Clozapine-, but not haloperidol-, induced increases in ΔFosB-like immunoreactivity are completely blocked in the striatum of mice lacking D3 dopamine receptors

George S. Robertson, Christopher J. Lee, Kavita Sridhar, Yusaku Nakabeppu, Michael Cheng, Yan Min Wang, Marc G. Caron

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

On the basis of anatomical and pharmacological evidence, we have proposed that D3 receptor antagonism plays a role in the mediation of clozapine-, but not haloperidol-, induced immediate-early gene expression in the striatum. To test this hypothesis directly, we compared the effects of repeated administration of vehicle (8 mL/kg/day), clozapine (20 mg/kg/day) and haloperidol (2 mg/kg/day) for 17 days on expression of ΔFosB-like immunoreactivity (ΔFosB-Ir) in the island of Calleja major, nucleus accumbens and caudate-putamen of wild-type C57BI6 (WT) and D3 receptor knockout (D3KO) mice. In vehicle-treated mice, the number of ΔFosB-Ir neurons in the nucleus accumbens was greater in D3KO than in WT mice. This finding is consistent with results implicating D3 receptor activation in the tonic inhibition of this limbic structure. Unlike rats, clozapine significantly increased the number of ΔFosB-Ir neurons in both the nucleus accumbens and the caudate-putamen of WT mice albeit to a lesser extent in the caudate-putamen than nucleus accumbens. Similar to rats, however, ΔFosB-Ir in the island of Calleja major of WT mice was elevated by clozapine but not by haloperidol. In the nucleus accumbens and caudate-putamen, haloperidol produced similar increases in ΔFosB-Ir in WT and D3KO mice. By contrast, clozapine-induced increases in ΔFosB-Ir in the island of Calleja major, nucleus accumbens and caudate-putamen of WT mice were absent in D3KO mice. These findings, which indicate that D3 receptor blockade is essential for clozapine-induced increases in striatal ΔFosB-Ir, suggest that D3 receptor antagonism may contribute to the unique therapeutic profile of this atypical antipsychotic.

Original languageEnglish
Pages (from-to)3189-3194
Number of pages6
JournalEuropean Journal of Neuroscience
Volume20
Issue number11
DOIs
Publication statusPublished - Dec 1 2004

Fingerprint

Dopamine D3 Receptors
Clozapine
Nucleus Accumbens
Haloperidol
Putamen
Islands of Calleja
Knockout Mice
Neurons
Corpus Striatum
Immediate-Early Genes
Caudate Nucleus
Antipsychotic Agents
Pharmacology
Gene Expression

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

Clozapine-, but not haloperidol-, induced increases in ΔFosB-like immunoreactivity are completely blocked in the striatum of mice lacking D3 dopamine receptors. / Robertson, George S.; Lee, Christopher J.; Sridhar, Kavita; Nakabeppu, Yusaku; Cheng, Michael; Wang, Yan Min; Caron, Marc G.

In: European Journal of Neuroscience, Vol. 20, No. 11, 01.12.2004, p. 3189-3194.

Research output: Contribution to journalArticle

Robertson, George S. ; Lee, Christopher J. ; Sridhar, Kavita ; Nakabeppu, Yusaku ; Cheng, Michael ; Wang, Yan Min ; Caron, Marc G. / Clozapine-, but not haloperidol-, induced increases in ΔFosB-like immunoreactivity are completely blocked in the striatum of mice lacking D3 dopamine receptors. In: European Journal of Neuroscience. 2004 ; Vol. 20, No. 11. pp. 3189-3194.
@article{d7841fa521614a3ead21c903c537fc74,
title = "Clozapine-, but not haloperidol-, induced increases in ΔFosB-like immunoreactivity are completely blocked in the striatum of mice lacking D3 dopamine receptors",
abstract = "On the basis of anatomical and pharmacological evidence, we have proposed that D3 receptor antagonism plays a role in the mediation of clozapine-, but not haloperidol-, induced immediate-early gene expression in the striatum. To test this hypothesis directly, we compared the effects of repeated administration of vehicle (8 mL/kg/day), clozapine (20 mg/kg/day) and haloperidol (2 mg/kg/day) for 17 days on expression of ΔFosB-like immunoreactivity (ΔFosB-Ir) in the island of Calleja major, nucleus accumbens and caudate-putamen of wild-type C57BI6 (WT) and D3 receptor knockout (D3KO) mice. In vehicle-treated mice, the number of ΔFosB-Ir neurons in the nucleus accumbens was greater in D3KO than in WT mice. This finding is consistent with results implicating D3 receptor activation in the tonic inhibition of this limbic structure. Unlike rats, clozapine significantly increased the number of ΔFosB-Ir neurons in both the nucleus accumbens and the caudate-putamen of WT mice albeit to a lesser extent in the caudate-putamen than nucleus accumbens. Similar to rats, however, ΔFosB-Ir in the island of Calleja major of WT mice was elevated by clozapine but not by haloperidol. In the nucleus accumbens and caudate-putamen, haloperidol produced similar increases in ΔFosB-Ir in WT and D3KO mice. By contrast, clozapine-induced increases in ΔFosB-Ir in the island of Calleja major, nucleus accumbens and caudate-putamen of WT mice were absent in D3KO mice. These findings, which indicate that D3 receptor blockade is essential for clozapine-induced increases in striatal ΔFosB-Ir, suggest that D3 receptor antagonism may contribute to the unique therapeutic profile of this atypical antipsychotic.",
author = "Robertson, {George S.} and Lee, {Christopher J.} and Kavita Sridhar and Yusaku Nakabeppu and Michael Cheng and Wang, {Yan Min} and Caron, {Marc G.}",
year = "2004",
month = "12",
day = "1",
doi = "10.1111/j.1460-9568.2004.03774.x",
language = "English",
volume = "20",
pages = "3189--3194",
journal = "European Journal of Neuroscience",
issn = "0953-816X",
publisher = "Wiley-Blackwell",
number = "11",

