This is a request for a NIDA Mentored Research Career Award (KO1) to study the candidate's interest in the role of L-type Ca2+ channels in amphetamine-mediated CREB phosphorylation and dynorphin gene expression. Much of the progress in substance abuse research has focused on the neuro- and behavioral pharmacology of drugs of abuse. However only recently the significance of the molecular changes associated with chronic drug use are being unraveled. Towards a better understanding of the addictive properties of these drugs, the candidate will apply her molecular biology background to study the molecular mechanisms underlying addictive behavior. As a research fellow, the candidate has gained knowledge and received training in the molecular mechanism of the dopamine signal transduction pathway in primary striatal cultures. The in vitro studies indicate a dependence of dopamine-mediated CREB phosphorylation and gene expression on L-type Ca2+ channels. This is highly relevant because of the recent implication of L-type Ca2+ channels in psychostimulant-induced behavior. Through this award the candidate will correlate the molecular events observed in vitro to an in vivo model of chronic amphetamine, in rats. The role of L-type Ca2+ channels in amphetamine-mediated CREB phosphorylation and dynorphin gene expression will be examined. Both CREB and dynorphin have been directly implicated in the addictive properties of the psychostimulant, cocaine. The candidate's training has primarily been in in vitro and cell cultures systems. Through this award she will further expand her repertoire of training to in vivo work. The training received through this award will include learning the neuroanatomy, neuropharmacology and behavioral effects of psychostimulant abuse. In particular the candidate will learn (1) in situ hybridization in brain slices (2) stereotaxic surgeries to introduce drugs, antisense oligonucleotides and viral vectors directly into the brain, (3) viral vector technology, a powerful new method to manipulate neuronal function, and (4) test locomotor activity.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DA014057-03
Application #
6523318
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Colvis, Christine
Project Start
2000-09-01
Project End
2005-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
3
Fiscal Year
2002
Total Cost
$119,353
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Schierberl, Kathryn; Giordano, Thomas; Satpute, Shirish et al. (2012) Cav 1.3 L-type Ca ( 2+) channels mediate long-term adaptation in dopamine D2L-mediated GluA1 trafficking in the dorsal striatum following cocaine exposure. Channels (Austin) 6:11-7
Schierberl, Kathryn; Hao, Jin; Tropea, Thomas F et al. (2011) Cav1.2 L-type Ca²? channels mediate cocaine-induced GluA1 trafficking in the nucleus accumbens, a long-term adaptation dependent on ventral tegmental area Ca(v)1.3 channels. J Neurosci 31:13562-75
Giordano, Thomas P; Tropea, Thomas F; Satpute, Shirish S et al. (2010) Molecular switch from L-type Ca v 1.3 to Ca v 1.2 Ca2+ channel signaling underlies long-term psychostimulant-induced behavioral and molecular plasticity. J Neurosci 30:17051-62
Covington 3rd, Herbert E; Tropea, Thomas F; Rajadhyaksha, Anjali M et al. (2008) NMDA receptors in the rat VTA: a critical site for social stress to intensify cocaine taking. Psychopharmacology (Berl) 197:203-16
Tropea, Thomas F; Kosofsky, Barry E; Rajadhyaksha, Anjali M (2008) Enhanced CREB and DARPP-32 phosphorylation in the nucleus accumbens and CREB, ERK, and GluR1 phosphorylation in the dorsal hippocampus is associated with cocaine-conditioned place preference behavior. J Neurochem 106:1780-90
Giordano 3rd, T P; Satpute, S S; Striessnig, J et al. (2006) Up-regulation of dopamine D(2)L mRNA levels in the ventral tegmental area and dorsal striatum of amphetamine-sensitized C57BL/6 mice: role of Ca(v)1.3 L-type Ca(2+) channels. J Neurochem 99:1197-206
Rajadhyaksha, Anjali M; Kosofsky, Barry E (2005) Psychostimulants, Protein phosphorylation and Gene expression: a growing role of L-type calcium channels. Cellscience 2:127-144
Rajadhyaksha, Anjali M; Kosofsky, Barry E (2005) Psychostimulants, L-type calcium channels, kinases, and phosphatases. Neuroscientist 11:494-502
Rajadhyaksha, Anjali; Husson, Isabelle; Satpute, Shirish S et al. (2004) L-type Ca2+ channels mediate adaptation of extracellular signal-regulated kinase 1/2 phosphorylation in the ventral tegmental area after chronic amphetamine treatment. J Neurosci 24:7464-76