, USA; [email protected] (Y.A.); [email protected] (A.D.K.); [email protected] (W.T.); [email protected] (M.N.); [email protected] (B.P.H.)
2Department of Anesthesiology, University of California San Diego, San Diego, CA 92037, USA
3Department of Molecular Medicine, Scripps Research, La Jolla, CA 92037, USA; [email protected]
*Correspondence: [email protected]




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.



Recordings were made in the dorsal striatum (Figure 4b,c), in a submersion-type recording chamber superfused with oxygenated ACSF at a rate of 2–3 mL/min at 25 °C and positioned on the stage of an upright motorized microscope (Olympus BX51 WI, Scientifica, Clarksburg, NJ, USA) equipped with a back Illuminated sCMOS camera (Prime 95B, Photometrics, Tucson, AZ, USA) and a broad-spectrum LED illuminator (pE-300, CoolLED).

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The pE-300white is a popular illuminator for everyday fluorescent screening and analysis with simple operatation and individual irradiance control of each LED channel.

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Int. J. Mol. Sci.

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