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Articles, Neurobiology of Disease

Behavioral and Structural Responses to Chronic Cocaine Require a Feedforward Loop Involving ΔFosB and Calcium/Calmodulin-Dependent Protein Kinase II in the Nucleus Accumbens Shell

Alfred J. Robison, Vincent Vialou, Michelle Mazei-Robison, Jian Feng, Saïd Kourrich, Miles Collins, Sunmee Wee, George Koob, Gustavo Turecki, Rachael Neve, Mark Thomas and Eric J. Nestler
Journal of Neuroscience 6 March 2013, 33 (10) 4295-4307; DOI: https://doi.org/10.1523/JNEUROSCI.5192-12.2013
Alfred J. Robison
1Fishberg Department of Neuroscience and Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York, 10029,
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Vincent Vialou
1Fishberg Department of Neuroscience and Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York, 10029,
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Michelle Mazei-Robison
1Fishberg Department of Neuroscience and Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York, 10029,
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Jian Feng
1Fishberg Department of Neuroscience and Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York, 10029,
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Saïd Kourrich
2Departments of Neuroscience and Psychology, Institute of Human Genetics, University of Minnesota, Minneapolis, Minnesota 55455,
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Miles Collins
1Fishberg Department of Neuroscience and Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York, 10029,
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Sunmee Wee
3Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037
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George Koob
3Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037
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Gustavo Turecki
4Depressive Disorders Program, Douglas Mental Health University Institute and McGill University, Montréal, Québec, Canada, H4H 1R3, and
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Rachael Neve
5Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
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Mark Thomas
2Departments of Neuroscience and Psychology, Institute of Human Genetics, University of Minnesota, Minneapolis, Minnesota 55455,
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Eric J. Nestler
1Fishberg Department of Neuroscience and Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York, 10029,
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    Figure 1.

    Shell-specific induction of CaMKII in NAc by cocaine. A, Depiction of the “skewed donut” method of dissecting NAc core (blue circle) and shell (remaining half-moon between red and blue circles) from a rat coronal brain slice. B, Locomotor activity analysis reveals that chronic (green) but not acute (yellow) preexposure to cocaine sensitizes animals to a cocaine challenge when compared with a saline control group (red) (n = 10; *p < 0.05, one-way ANOVA). C, Western blots of NAc shell and core from rats in B. D, Quantitation of Western blots in C shows significant increases in ΔFosB in both NAc shell and core, whereas significant increases in total CaMKIIα and phospho-Ser831 GluA1 are shell specific (n = 10; *p < 0.05, one-way ANOVA). E, Quantitation of Western blot analysis of rat NAc shell 14 d after the last injection of saline or cocaine either before (14d WD) or 1 h after a challenge dose of cocaine (14d WD Chal) (n = 9–10; *p < 0.05, two-tailed t test vs saline).

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    Figure 2.

    Induction of CaMKII in NAc shell of self-administering rats and human cocaine addicts. A, Lever presses by rats allowed long or short access to cocaine self-administration. B, Immunohistochemical analysis reveals increased ΔFosB in NAc core and shell of long-access rats, whereas increases in CaMKIIα are shell specific; quantified in C (n = 6; *p < 0.05, one-way ANOVA). D, Western blots (below) reveal that cocaine-dependent humans display increased ΔFosB and CaMKIIα levels in shell-enriched NAc samples (n = 18–20; *p < 0.05, two-tailed t test).

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    Figure 3.

    Cell type- and region-specific ΔFosB induction of CaMKIIα in vivo. A, qChIP assays reveal increased ΔFosB binding to the CaMKIIα gene promoter in rat NAc shell but not core after chronic cocaine exposure (n = 6–7; *p < 0.05, two-tailed t test). B, qChIP also reveals decreased H3 acetylation after cocaine exposure in NAc core compared to shell (n = 6–7; p < 0.05, two-tailed t test). C, qChIP data suggesting reduced H3K9 dimethylation in both NAc shell and core after chronic cocaine. D, Quantitative PCR shows that mice overexpressing ΔFosB in D1-type, but not in D2-type, MSNs exhibit increased levels of CaMKIIα mRNA in NAc (n = 8–10; *p < 0.05 two-tailed t test). E, Immunohistochemical analysis shows that the D1- and D2-specific mouse lines overexpress ΔFosB to similar levels in NAc shell and core but that only D1-specific overexpression of ΔFosB increases total CaMKIIα protein; quantified in F (n = 6–8; *p < 0.05 two-tailed t test). G, Western blotting reveals that D1-specific, but not D2-specific, antagonist (Antag) coadministration prevents cocaine-mediated ΔFosB and CaMKIIα induction in rat NAc shell; quantified in H (n = 4–5; *p < 0.05 one-way ANOVA, different from vehicle). Con, Control.

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    Figure 4.

