Aim 1. The role of enhanced release of excitatory amino acids and an up- regulation of cAMP pathways in the locus coeruleus (LC) in the expression of opiate withdrawal measured behaviorally will be evaluated. The effects of local infusion into the LC of excitatory amino acid antagonists, dextromethorphan, or cAMP-dependent protein kinase inhibitors will be measured in morphine-dependent rats to see if these local treatments will reduce opiate withdrawal. Possible additive effects of local infusion into the LC of excitatory amino acid inhibitors and cAMP-dependent protein kinase inhibitors or of clonidine and excitatory amino acid antagonists will also be tested. The ability of local infusion into the LC of carbachol or the phosphodiesterase inhibitor IBMX to produce withdrawal- like behavior in non-dependent rats, including Lewis vs. Fisher strains, will also be tested.
Aim 2. Animal models to measure the anhedonic aspects of drug withdrawal that can be classically conditioned to the experimental context in which withdrawal occurs will be developed. These will include the conditioned place aversion test and potentiation of the acoustic startle reflex when animals are reintroduced to a context in which they previously experienced opiate withdrawal. Parameters to produce withdrawal induced context potentiated startle and its context specificity will be explored. Effects of lesions of the amygdala or nucleus accumbens (NAc) on the expression vs. acquisition of opiate-withdrawal induced place aversion or withdrawal induced context potentiated startle will be tested. The effects of local infusion of excitatory amino acid antagonists into the LC, NAc or the amygdala on the expression vs. acquisition of these measures will be tested. The effectiveness of local infusion of carbachol into the LC in producing place aversion or context potentiated startle to the context in which carbachol was infused will be measured.
Aim 3. Animal models to measure the hedonic aspects of drug intake using classical conditioning of stimuli associated with drug intake will be developed. These will include the conditioned place preference and conditioned reinforcement paradigms. Effects of lesions of the NAc or amygdala on the expression vs. acquisition of conditioned place preference or conditioned reinforcement will be studied. Effects of local infusion of excitatory amino acid antagonists into the NAc or the amygdala on the expression vs. acquisition of these behaviors will be tested. Effects of chronic morphine exposure and precipitated withdrawal on morphine conditioned place preference and conditioned reinforcement, as well as the effects of drug 'priming' on reinstatement of conditioned reinforcement will be evaluated.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Program Projects (P01)
Project #
5P01DA008227-04
Application #
5209702
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
1996
Total Cost
Indirect Cost
Miller, M L; Ren, Y; Szutorisz, H et al. (2018) Ventral striatal regulation of CREM mediates impulsive action and drug addiction vulnerability. Mol Psychiatry 23:1328-1335
Monteggia, Lisa M; Heimer, Hakon; Nestler, Eric J (2018) Meeting Report: Can We Make Animal Models of Human Mental Illness? Biol Psychiatry 84:542-545
Clark, Christopher R; Maile, Makayla; Blaney, Patrick et al. (2018) Transposon mutagenesis screen in mice identifies TM9SF2 as a novel colorectal cancer oncogene. Sci Rep 8:15327
Cates, Hannah M; Heller, Elizabeth A; Lardner, Casey K et al. (2018) Transcription Factor E2F3a in Nucleus Accumbens Affects Cocaine Action via Transcription and Alternative Splicing. Biol Psychiatry 84:167-179
Cahill, M E; Walker, D M; Gancarz, A M et al. (2018) The dendritic spine morphogenic effects of repeated cocaine use occur through the regulation of serum response factor signaling. Mol Psychiatry 23:1474-1486
Hamilton, Peter J; Burek, Dominika J; Lombroso, Sonia I et al. (2018) Cell-Type-Specific Epigenetic Editing at the Fosb Gene Controls Susceptibility to Social Defeat Stress. Neuropsychopharmacology 43:272-284
Egervari, Gabor; Kozlenkov, Alexey; Dracheva, Stella et al. (2018) Molecular windows into the human brain for psychiatric disorders. Mol Psychiatry :
de la Fuente Revenga, Mario; Ibi, Daisuke; Saunders, Justin M et al. (2018) HDAC2-dependent Antipsychotic-like Effects of Chronic Treatment with the HDAC Inhibitor SAHA in Mice. Neuroscience 388:102-117
Anderson, Ethan M; Sun, Haosheng; Guzman, Daniel et al. (2018) Knockdown of the histone di-methyltransferase G9a in nucleus accumbens shell decreases cocaine self-administration, stress-induced reinstatement, and anxiety. Neuropsychopharmacology :
Hamilton, Peter J; Lim, Carissa J; Nestler, Eric J et al. (2018) Stereotaxic Surgery and Viral Delivery of Zinc-Finger Epigenetic Editing Tools in Rodent Brain. Methods Mol Biol 1867:229-238

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