A key obstacle to successful treatment of drug addiction is relapse, which is frequently precipitated by exposure to stress. Relapse has been modeled in animal studies through reinstatement of responses to drug self-administration or conditioned place preference (CPP) by drug, cue or stress. We and others, have demonstrated that a variety of drugs of abuse, such as morphine, cocaine and more recently nicotine, can activate the transcription factor CREB (cAMP response element binding protein) and this activation is necessary for subsequent behavioral responses to these drugs. More recently, we have shown that CREB is required for stress-induced reinstatement of cocaine conditioned place preference (CPP), but not drug- induced reinstatement. The mouse is a tractable animal model that allows for investigation of relapse at the levels of behavior, neural circuitry and molecular mechanisms. In this proposal we will utilize mice homozygous for a targeted mutation in CREB (CREB1^ mutant mice) to test the hypothesis that CREB is a central signaling molecule required for stress inducedreinstatement of drug seeking behavior.We will test this central hypothesis in three specific aims.
In Aim 1, we will investigate if activation of the transcription factor CREB is critical for the manifestation of reinstatement behavior following various stressors using a conditioned place preference paradigm (CPP), and determine the role of corticosterone and CRF in this response. As both stress and cocaine reinstate CPP in wild type mice, these circuits must converge on a final common pathway.
In Aim 2, we will identify the pathways specific for stress versus drug induced reinstatement, as well as points of convergence. Moreover, retrograde tracing studies will enable us to identify the precise location of these neurons in key brain areas in the reinstatement circuitry. Lastly, in Aim 3 we will determine which genes in these key brain areas are direct CREB target genes. These studies will allow us to address the molecular mechanisms underlying drug relapse. This information will be valuable for the development of pharmacotherapeutic approaches that focus on regulation of CREB and its target genes. These studies may give rise to novel potential therapeutics that can ultimately be translated to the clinic for relapse prevention in humans.

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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Koustova, Elena
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University of Pennsylvania
Schools of Medicine
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Briand, Lisa A; Lee, Bridgin G; Lelay, John et al. (2015) Serine 133 phosphorylation is not required for hippocampal CREB-mediated transcription and behavior. Learn Mem 22:109-15
Turner, Jill R; Ecke, Laurel E; Briand, Lisa A et al. (2013) Cocaine-related behaviors in mice with deficient gliotransmission. Psychopharmacology (Berl) 226:167-76
Briand, Lisa A; Blendy, Julie A (2013) Not all stress is equal: CREB is not necessary for restraint stress reinstatement of cocaine-conditioned reward. Behav Brain Res 246:63-8
Gundersen, Brigitta B; Briand, Lisa A; Onksen, Jennifer L et al. (2013) Increased hippocampal neurogenesis and accelerated response to antidepressants in mice with specific deletion of CREB in the hippocampus: role of cAMP response-element modulator ?. J Neurosci 33:13673-85
Briand, Lisa A; Lee, Francis S; Blendy, Julie A et al. (2012) Enhanced extinction of cocaine seeking in brain-derived neurotrophic factor Val66Met knock-in mice. Eur J Neurosci 35:932-9
Onksen, J L; Briand, L A; Galante, R J et al. (2012) Running-induced anxiety is dependent on increases in hippocampal neurogenesis. Genes Brain Behav 11:529-38
Onksen, Jennifer L; Brown, Eric J; Blendy, Julie A (2011) Selective deletion of a cell cycle checkpoint kinase (ATR) reduces neurogenesis and alters responses in rodent models of behavioral affect. Neuropsychopharmacology 36:960-9
Ecke, Laurel E; Cleck, Jessica N; White, Peter et al. (2011) CREB-mediated alterations in the amygdala transcriptome: coordinated regulation of immune response genes following cocaine. Int J Neuropsychopharmacol 14:1111-26
Mague, Stephen D; Blendy, Julie A (2010) OPRM1 SNP (A118G): involvement in disease development, treatment response, and animal models. Drug Alcohol Depend 108:172-82
Briand, Lisa A; Blendy, Julie A (2010) Molecular and genetic substrates linking stress and addiction. Brain Res 1314:219-34

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