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Altered Sensitivity to Rewarding and Aversive Drugs in Mice with Inducible Disruption of cAMP Response Element-Binding Protein Function within the Nucleus Accumbens

Jennifer A. DiNieri, Christina L. Nemeth, Aram Parsegian, Tiffany Carle, Vsevolod V. Gurevich, Eugenia Gurevich, Rachael L. Neve, Eric J. Nestler and William A. Carlezon Jr
Journal of Neuroscience 11 February 2009, 29 (6) 1855-1859; DOI: https://doi.org/10.1523/JNEUROSCI.5104-08.2009
Jennifer A. DiNieri
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Christina L. Nemeth
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Aram Parsegian
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Tiffany Carle
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Vsevolod V. Gurevich
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Eugenia Gurevich
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Rachael L. Neve
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Eric J. Nestler
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William A. Carlezon Jr
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    Figure 1.

    Effect of inducible expression of mCREB on brain stimulation reward. a, Stimulating electrodes were located in the MFB. b, There were no differences between mCREB transgenic mice and controls in the minimal current (mean ± SEM) required for reliable ICSS at 3 weeks (n = 19–21) or 6 weeks (n = 7–10) after DOX discontinuation.

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    Figure 2.

    Effect of inducible expression of mCREB on sensitivity to cocaine (COC) in the ICSS test 6 weeks after DOX discontinuation. a, b, Rate of responding as a function of stimulation frequency during preinjection baseline, and after COC (10 mg/kg, i.p.). COC induced parallel leftward shifts and reductions in ICSS thresholds in control (a) and mCREB (b) mice, but the effects were larger in the mutants. Data are from representative mice. c, Time course of COC effects (10 mg/kg, i.p.); drug effects were evident over the 1 h test period. d, When data are expressed as mean (±SEM) percentage of pretreatment threshold for this test period, COC had significant threshold-lowering effects at a lower dose in mCREB mice (2.5 mg/kg) than in controls (5.0 mg/kg). Furthermore, the threshold-lowering effects of 10 mg/kg COC were significantly larger in mCREB mice. *p < 0.05, **p < 0.01 for within-group comparisons with saline (SAL; 0.0 dose) treatment, ^p < 0.05, ^^p < 0.01 for between-genotype comparisons, n = 9 mice/group.

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    Figure 3.

    Effect of inducible expression of mCREB on sensitivity to U50 in the ICSS test 6 weeks after DOX discontinuation. a, b, Rate of responding as a function of stimulation frequency during preinjection baseline, and after U50 (3.0 mg/kg, i.p.). U50 induced parallel rightward shifts and increases in ICSS thresholds in control mice (a), but had negligible effects in mCREB mice (b). Data are from representative mice. c, Time course of U50 effects (3.0 mg/kg, i.p.); drug effects were evident from 30 to 75 min of the 90 min test period. d, When data are expressed as mean (±SEM) percentage of pretreatment threshold for the 30–75 min period, U50 had significant threshold-elevating effects in control mice (3.0 and 5.5 mg/kg) without affecting mCREB mice. *p < 0.05, **p < 0.01 for within-group comparisons with saline (SAL; 0.0 dose) treatment; ^p < 0.05, ^^p < 0.01 for between-genotype comparisons, n = 10–12 mice/group.

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    Figure 4.

    Effects of HSV-mediated transgene expression in the NAc shell on ICSS. Expression of mCREB and dnGRK3 reduced mean (±SEM) ICSS thresholds in 30 min test on days 3 and 5. Data are expressed as percentage pre-gene transfer baselines. *p < 0.05, n = 9–14 rats/group.

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    Table 1.

    Effect of inducible expression of mCREB on mRNA levels (mean ± SEM) of select G-protein-related genes in the NAc

    GenotypeGRK3RGS9Gβ5Gαi2
    Control1.00 (±0.09)1.00 (±0.18)1.00 (±0.09)1.00 (±0.16)
    mCREB0.46 (±0.08)**1.07 (±0.13)1.17 (±0.09)0.92 (±0.02)
    • ↵**p < 0.01, n = 4 per group.

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The Journal of Neuroscience: 29 (6)
Journal of Neuroscience
Vol. 29, Issue 6
11 Feb 2009
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Altered Sensitivity to Rewarding and Aversive Drugs in Mice with Inducible Disruption of cAMP Response Element-Binding Protein Function within the Nucleus Accumbens
Jennifer A. DiNieri, Christina L. Nemeth, Aram Parsegian, Tiffany Carle, Vsevolod V. Gurevich, Eugenia Gurevich, Rachael L. Neve, Eric J. Nestler, William A. Carlezon Jr
Journal of Neuroscience 11 February 2009, 29 (6) 1855-1859; DOI: 10.1523/JNEUROSCI.5104-08.2009

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Altered Sensitivity to Rewarding and Aversive Drugs in Mice with Inducible Disruption of cAMP Response Element-Binding Protein Function within the Nucleus Accumbens
Jennifer A. DiNieri, Christina L. Nemeth, Aram Parsegian, Tiffany Carle, Vsevolod V. Gurevich, Eugenia Gurevich, Rachael L. Neve, Eric J. Nestler, William A. Carlezon Jr
Journal of Neuroscience 11 February 2009, 29 (6) 1855-1859; DOI: 10.1523/JNEUROSCI.5104-08.2009
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