Female and male glial fibrillary acidic protein-thymidine kinase (GFAP-TK) transgenic rats were made ethanol dependent via a six-week chronic intermittent ethanol vapor (CIE) and ethanol drinking (ED) procedure. During the last week of CIE, a subset of male and female TK rats was fed valcyte to ablate dividing progenitor cells and continued the diet until the end of this study. Following week six, all CIE rats experienced two weeks of forced abstinence from CIE-ED, after which they experienced relapse to drinking, extinction, and reinstatement of ethanol seeking sessions. CIE increased ED in female and male rats, with females having higher ethanol consumption during CIE and relapse sessions compared with males. In both sexes, valcyte reduced the levels of Ki-67-labeled progenitor cells in the subgranular zone of the dentate gyrus and did not alter the levels in the medial prefrontal cortex (mPFC). Valcyte increased ED during relapse, increased lever responses during extinction and, interestingly, enhanced latency to extinguish ethanol-seeking behaviors in males. Valcyte reduced the reinstatement of ethanol-seeking behaviors triggered by ethanol cues in females and males. Reduced seeking by valcyte was associated with the normalization of cytokines and chemokines in plasma isolated from trunk blood, indicating a role for progenitor cells in peripheral inflammatory responses. Reduced seeking by valcyte was associated with increases in tight junction protein claudin-5 and oligodendrogenesis in the dentate gyrus and reduction in microglial activity in the dentate gyrus and mPFC in females and males, demonstrating a role for progenitor cells in the dentate gyrus in dependence-induced endothelial and microglial dysfunction. These data suggest that progenitor cells born during withdrawal and abstinence from CIE in the dentate gyrus are aberrant and could play a role in strengthening ethanol memories triggered by ethanol cues via central and peripheral immune responses.

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.