    ΔFosB is both necessary and sufficient for cocaine-mediated D1 receptor-dependent CaMKIIα induction in NAc shell. A, AAV-mediated overexpression of ΔFosB in NAc shell promotes locomotor responses to an acute cocaine injection in adult male rats. B, Western blot analysis of NAc shell shows that ΔFosB is sufficient to increase levels of total CaMKIIα and both autophosphorylation of CaMKIIα and Ser831 phosphorylation of GluA1; quantified in C (n = 14–18; *p < 0.05, two-tailed t test). D, AAV-mediated ΔJunD overexpression prevents locomotor sensitization induced by chronic exposure to cocaine. E, ΔJunD overexpression in NAc shell is sufficient to block cocaine-mediated increases in total and Thr286 phospho-CaMKII and to reduce levels of ΔFosB in both saline- and cocaine-treated animals; quantified in F (n = 8–10; *p < 0.05, one-way ANOVA).

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    Figure 5.

    ΔFosB is a potent substrate for CaMKIIα. A, Western blotting shows an ATP-dependent multi-band shift in electrophoretic mobility of ΔFosB after exposure to CaMKIIα. IB, Immunoblot. B, Autoradiogram reveals a CaMKII-dependent incorporation of radiolabeled phosphate into ΔFosB (left), and a ΔFosB Ser27 phospho-specific antibody shows phosphorylation of this site by CaMKII (right). Analyses reveal robust kinase kinetics (C) and incorporation of multiple phosphates into ΔFosB by CaMKII (D). E, The precursor (inset) and fragment spectra of a TiO2 enriched phosphopeptide detected from ΔFosB after in vitro phosphorylation by CaMKII. After using both trypsin and GluC digestion and enrichment of the phosphopeptide samples by TiO2, analysis reveals phosphorylation of Ser27 as well as of several other sites not characterized further here. F, MRM analysis of ΔFosB phosphorylated in vitro by CaMKIIα reveals that Ser27 is a potent CaMKII substrate. Non, Nonphosphorylated peptide; Phos, phosphorylated peptide. G, Immunohistochemical analysis reveals increased ΔFosB in both the NAc shell and core of adult male wild-type (WT) mice exposed to chronic cocaine. Littermates overexpressing a constitutively active form of CaMKIIα show basal elevation in ΔFosB in the NAc shell only and show no effect of cocaine on ΔFosB levels in either region; quantified in H (n = 9–10; *p < 0.05, one-way ANOVA).

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    Figure 6.

    Blockade of CaMKII activity prevents the morphological and behavioral effects of ΔFosB in NAc. A, Increases in the spine density of MSNs in NAc shell induced by HSV-mediated overexpression of ΔFosB are prevented by coexpression of the CaMKII inhibitor peptide AC3I (n = 14–16); quantified in B. C–E, ΔFosB effects on thin and stubby spines are blocked by coexpression of AC3I. F, The ΔFosB-mediated increase in locomotor sensitivity to cocaine is also prevented by AC3I coexpression. G, Model depicting the D1-receptor-dependent induction of a CaMKII/ΔFosB feedforward loop by cocaine, including upstream signaling cascades and physiological processes that may be affected. DA, Dopamine; D1DR, D1 dopamine receptor; LTCC, L-type calcium channel (n = 9–10; *p < 0.05, one-tailed t test).

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    Table 1.

    Characterization of samples from human cocaine addicts and matched control group

    GroupPercentage suicideAge (years)Gender (% male)Brain weight (g)pHRefrigeration delay (h)
    Control32%33.05 ± 3.19395%1508 ± 37.086.569 ± 0.0625.934 ± 1.038
    Cocaine dependent80%39.80 ± 2.15395%1434 ± 26.326.546 ± 0.0728.850 ± 1.812
    p value0.110.180.480.016
    • The control group contains 19 individuals, and the cocaine-dependent group contains 20 individuals. All values are mean ± SE. p values calculated using two-tailed Student's t test.

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The Journal of Neuroscience: 33 (10)
Journal of Neuroscience
Vol. 33, Issue 10
6 Mar 2013
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Behavioral and Structural Responses to Chronic Cocaine Require a Feedforward Loop Involving ΔFosB and Calcium/Calmodulin-Dependent Protein Kinase II in the Nucleus Accumbens Shell
Alfred J. Robison, Vincent Vialou, Michelle Mazei-Robison, Jian Feng, Saïd Kourrich, Miles Collins, Sunmee Wee, George Koob, Gustavo Turecki, Rachael Neve, Mark Thomas, Eric J. Nestler
Journal of Neuroscience 6 March 2013, 33 (10) 4295-4307; DOI: 10.1523/JNEUROSCI.5192-12.2013

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Behavioral and Structural Responses to Chronic Cocaine Require a Feedforward Loop Involving ΔFosB and Calcium/Calmodulin-Dependent Protein Kinase II in the Nucleus Accumbens Shell
Alfred J. Robison, Vincent Vialou, Michelle Mazei-Robison, Jian Feng, Saïd Kourrich, Miles Collins, Sunmee Wee, George Koob, Gustavo Turecki, Rachael Neve, Mark Thomas, Eric J. Nestler
Journal of Neuroscience 6 March 2013, 33 (10) 4295-4307; DOI: 10.1523/JNEUROSCI.5192-12.2013
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