}

TY - JOUR

T1 - Clozapine-, but not haloperidol-, induced increases in ΔFosB-like immunoreactivity are completely blocked in the striatum of mice lacking D3 dopamine receptors

AU - Robertson, George S.

AU - Lee, Christopher J.

AU - Sridhar, Kavita

AU - Nakabeppu, Yusaku

AU - Cheng, Michael

AU - Wang, Yan Min

AU - Caron, Marc G.

PY - 2004/12/1

Y1 - 2004/12/1

N2 - On the basis of anatomical and pharmacological evidence, we have proposed that D3 receptor antagonism plays a role in the mediation of clozapine-, but not haloperidol-, induced immediate-early gene expression in the striatum. To test this hypothesis directly, we compared the effects of repeated administration of vehicle (8 mL/kg/day), clozapine (20 mg/kg/day) and haloperidol (2 mg/kg/day) for 17 days on expression of ΔFosB-like immunoreactivity (ΔFosB-Ir) in the island of Calleja major, nucleus accumbens and caudate-putamen of wild-type C57BI6 (WT) and D3 receptor knockout (D3KO) mice. In vehicle-treated mice, the number of ΔFosB-Ir neurons in the nucleus accumbens was greater in D3KO than in WT mice. This finding is consistent with results implicating D3 receptor activation in the tonic inhibition of this limbic structure. Unlike rats, clozapine significantly increased the number of ΔFosB-Ir neurons in both the nucleus accumbens and the caudate-putamen of WT mice albeit to a lesser extent in the caudate-putamen than nucleus accumbens. Similar to rats, however, ΔFosB-Ir in the island of Calleja major of WT mice was elevated by clozapine but not by haloperidol. In the nucleus accumbens and caudate-putamen, haloperidol produced similar increases in ΔFosB-Ir in WT and D3KO mice. By contrast, clozapine-induced increases in ΔFosB-Ir in the island of Calleja major, nucleus accumbens and caudate-putamen of WT mice were absent in D3KO mice. These findings, which indicate that D3 receptor blockade is essential for clozapine-induced increases in striatal ΔFosB-Ir, suggest that D3 receptor antagonism may contribute to the unique therapeutic profile of this atypical antipsychotic.

AB - On the basis of anatomical and pharmacological evidence, we have proposed that D3 receptor antagonism plays a role in the mediation of clozapine-, but not haloperidol-, induced immediate-early gene expression in the striatum. To test this hypothesis directly, we compared the effects of repeated administration of vehicle (8 mL/kg/day), clozapine (20 mg/kg/day) and haloperidol (2 mg/kg/day) for 17 days on expression of ΔFosB-like immunoreactivity (ΔFosB-Ir) in the island of Calleja major, nucleus accumbens and caudate-putamen of wild-type C57BI6 (WT) and D3 receptor knockout (D3KO) mice. In vehicle-treated mice, the number of ΔFosB-Ir neurons in the nucleus accumbens was greater in D3KO than in WT mice. This finding is consistent with results implicating D3 receptor activation in the tonic inhibition of this limbic structure. Unlike rats, clozapine significantly increased the number of ΔFosB-Ir neurons in both the nucleus accumbens and the caudate-putamen of WT mice albeit to a lesser extent in the caudate-putamen than nucleus accumbens. Similar to rats, however, ΔFosB-Ir in the island of Calleja major of WT mice was elevated by clozapine but not by haloperidol. In the nucleus accumbens and caudate-putamen, haloperidol produced similar increases in ΔFosB-Ir in WT and D3KO mice. By contrast, clozapine-induced increases in ΔFosB-Ir in the island of Calleja major, nucleus accumbens and caudate-putamen of WT mice were absent in D3KO mice. These findings, which indicate that D3 receptor blockade is essential for clozapine-induced increases in striatal ΔFosB-Ir, suggest that D3 receptor antagonism may contribute to the unique therapeutic profile of this atypical antipsychotic.

UR - http://www.scopus.com/inward/record.url?scp=10844261731&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=10844261731&partnerID=8YFLogxK

U2 - 10.1111/j.1460-9568.2004.03774.x

DO - 10.1111/j.1460-9568.2004.03774.x

M3 - Article

C2 - 15579174

AN - SCOPUS:10844261731

VL - 20

SP - 3189

EP - 3194

JO - European Journal of Neuroscience

JF - European Journal of Neuroscience

SN - 0953-816X

IS - 11

ER -