The neurobiological bases for the transition from occasional to compulsive drug intake remain largely unknown. Mounting evidence points to a key role for neurocircuits involving the hypothalamus in the drug-induced dysregulations that drive compulsive drug taking and relapse after abstinence. Work during the previous (first) funding period uncovered gene expression evidence of remodeling of intrinsic lateral hypothalamic (LH) circuitry in rats with an escalated pattern of cocaine intake. Among the genes affected by cocaine self-administration in the LH was syndecan-3, a hypothalamic proteoglycan previously implicated in feeding. To test the role of syndecan-3 in cocaine escalation we have adapted to the mouse the extended access paradigm previously optimized only for the rat. With this model, we observed that syndecan-3 null mice self- administered more cocaine than wild-type mice and that transgenic mice with ectopic expression in the hypothalamus of a constitutive active allele were resistant to escalating cocaine intake under extended access conditions. These findings suggest that syndecan-3-mediated signaling in the LH is a novel pathway contributing to compulsive drug intake. Building on the results of the previous funding period, the purpose of this proposal is to develop a mechanistic understanding of the role of hypothalamic syndecan-3 in the development of escalated cocaine self-administration. To this aim we propose to investigate regulators and targets of syndecan-3 and the gene networks in which they are active using genomics, mutant mice, biochemical, morphological and behavioral strategies. Collectively, these studies will provide novel information regarding the role of LH dysregulation in the development of compulsive cocaine intake.

Public Health Relevance

The abuse of cocaine and other drugs is epidemic in our society. Research toward a better understanding of the neurobiological bases of drug addiction is necessary to guide the development of pharmacotherapeutic agents for the treatment of drug abuse. Results of the previous funding period suggest the hypothesis that the dysregulation of a specific lateral hypothalamic cellular signaling system may be key in the development of escalated cocaine intake. To extend these results, this proposal is aimed at the exploration of this molecular system and its role in the regulation of cocaine intake. The proposed research will deepen our understanding of the neurobiology of cocaine abuse and may reveal new testable pathogenetic hypotheses and novel therapeutic targets for compulsive drug taking and relapse after cessation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA013821-05
Application #
7575700
Study Section
Special Emphasis Panel (ZRG1-BDCN-A (90))
Program Officer
Caulder, Mark
Project Start
2000-09-29
Project End
2013-01-31
Budget Start
2009-02-01
Budget End
2010-01-31
Support Year
5
Fiscal Year
2009
Total Cost
$402,688
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Chen, Jihuan; Repunte-Canonigo, Vez; Kawamura, Tomoya et al. (2013) Hypothalamic proteoglycan syndecan-3 is a novel cocaine addiction resilience factor. Nat Commun 4:1955
Szucs, Attila; Berton, Fulvia; Nowotny, Thomas et al. (2010) Consistency and diversity of spike dynamics in the neurons of bed nucleus of stria terminalis of the rat: a dynamic clamp study. PLoS One 5:e11920
Lefebvre, Celine; Rajbhandari, Presha; Alvarez, Mariano J et al. (2010) A human B-cell interactome identifies MYB and FOXM1 as master regulators of proliferation in germinal centers. Mol Syst Biol 6:377
Francesconi, Walter; Berton, Fulvia; Koob, George F et al. (2009) Intrinsic neuronal plasticity in the juxtacapsular nucleus of the bed nuclei of the stria terminalis (jcBNST). Prog Neuropsychopharmacol Biol Psychiatry 33:1347-55
Francesconi, Walter; Berton, Fulvia; Repunte-Canonigo, Vez et al. (2009) Protracted withdrawal from alcohol and drugs of abuse impairs long-term potentiation of intrinsic excitability in the juxtacapsular bed nucleus of the stria terminalis. J Neurosci 29:5389-401
Karpova, A; Sanna, P P; Behnisch, T (2006) Involvement of multiple phosphatidylinositol 3-kinase-dependent pathways in the persistence of late-phase long term potentiation expression. Neuroscience 137:833-41
Ahmed, Serge H; Lutjens, Robert; van der Stap, Lena D et al. (2005) Gene expression evidence for remodeling of lateral hypothalamic circuitry in cocaine addiction. Proc Natl Acad Sci U S A 102:11533-8
Sanna, Pietro Paolo; King, Alvin R; van der Stap, Lena D et al. (2005) Gene profiling of laser-microdissected brain regions and sub-regions. Brain Res Brain Res Protoc 15:66-74
Koob, George F; Ahmed, Serge H; Boutrel, Benjamin et al. (2004) Neurobiological mechanisms in the transition from drug use to drug dependence. Neurosci Biobehav Rev 27:739-49
Izzo, Emanuela; Martin-Fardon, Remi; Koob, George F et al. (2002) Neural plasticity and addiction: PI3-kinase and cocaine behavioral sensitization. Nat Neurosci 5:1263-4