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

Yosef Avchalumov,Juan C Piña-Crespo,Chitra D Mandyam,Brian P Head,Alison D Kreisler,Mahasweta Nayak,Wulfran Trenet

doi:10.3390/ijms22158219

Abstract

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.

Highlights

Substance use disorder is a learned behavior characterized by compulsive drug seeking that is fueled and maintained by negative affective states [1,2,3,4]
Immunohistochemistry was performed to determine whether Green Fluorescent Protein (GFP) labeled cells were expressed in neurons or astrocytes via co-labeling with NeuN and GFAP
The current study provided evidence that extended access methamphetamine selfadministration is associated with escalation of methamphetamine intake and altered corticostriatal synaptic transmission and plasticity

Summary

Introduction

Substance use disorder is a learned behavior characterized by compulsive drug seeking that is fueled and maintained by negative affective states [1,2,3,4]. In the context of methamphetamine exposure, protracted withdrawal from experimenter delivered methamphetamine or self-administered methamphetamine prevents high frequency stimulation (HFS)-induced LTD and produces LTP in the dorsal striatum [13,14]. No studies have evaluated the ongoing effect of methamphetamine addiction-like behavior on striatal plasticity, HFS-induced LTP in the dorsal striatum, and whether the alterations in striatal LTP correlate with enhancing or reducing methamphetamine addiction-like behavior. In this context, recent findings demonstrate that superfusion of methamphetamine on dorsal striatal slices reduces HFS-induced LTP, indicating methamphetamine-induced occlusion of plasticity [15,16]. More notable is that methamphetamine-induced reduction of LTP is prevented by SCH23390, indicating that

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Conclusion