Our working hypothesis is that drug addiction is a maladaptive form of glutamate-dependent plasticity. Our prior work has used behavioral sensitization as an animal model for intensification of drug craving. We have shown that glutamate transmission is required for the development of sensitization and that glutamate systems are dramatically altered in sensitized rats. This proposal will further characterize mechanisms underlying changes in glutamate transmission produced by amphetamine or by drug-associated environmental cues. Each of the aims focuses on a different aspect of glutamate's role in sensitization.
Aim 1 is based on the hypothesis that the induction of sensitization requires potentiation of AMPA transmission within the ventral tegmental area (VTA). We propose to determine if this is mediated by Narp, a secreted immediate early gene product that clusters AMPA receptors at synaptic sites. Preliminary data show that Narp is elevated in VTA after both acute and repeated amphetamine treatment. Experiments will characterize Narp distribution in VTA, further examine the effects of amphetamine on its expression, and determine if the development of sensitization is prevented by chronic intra-VTA infusion of antisense oligodeoxynucleotides to Narp.
Aim 2 builds on prior studies showing that repeated amphetamine decreases GluR1, GluR2 and NR1 levels in the nucleus accumbens (NAc), leading to changes in neuronal excitability that are hypothesized to mediate the long-term maintenance of sensitization. We will compare the persistence of these changes to that of behavioral sensitization, identify cell types within NAc that exhibit altered subunit expression, and examine amphetamine's possible effects on NR2 subunits and NR1 slice variants.
Aim 3 will extend our studies of drug-induced plasticity to conditioned locomotion, a phenomenon that may provide insight into situational drug craving. We hypothesize that expression of conditioned locomotion requires increased activity of glutamate projections from prefrontal and cingulate cortices, or amygdala to the NAc. We will determine if the expression of conditioned locomotion is prevented by reversibly inactivating these regions with lidocaine or by blocking AMPA transmission. Microdialysis studies will directly examine the possibility that drug-associated cues activate glutamate transmission. Finally, we will determine if pharmacological treatments that reverse established locomotor sensitization also reverse conditioned locomotion.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA009621-05
Application #
6206957
Study Section
Special Emphasis Panel (ZRG1-MDCN-7 (03))
Program Officer
Frankenheim, Jerry
Project Start
1996-09-01
Project End
2005-05-31
Budget Start
2000-08-20
Budget End
2001-05-31
Support Year
5
Fiscal Year
2000
Total Cost
$319,080
Indirect Cost
Name
Rosalind Franklin University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
069501252
City
North Chicago
State
IL
Country
United States
Zip Code
60064
Scheyer, Andrew F; Christian, Daniel T; Wolf, Marina E et al. (2018) Emergence of Endocytosis-Dependent mGlu1 LTD at Nucleus Accumbens Synapses After Withdrawal From Cocaine Self-Administration. Front Synaptic Neurosci 10:36
Dong, Yan; Taylor, Jane R; Wolf, Marina E et al. (2017) Circuit and Synaptic Plasticity Mechanisms of Drug Relapse. J Neurosci 37:10867-10876
Purgianto, Anthony; Weinfeld, Michael E; Wolf, Marina E (2017) Prolonged withdrawal from cocaine self-administration affects prefrontal cortex- and basolateral amygdala-nucleus accumbens core circuits but not accumbens GABAergic local interneurons. Addict Biol 22:1682-1694
Werner, Craig T; Murray, Conor H; Reimers, Jeremy M et al. (2017) Trafficking of calcium-permeable and calcium-impermeable AMPA receptors in nucleus accumbens medium spiny neurons co-cultured with prefrontal cortex neurons. Neuropharmacology 116:224-232
Christian, Daniel T; Wang, Xiaoting; Chen, Eugenia L et al. (2017) Dynamic Alterations of Rat Nucleus Accumbens Dendritic Spines over 2 Months of Abstinence from Extended-Access Cocaine Self-Administration. Neuropsychopharmacology 42:748-756
Wolf, Marina E (2016) Synaptic mechanisms underlying persistent cocaine craving. Nat Rev Neurosci 17:351-65
Scheyer, Andrew F; Loweth, Jessica A; Christian, Daniel T et al. (2016) AMPA Receptor Plasticity in Accumbens Core Contributes to Incubation of Methamphetamine Craving. Biol Psychiatry 80:661-670
Purgianto, Anthony; Loweth, Jessica A; Miao, Julia J et al. (2016) Surface expression of GABAA receptors in the rat nucleus accumbens is increased in early but not late withdrawal from extended-access cocaine self-administration. Brain Res 1642:336-343
Li, Xuan; Wolf, Marina E (2015) Multiple faces of BDNF in cocaine addiction. Behav Brain Res 279:240-54
Werner, Craig T; Milovanovic, Mike; Christian, Daniel T et al. (2015) Response of the Ubiquitin-Proteasome System to Memory Retrieval After Extended-Access Cocaine or Saline Self-Administration. Neuropsychopharmacology 40:3006-14

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