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Browsing by Subject "nucleus accumbens"

Now showing 1 - 4 of 4
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    From Estradiol to the Endogenous Cannabinoid System: A Gateway to Drug Addiction in Females
    (2016-07) Peterson, Brittni
    Drug addiction is a widespread condition affecting 8-10% of the population nationwide. Although men and women are both affected by drug addiction, sex-differences in responsiveness to drugs of abuse are apparent, with women showing a greater sensitivity than men. For over 30 years, the ovarian hormone estradiol has been recognized as a key biological factor contributing to the development of drug addiction in females, with little understanding of the neurobiological underpinnings. Here we propose a neural mechanism through which estradiol primes females to respond more strongly to drugs of abuse. Estradiol can act at intracellular or membrane-localized estrogen receptors to influence cellular function. Exclusively in females, a subset of these membrane estrogen receptors are coupled to group I metabotropic glutamate receptors (mGluRs). We demonstrate that it is through group I mGluRs that estradiol structurally remodels reward circuits in the nucleus accumbens (NAc), an effect associated with heightened sensitivity to drugs of abuse in females. In the nervous system, both estradiol and group I mGluRs can influence the activity of the endogenous cannabinoid (endoCB) system, an emerging mediator of neural plasticity and behavioral responses to drugs of abuse. Interestingly, we find that estradiol enhances the activity of the endoCB system in the female NAc by rapidly altering concentrations of the two best known endoCBs and increasing cannabinoid receptor expression. Further we demonstrate that activation of the endoCB system is critical for estradiol to induce structural plasticity in the NAc and facilitate behavioral responses to repeated drug exposure. Collectively, our results suggest that estradiol, group I mGluRs and the endoCB system may be linked through a serial pathway that is principally important in female drug addiction. These findings begin to elucidate a neural mechanism underlying female vulnerability to addiction that contributes to sex differences in drug abuse and may actually provide putative therapeutic targets that are particularly effective in treating drug abuse in women.
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    A Non-Canonical Role of Angiotensin-Converting Enzyme in Synaptic Plasticity
    (2022-06) Trieu, Brian
    A diverse repertoire of endogenous opioid peptides are found within the brain, but because they are often co-expressed and co-released with other peptides, their role in synaptic plasticity remains elusive. These neuropeptides can have profound control over synaptic transmission upon binding to opioid receptors, particularly within the nucleus accumbens where converging signals are integrated to drive motivated behaviors. Neuropeptide effects are often terminated by extracellular degradation, but the mechanisms underlying this are also poorly understood. The identification of specific endogenous opioid peptides and insight into their extracellular regulation can reveal under-appreciated mechanisms that influence opioid receptor signaling to modulate the elaborate neuronal connectivity within this region. The studies presented in this dissertation show that an unconventional and potent endogenous opioid called Met-Enkephalin-Arg-Phe (“MERF”), an enkephalin heptapeptide, dose-dependently inhibited excitatory synaptic transmission onto medium spiny neurons (MSNs) in mouse brain slices. Angiotensin-converting enzyme (ACE) classically regulates blood pressure in the periphery and was found to non-canonically degrade endogenous MERF thereby regulating its effect in the nucleus accumbens. Liquid chromatography-tandem mass spectrometry analysis showed that a class of cardiovascular medications called ACE inhibitors selectively preserved extracellular MERF without affecting conventional enkephalins. ACE inhibitors alone unveiled cell type-specific depression of glutamate release onto MSNs expressing the Drd1 dopamine receptor (D1-MSNs), but not onto those expressing the Drd2 receptor (D2-MSNs). Glutamatergic synaptic depression was mediated by MERF binding to presynaptic µ-opioid receptors and was absent after conditional genetic deletion of ACE. Fiber photometry recordings of D1-MSNs in vivo demonstrated decreased sensitivity to optogenetic stimulation of excitatory medial prefrontal cortex following systemic administration of the ACE inhibitor captopril. Furthermore, mice given captopril displayed attenuated fentanyl-induced place preference and increased social behavior with other mice. Collectively, this dissertation defines an endogenous mechanism of synaptic plasticity induced by MERF and gated by ACE. We interpret this to be preclinical evidence for a class of safe and efficacious cardiovascular medications that could be repositioned or redesigned to mitigate brain conditions with underlying aberrant striatal pathophysiology characterized by an imbalance of D1- to D2-MSN synaptic activity.
