Better explicating the strengths and shortcomings of these models will help refine projections and improve transparency in the years ahead.
Image credit: Witsawat.S.
Edited by Leslie Lars Iversen, University of Oxford, Oxford, United Kingdom, and approved August 19, 2011 (received for review April 19, 2011)
Article Figures & SI
Figures
- Fig. 1.
Reduced nicotine consumption and preference in mice lacking PKCε. (A) Prkce−/− mice (n = 23) consumed less 15 μg/mL nicotine solution than wild-type mice did (Prkce+/+; n = 24) during weeks 2–4. *P < 0.001 compared with wild-type mice on same week. (B) Prkce−/− mice showed decreased preference for nicotine compared with wild-type mice. (C) Plasma nicotine clearance after a s.c. injection of 3 mg/kg nicotine did not differ between genotypes (n = 2–6 mice per genotype per time point). (D) Wild-type mice developed nicotine conditioned place preference for 0.05 mg/kg i.p. nicotine, whereas Prkce−/− mice did not. *P < 0.05 compared with saline-treated wild-type mice by one-way ANOVA and Dunnett's post hoc analysis; †P < 0.05 compared with Prkce−/− mice at the same dose by two-way ANOVA and Tukey's post hoc analysis. Numbers in the bars indicate the number of mice in each group.
- Fig. 2.
Decreased function of α6* nAChRs in Prkce−/− NAc core. (A and B) Average profiles of [DA]o after stimulation by one pulse (1p) and four pulses (4p) (100 Hz, 0.6 mA) in control ACSF (left traces), after addition of αCTXMII (30 nM, center traces), and after αCTXMII plus DHβE (100 nM, right traces) for wild-type (A; n = 11) and Prkce−/− (B; n = 12) brain slices. (C) Typical dopamine voltammogram elicited by one 0.6-mA pulse of 250-μs duration. (D) Peak [DA]o levels after 1p and 4p stimulation in control ACSF (solid lines) or in the presence of 30 nM αCTXMII (dashed lines) in wild-type (+/+) and Prkce−/− (−/−) NAc core. The slopes of the lines for αCTXMII versus ACSF were different (P < 0.05) for wild-type but not for Prkce−/− slices. (E) Enhancement of peak [DA]o by αCTXMII or by αCTXMII plus DHβE shown as the percentage increase in peak [DA]o evoked by 4p over 1p stimulation. αCTXMII increased peak [DA]o evoked by 4p to a lesser extent in Prkce−/− than in wild-type NAc. *P < 0.05 compared with αCTXMII-treated wild-type slices by Bonferroni post hoc analysis. Compared with αCTXMII alone, addition of DHβE further increased peak [DA]o evoked by 4p in Prkce−/− but not in wild-type NAc. †P < 0.05 compared with αCTXMII-treated Prkce−/− slices by Bonferroni post hoc analysis. (F) Low doses of nicotine (100–500 nM) increased peak [DA]o evoked by 4p versus 1p stimulation to a lesser extent in Prkce−/− than in wild-type NAc. *P < 0.05 compared with nicotine-treated wild-type slices by Tukey's post hoc analysis.
Tables
- Table 1.
Relative gene expression levels of nAChR subunits in wild-type and Prkce−/− mouse brain regions by quantitative PCR
nAChR subunit β2 β3 α3 α4 α5 α6 Ventral midbrain Prkce+/+ 1.00 ± 0.11 1.00 ± 0.08 1.00 ± 0.15 1.00 ± 0.07 1.00 ± 0.07 1.00 ± 0.07 Prkce−/− 0.96 ± 0.08 0.78 ± 0.06* 0.82 ± 0.07 0.90 ± 0.07 0.91 ± 0.06 0.78 ± 0.05* Striatum Prkce+/+ 1.00 ± 0.05 1.00 ± 0.06 — 1.00 ± 0.12 1.00 ± 0.06 1.00 ± 0.08 Prkce−/− 1.03 ± 0.06 0.74 ± 0.06* — 0.94 ± 0.13 0.95 ± 0.09 0.72 ± 0.09* Results for each subunit were normalized to GAPDH mRNA detected in the same sample and then were normalized to the average value for wild-type (Prkce+/+) samples from the same brain region. n = 5–8 mice per condition.
*P < 0.05 by unpaired, two-tailed t tests. α3 mRNA was not assessed in the striatum because α3-subunits are not found in nAChRs on dopaminergic terminals in that brain region (45).
Protein kinase C epsilon modulates nicotine consumption and dopamine reward signals in the nucleus accumbens
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