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Regulation of Cocaine Reward by CREB

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Science  18 Dec 1998:
Vol. 282, Issue 5397, pp. 2272-2275
DOI: 10.1126/science.282.5397.2272

Figures

  • Figure 1

    Sensitivity to cocaine after gene transfer. (A) Rats spent significantly less time in cocaine-associated environments after microinjections of HSV-CREB into the nucleus accumbens shell but significantly more time after similar microinjections of HSV-mCREB (mean ± SEM) (treatment × days interaction: F 3,25 = 4.16, P < 0.02). (B) Effects were not statistically reliable with nucleus accumbens core microinjections (treatment × days interaction: F 1,12 = 2.70, not significant). (C) Differences between groups did not persist when place conditioning occurred on day 7 or 8 rather than on day 3 or 4 after gene transfer (treatment × days interaction:F 1,14 = 0.16, not significant). (D) Dose dependency of changes in effects of cocaine expressed as change (before minus after) in time spent in the cocaine-associated environment. Effects of cocaine depended on vector treatment and dose (treatment × dose interaction: F 4,67 = 2.77, P < 0.05). In rats given vehicle microinjections, cocaine was rewarding at 5.0 mg/kg only. In rats given HSV-mCREB, cocaine was maximally rewarding at 1.25 mg/kg. In rats given HSV-CREB, cocaine was maximally aversive at 1.25 mg/kg, whereas higher doses occasionally established place preferences. Groups consisted of 7 to 11 rats; *P < 0.05 compared with vehicle, ††P < 0.01 compared with HSV-mCREB (Fisher'st test). NASh, nucleus accumbens shell; NACo, nucleus accumbens core.

  • Figure 2

    Histological examination of nucleus accumbens after gene transfer. (A) Schematic of nucleus accumbens (9). Red box shows field of view in (B), (C), (D), and (F); blue box shows field of view in (G). (B) Expression of β-galactosidase 3 days after unilateral microinjection of HSV-LacZ (×25) (13). Brain slices were reacted in sodium phosphate buffer solution (pH 7.4) containing 5-bromo-4-chloro-3-indolyl β-d-galactopyranoside (0.2 mg/ml; American Bioanalytical). (C) An adjacent, Nissl-stained slice from the same brain. (D) Expression of CREB 3 days after microinjection of HSV-CREB into the right nucleus accumbens shell (13). (E) Higher magnification (×100) of the injection site in (D), showing nuclear localization of CREB expression. (F) Tyrosine hydroxylase expression (13) in a slice adjacent to that in (D). (G) Expression of mCREB 3 days after injection of HSV-mCREB into the right nucleus accumbens core (×100), using the same antibody to CREB as in (D). AC, anterior commissure; NASh, nucleus accumbens shell; NACo, nucleus accumbens core; ICj, Islands of Calleja.

  • Figure 3

    Northern blot of dynorphin (DYN) mRNA in nucleus accumbens shell after gene transfer. L, LacZ; C, CREB; mC, mCREB. Dynorphin mRNA concentrations were significantly increased by HSV-CREB and significantly decreased by HSV-mCREB (F 2,15 = 13.4, P < 0.001). Data are expressed as percentage (mean ± SEM) of HSV-LacZ and are corrected for cyclophilin (CYC) mRNA content. *P < 0.05 compared with HSV-LacZ (Fisher's t test).

  • Figure 4

    Effects of norBNI (5.0 μg, intracerebroventricularly) on cocaine (1.25 mg/kg, ip) place conditioning in rats given gene transfer, expressed as change (before minus after) in time spent in the cocaine-associated environment. The effects of norBNI on place conditioning depended on HSV vector treatment (vector × intracerebroventricular treatment interaction: F 2,45 = 4.77, P < 0.02). Aversive effects of cocaine were blocked by norBNI in rats given HSV-CREB but were not significantly altered in rats given HSV-mCREB or vehicle. Groups consisted of 7 to 10 rats; **P < 0.01 compared with HSV-CREB/no intracerebroventricular (ICV) treatment (Fisher's t test).

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