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    Palmitoylation of Caveolin-1 and its importance for structural and functional plasticity
    (2018-11) Eisinger, Katherine
    This dissertation examines the regulation and function of caveolin-1 (Cav1). Cav1 is an integral membrane protein that creates functional microdomains of neuronal proteins within lipid rafts. Cav1 regulates a variety of signaling pathways, including mGluR-activated G protein cascades, and is involved in membrane trafficking of proteins such as estrogen and dopamine receptors. The function of Cav1 is regulated by palmitoylation, a reversible post-translational addition of a 16-carbon lipid chain that is involved in trafficking and compartmentalizing target proteins. This regulatory mechanism is important not only for Cav1, but also for membrane association of estrogen receptors. Within the nervous system, palmitoylation of estrogen receptor alpha (ERα) is necessary for surface membrane localization and mediation of downstream signaling through the activation of metabotropic glutamate receptors (mGluRs). Mutation of the single palmitoylation site on ERα prevents its physical association with Cav1, which in turn is required for the formation of the estrogen receptor/mGluR signaling complex. Interestingly, siRNA knockdown of either of two palmitoyl acyltransferases, DHHC7 or DHHC21, also eliminates this signaling mechanism. As ERα has only one palmitoylation site, I hypothesized that one of these DHHCs palmitoylates another essential protein in this signaling complex, namely Cav1. I investigated this using an acyl-biotin exchange assay in HEK293 cells in conjunction with DHHC overexpression, and found that DHHC7 increased Cav1 palmitoylation. Mutation of the palmitoylation sites on Cav1 eliminated this effect, but did not disrupt the ability of the DHHC enzyme to associate with the protein. In contrast, siRNA knockdown of DHHC7 alone was not sufficient to decrease Cav1 palmitoylation, but rather required simultaneous knockdown of DHHC21. These findings raise questions about the overall influence of palmitoylation on the membrane-initiated estrogen signaling pathway, and highlight the importance of considering the influence of palmitoylation on other Cav1-dependent processes. Additionally, recent studies have shown that altering Cav1 expression influences neuronal plasticity and related behaviors in contexts ranging from learning and memory to chronic injury. Given this relationship between Cav1 and experience-dependent plasticity, I hypothesized that Cav1 expression would also be involved in drug-induced changes in neuronal signaling. I utilized a locomotor sensitization paradigm to test this hypothesis. Animals receiving repeated cocaine displayed behavioral sensitization and greater expression of Cav1 mRNA in the nucleus accumbens when compared to saline-treated controls. Overexpression of Cav1 in the nucleus accumbens enhanced cocaine-induced locomotor responses to cocaine, while Cav1 KO animals did not sensitize. Cultured neurons from the nucleus accumbens, a brain region critical for the development of sensitization, had enhanced dendritic complexity in Cav1 KO mice and altered responses to cocaine. Finally, I report that Cav1 palmitoylation is required for its normal function. Together, these findings suggest that (1) Cav1 KO mice may be structurally saturated such that normal drug-induced plasticity is prevented, (2) Cav1 palmitoylation plays an important role in facilitating the proper activity of signaling molecules associated with Cav1, and (3) understanding Cav1 function will be necessary for fully understanding the development of addiction.
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    Sex differences in morphine reward and glutamatergic regulation of the nucleus accumbens
    (2021-12) Lopresti, Natalie
    Opioid substance use disorder (SUD) affects millions of Americans, and death rates are increasing with the introduction of more potent opioids. Sex differences in the analgesic properties of opioids are well established. Whether similar sex differences are observed in the addictive properties of opioids is less-well understood. Making comparisons across experiments is problematic as methodology vary. In this dissertation, we examined the effects of morphine in male, female, gonadectomized (GDX) male, and GDX female mice using conditioned place preference, a behavioral paradigm specifically looking at the rewarding effects of a drug. We found that GDX males had significantly higher reinstatement to re-exposure to morphine compared to intact males, whereas there were no differences between intact males and intact females. Replacement of testosterone to GDX males did not cause their reinstatement to resemble that of intact males, suggesting that circulating testosterone was not the cause of the difference in behavior. In a separate study we next examined potential sex differences to acute morphine exposure using transgenic mice that allowed us to visualize neurons that were active during exposure to drug. Using Fos-TRAP, we quantified active neurons in the nucleus accumbens (NAc), a region known to be involved in processing of reward. With this acute exposure, we see that the NAc shell (NAcSh) has significantly more active cells after acute morphine than our control saline mice. This importance of the NAcSh led us to finally examine excitatory inputs to the NAcSh and see how their activation impacts behavior in intra-cranial self-stimulation, specifically examining the medial prefrontal cortex (mPFC) and ventral hippocampus (vHPC). We find that female mice learn more quickly how to increase their time receiving mPFC stimulation compared to male mice. We also see that mPFC stimulation tends to cause animals to reside in the region where they receive stimulation, whereas vHPC stimulation causes animals to dart in and out of the stimulation region to increase stimulation time by bypassing the timeout period. Overall, these studies show us that, while there are no overt male / female differences in our CPP reward paradigm, we see male / GDX male differences that are not restored by addition of exogenous testosterone. We also showed that the NAcSh shows increased activation after acute morphine exposure, and that the two glutamatergic inputs we examined elicit differing strategies for increased stimulation of the region. Together, these findings show that further studying the sex differences in opioid reward and understanding how the NAcSh processes reward are important to help better treat SUD.