Imbalances in Prefrontal Cortex CC-Homer1 versus CC-Homer2 Expression Promote Cocaine Preference

Abstract

Homer post-synaptic scaffolding proteins regulate forebrain glutamate transmission and thus, are likely molecular candidates mediating hypofrontality in addiction. Protracted withdrawal from cocaine experience increases the relative expression of Homer2 versus Homer1 isoforms within medial prefrontal cortex (mPFC). Thus, this study employed virus-mediated gene transfer strategies to investigate the functional relevance of an imbalance in mPFC Homer1/2 expression as it relates to various measures of sensorimotor, cognitive, emotional and motivational processing, as well as accompanying alterations in extracellular glutamate in C57BL/6J mice. mPFC Homer2b over-expression elevated basal glutamate content and blunted cocaine-induced glutamate release within the mPFC, while Homer2b knock-down produced the opposite effects. Despite altering mPFC glutamate, Homer2b knock-down failed to influence cocaine-elicited conditioned place-preferences, nor did it produce consistent effects on any other behavioral measures. In contrast, elevating the relative expression of Homer2b versus Homer1 within mPFC, by over-expressing Homer2b or knocking down Homer1c, shifted the dose-response function for cocaine-conditioned reward to the left, without affecting cocaine locomotion or sensitization. Intriguingly, both these transgenic manipulations produced glutamate anomalies within the nucleus accumbens (NAC) of cocaine-naïve animals that are reminiscent of those observed in cocaine experienced animals, including reduced basal extracellular glutamate content, reduced Homer1/2 and glutamate receptor expression, and augmented cocaine-elicited glutamate release. Together, these data provide novel evidence in support of opposing roles for constitutively expressed Homer1 and Homer2 isoforms in regulating mPFC glutamate transmission in vivo and support the hypothesis that cocaine-elicited increases in the relative amount of mPFC Homer2 versus Homer1 signaling produces abnormalities in NAC glutamate transmission that enhance vulnerability to cocaine reward.

Homer1/mGluR5 Activity Moderates Vulnerability to Chronic Social Stress

“…Hyperactive corticosterone responses induced by CSDS are frequently observed in this paradigm Wagner et al, 2011;Hartmann et al, 2012) and deletion of Homer1 further increased this effect, indicating a prominent regulatory role of this glutamatergic pathway in the feedback regulation of the HPA axis. Compensatory effects caused by changes in mGluR5 or Homer2a/b expression (Ary et al, 2013) in Homer1 KO mice seem unlikely, as the observed effects in the hippocampus were rather modest.…”

Binge Alcohol Drinking by Mice Requires Intact Group1 Metabotropic Glutamate Receptor Signaling Within the Central Nucleus of the Amygdale

“…Despite no alcohol-induced change in protein expression, intra-CeA mGluR5 blockade reduced alcohol intake in both B6 mice and B6-129 hybrid mice, suggesting an increase in CeA mGluR5 function by a month-long history of binge drinking. The increase in mGluR5 function likely relates to the alcohol-induced rise in CeA Homer2a/b expression, as (1) Homers are well characterized to regulate Group1 mGluR expression, trafficking and signaling in vivo (Ary et al, 2013;c.f., Szumlinski et al, 2008); (2) Homer2 knockdown is sufficient to lower binge alcohol intake (albeit only at a high concentration); and (3) the attenuating effects of intraCeA mGluR5 antagonists are absent in the Homer2 KO mice. Thus, as reported for the NACshell (Cozzoli et al, 2009;, mGluR/Homer2 signaling in the CeA maintains excessive alcohol drinking, although it remains to be determined whether or not this signaling contributes to the initiation of binge alcohol intake.…”

“…As Homer2 deletion produces an alcohol-intolerant and -adverse animal (Szumlinski et al, 2005), the possibility exists that Homer2, particularly within the CeA, may facilitate the development of tolerance to the aversive properties of alcohol, although the mechanisms through which this occurs require comprehensive investigation. One possibility might relate to effects of our shRNAHomer2b construct upon the expression of glutamate receptors, as we have recently reported a coincident reduction in Homer2b and mGluR5 (but not mGluR1) upon intraprefrontal cortex infusion of our shRNA-Homer2b AAV (Ary et al, 2013). Nevertheless, the current studies showing the necessary role of Homer2 for the attenuating effects of intra-CeA mGluR1, mGluR5 and PLC antagonism demonstrates the importance of Homer2 for mGluR1 and mGluR5-PLC signaling within the CeA for the maintenance of an excessive drinking phenotype.…”

Glutamate Signaling in Alcohol Abuse and Dependence

“…ShiraishiYamaguchi & Furuichi, 2007;Szumlinski, Ary, Lominac, Klugmann, Kippin, et al, 2008). In vivo, constitutive deletion of either Homer1 or Homer2 or adeno-associated virus-mediated knockdown of the major rodent isoforms Homer1c and Homer2b alter basal extracellular levels of glutamate within nucleus accumbens and prefrontal cortex, reduce the capacity of Group 1 mGluR agonists to stimulate glutamate release , and lower the total protein expression of both Group 1 mGluRs and GluN2 subunits of the NMDA receptor (e.g., Ary et al, 2013), demonstrating a critical role for these proteins in regulating both Group 1 mGluR and NMDA receptor function/expression.…”