Opioid dependence is characterized by negative physiological and psychological symptoms that arise following termination of drug exposure. Since these symptoms can be relieved or avoided by continued drug use, dependence contributes to the cycle of addiction. While the neural substrates of dependence are poorly understood, evidence is emerging that functional ionotropic (NMDA and AMPA) glutamate receptors in the central amygdala (CeA) play a critical role in this form of opioid-dependent plasticity. Studies conducted during the PI's current Research Scientist Development Award have shown that Cre-loxP technology can be used to delete the NMDA-NR1 (NR1) receptor subunit gene in CeA neurons and prevent morphine withdrawal-induced aversion, without affecting physical symptoms. The goal of the present proposal is to expand on these findings by testing the following global hypothesis: Central amygdala NMDA receptors play critical roles in both conditioned aversion and AMPA receptor plasticity associated with opioid dependence. This hypothesis will be addressed by the following Specific Aims:
Aim 1 will test the hypothesis that CeA knockout of NR1 will produce a specific inhibition of opioid withdrawal aversion.
Aim 2 will examine the hypothesis that mu-opioid receptors (OR) and ionotropic glutamate receptors are co-localized in dendrites and dendritic spines (i.e. postsynaptically) in CeA neurons.
Aim 3 will test the hypothesis that acute opioid exposure can affect the trafficking of the AMPA-GluR2 receptor subunit at postsynaptic sites in CeA neurons, a process that can be inhibited by local NR1 gene deletion. To address these hypotheses, state-of-the-art technology, including spatial-temporal knockout methods and quantitative ultrastructural analysis of receptor trafficking, will be employed within the context of models of opioid dependence. These studies should elucidate the role of key molecules and intracellular processes involved in both behavioral and neural plasticity associated with morphine use, thus expanding our knowledge of the neurogenetic and neuroanatomical substrates of opioid dependence. Despite the clinical efficacy of opioids, their abuse and addictive liability are a significant source of public health problems. Chronic use of opioids appear to engage a complex network of signaling molecules, particularly glutamate receptors, in limbic brain regions that produce neural changes similar to those involved in normal learning and memory. Using state of the art molecular pharmacological and neuroanatomical techniques, this proposal will identify the role of glutamate receptors in opioid dependence in specific brain pathways. By elucidating the neurobiological processes that mediate the adverse consequences of dependence, we may provide critical information needed to develop pharmacological interventions for reducing these deleterious actions.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Neurobiology of Motivated Behavior Study Section (NMB)
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Frankenheim, Jerry
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Weill Medical College of Cornell University
Schools of Medicine
New York
United States
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Glass, Michael J; Chan, June; Pickel, Virginia M (2017) Ultrastructural characterization of tumor necrosis factor alpha receptor type 1 distribution in the hypothalamic paraventricular nucleus of the mouse. Neuroscience 352:262-272
Van Kempen, T A; Dodos, M; Woods, C et al. (2015) Sex differences in NMDA GluN1 plasticity in rostral ventrolateral medulla neurons containing corticotropin-releasing factor type 1 receptor following slow-pressor angiotensin II hypertension. Neuroscience 307:83-97
Glass, Michael J; Wang, Gang; Coleman, Christal G et al. (2015) NMDA Receptor Plasticity in the Hypothalamic Paraventricular Nucleus Contributes to the Elevated Blood Pressure Produced by Angiotensin II. J Neurosci 35:9558-67
Beckerman, Marc A; Van Kempen, Tracey A; Justice, Nicholas J et al. (2013) Corticotropin-releasing factor in the mouse central nucleus of the amygdala: ultrastructural distribution in NMDA-NR1 receptor subunit expressing neurons as well as projection neurons to the bed nucleus of the stria terminalis. Exp Neurol 239:120-32
Glass, Michael J; Robinson, Danielle C; Waters, Elizabeth et al. (2013) Deletion of the NMDA-NR1 receptor subunit gene in the mouse nucleus accumbens attenuates apomorphine-induced dopamine D1 receptor trafficking and acoustic startle behavior. Synapse 67:265-79
Beckerman, Marc A; Ogorodnik, Evgeny; Glass, Michael J (2013) Acute morphine associated alterations in the subcellular location of the AMPA-GluR1 receptor subunit in dendrites of neurons in the mouse central nucleus of the amygdala: comparisons and contrasts with other glutamate receptor subunits. Synapse 67:692-704
Beckerman, Marc A; Glass, Michael J (2012) The NMDA-NR1 receptor subunit and the mu-opioid receptor are expressed in somatodendritic compartments of central nucleus of the amygdala neurons projecting to the bed nucleus of the stria terminalis. Exp Neurol 234:112-26
Glass, Michael J (2011) Opioid dependence and NMDA receptors. ILAR J 52:342-51
Beckerman, Marc A; Glass, Michael J (2011) Ultrastructural relationship between the AMPA-GluR2 receptor subunit and the mu-opioid receptor in the mouse central nucleus of the amygdala. Exp Neurol 227:149-58
Glass, Michael J (2010) The role of functional postsynaptic NMDA receptors in the central nucleus of the amygdala in opioid dependence. Vitam Horm 82:145-66

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