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Title: PI3 kinase is involved in cocaine behavioral sensitization and its reversal with brain area specificity

Abstract

Phosphatidylinositol 3-kinase (PI3K) is an important signaling molecule involved in cell differentiation, proliferation, survival, and phagocytosis, and may participate in various brain functions. To determine whether it is also involved in cocaine sensitization, we measured the p85{alpha}/p110 PI3K activity in the nuclear accumbens (NAc) shell, NAc core, and prefrontal cortex (PFC) following establishment of cocaine sensitization and its subsequent reversal. Naive rats were rank-ordered and split into either daily cocaine or saline pretreatment group based on their locomotor responses to an acute cocaine injection (7.5 mg/kg, i.p.). These two groups were then injected with cocaine (40 mg/kg, s.c.) or saline for 4 consecutive days followed by 9-day withdrawal. Cocaine sensitization was subsequently reversed by 5 daily injections of the D{sub 1}/D{sub 2} agonist pergolide (0.1 mg/kg, s.c.) in combination with the 5-HT{sub 3} antagonist ondansetron (0.2 mg/kg, s.c., 3.5 h after pergolide injection). After another 9-day withdrawal, behavioral cocaine sensitization and its reversal were confirmed with an acute cocaine challenge (7.5 mg/kg, i.p.), and animals were sacrificed the next day for measurement of p85{alpha}/p110 PI3K activity. Cocaine-sensitized animals exhibited increased PI3K activity in the NAc shell, and this increase was reversed by combined pergolide/ondansetron treatment, which also reversed behavioral sensitization.more » In the NAc core and PFC, cocaine sensitization decreased and increased the PI3K activity, respectively. These changes, in contrast to that in the NAc shell, were not normalized following the reversal of cocaine-sensitization. Interestingly, daily injections of pergolide alone in saline-pretreated animals induced PI3K changes that were similar to the cocaine sensitization-associated changes in the NAc core and PFC but not the NAc shell; furthermore, these changes in saline-pretreated animals were prevented by ondansetron given 3.5 h after pergolide. The present study suggests that selective enhancement of the PI3K activity in the NAc shell may be one of key alterations underlying the long-term cocaine sensitization. To the extent cocaine sensitization is an important factor in human cocaine abuse, pharmacological interventions targeted toward the NAc shell PI3K alteration may be useful in cocaine abuse treatment.« less

Authors:
 [1];  [2];  [3];  [4];  [3];  [3];  [3];  [3];  [4];  [3]
  1. Department of Psychiatry and Behavioral Science, Duke University Medical Center, Durham, NC 27710 (United States). E-mail: xwzhang@duke.edu
  2. Department of Surgery, Duke University Medical Center, Durham, NC 27710 (United States)
  3. Department of Psychiatry and Behavioral Science, Duke University Medical Center, Durham, NC 27710 (United States)
  4. (United States)
Publication Date:
OSTI Identifier:
20798813
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 340; Journal Issue: 4; Other Information: DOI: 10.1016/j.bbrc.2005.12.114; PII: S0006-291X(05)02878-0; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BRAIN; CELL DIFFERENTIATION; COCAINE; INJECTION; PHAGOCYTOSIS; RATS; SPECIFICITY

Citation Formats

Zhang Xiuwu, Mi Jing, Wetsel, William C., Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, Davidson, Colin, Xiong Xieying, Chen Qiang, Ellinwood, Everett H., Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, and Lee, Tong H. PI3 kinase is involved in cocaine behavioral sensitization and its reversal with brain area specificity. United States: N. p., 2006. Web. doi:10.1016/j.bbrc.2005.12.114.
Zhang Xiuwu, Mi Jing, Wetsel, William C., Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, Davidson, Colin, Xiong Xieying, Chen Qiang, Ellinwood, Everett H., Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, & Lee, Tong H. PI3 kinase is involved in cocaine behavioral sensitization and its reversal with brain area specificity. United States. doi:10.1016/j.bbrc.2005.12.114.
Zhang Xiuwu, Mi Jing, Wetsel, William C., Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, Davidson, Colin, Xiong Xieying, Chen Qiang, Ellinwood, Everett H., Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, and Lee, Tong H. Fri . "PI3 kinase is involved in cocaine behavioral sensitization and its reversal with brain area specificity". United States. doi:10.1016/j.bbrc.2005.12.114.
@article{osti_20798813,
title = {PI3 kinase is involved in cocaine behavioral sensitization and its reversal with brain area specificity},
author = {Zhang Xiuwu and Mi Jing and Wetsel, William C. and Department of Cell Biology, Duke University Medical Center, Durham, NC 27710 and Davidson, Colin and Xiong Xieying and Chen Qiang and Ellinwood, Everett H. and Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710 and Lee, Tong H.},
abstractNote = {Phosphatidylinositol 3-kinase (PI3K) is an important signaling molecule involved in cell differentiation, proliferation, survival, and phagocytosis, and may participate in various brain functions. To determine whether it is also involved in cocaine sensitization, we measured the p85{alpha}/p110 PI3K activity in the nuclear accumbens (NAc) shell, NAc core, and prefrontal cortex (PFC) following establishment of cocaine sensitization and its subsequent reversal. Naive rats were rank-ordered and split into either daily cocaine or saline pretreatment group based on their locomotor responses to an acute cocaine injection (7.5 mg/kg, i.p.). These two groups were then injected with cocaine (40 mg/kg, s.c.) or saline for 4 consecutive days followed by 9-day withdrawal. Cocaine sensitization was subsequently reversed by 5 daily injections of the D{sub 1}/D{sub 2} agonist pergolide (0.1 mg/kg, s.c.) in combination with the 5-HT{sub 3} antagonist ondansetron (0.2 mg/kg, s.c., 3.5 h after pergolide injection). After another 9-day withdrawal, behavioral cocaine sensitization and its reversal were confirmed with an acute cocaine challenge (7.5 mg/kg, i.p.), and animals were sacrificed the next day for measurement of p85{alpha}/p110 PI3K activity. Cocaine-sensitized animals exhibited increased PI3K activity in the NAc shell, and this increase was reversed by combined pergolide/ondansetron treatment, which also reversed behavioral sensitization. In the NAc core and PFC, cocaine sensitization decreased and increased the PI3K activity, respectively. These changes, in contrast to that in the NAc shell, were not normalized following the reversal of cocaine-sensitization. Interestingly, daily injections of pergolide alone in saline-pretreated animals induced PI3K changes that were similar to the cocaine sensitization-associated changes in the NAc core and PFC but not the NAc shell; furthermore, these changes in saline-pretreated animals were prevented by ondansetron given 3.5 h after pergolide. The present study suggests that selective enhancement of the PI3K activity in the NAc shell may be one of key alterations underlying the long-term cocaine sensitization. To the extent cocaine sensitization is an important factor in human cocaine abuse, pharmacological interventions targeted toward the NAc shell PI3K alteration may be useful in cocaine abuse treatment.},
doi = {10.1016/j.bbrc.2005.12.114},
journal = {Biochemical and Biophysical Research Communications},
number = 4,
volume = 340,
place = {United States},
year = {Fri Feb 24 00:00:00 EST 2006},
month = {Fri Feb 24 00:00:00 EST 2006}
}
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  • No abstract prepared.