Increased response to morphine in mice lacking protein kinase C epsilon

The protein kinase C (PKC) family of serine–threonine kinases has been implicated in behavioral responses to opiates, but little is known about the individual PKC isozymes involved. Here, we show that mice lacking PKCε have increased sensitivity to the rewarding effects of morphine, revealed as the expression of place preference and intravenous self-administration at very low doses of morphine that do not evoke place preference or self-administration in wild-type mice. The PKCε null mice also show prolonged maintenance of morphine place preference in response to repeated testing when compared with wild-type mice. The supraspinal analgesic effects of morphine are enhanced in PKCε null mice, and the development of tolerance to the spinal analgesic effects of morphine is delayed. The density of μ-opioid receptors and their coupling to G-proteins are normal. These studies identify PKCε as a key regulator of opiate sensitivity in mice

Bayesian logistic regression in detection of gene–steroid interaction for cancer at PDLIM5 locus

The PDZ and LIM domain 5 (PDLIM5) gene may play a role in cancer, bipolar disorder, major depression, alcohol dependence and schizophrenia; however, little is known about the interaction effect of steroid and PDLIM5 gene on cancer. This study examined 47 single-nucleotide polymorphisms (SNPs) within the PDLIM5 gene in the Marshfield sample with 716 cancer patients (any diagnosed cancer, excluding minor skin cancer) and 2848 noncancer controls. Multiple logistic regression model in PLINK software was used to examine the association of each SNP with cancer. Bayesian logistic regression in PROC GENMOD in SAS statistical software, ver. 9.4 was used to detect gene–steroid interactions influencing cancer. Single marker analysis using PLINK identified 12 SNPs associated with cancer (P \u3c 0.05); especially, SNP rs6532496 revealed the strongest association with cancer (P = 6.84 × 10−3); while the next best signal was rs951613 (P = 7.46 × 10−3). Classic logistic regression in PROC GENMOD showed that both rs6532496 and rs951613 revealed strong gene–steroid interaction effects (OR = 2.18, 95% CI = 1.31−3.63 with P = 2.9 × 10−3 for rs6532496 and OR = 2.07, 95% CI = 1.24 −3.45 with P = 5.43 × 10−3 for rs951613, respectively). Results from Bayesian logistic regression showed stronger interaction effects (OR = 2.26, 95% CI = 1.2 −3.38 for rs6532496 and OR = 2.14, 95% CI = 1.14 −3.2 for rs951613, respectively). All the 12 SNPs associated with cancer revealed significant gene–steroid interaction effects (P \u3c 0.05); whereas 13 SNPs showed gene–steroid interaction effects without main effect on cancer. SNP rs4634230 revealed the strongest gene–steroid interaction effect (OR = 2.49, 95% CI = 1.5 −4.13 with P = 4.0 × 10−4 based on the classic logistic regression and OR = 2.59, 95% CI = 1.4 −3.97 from Bayesian logistic regression; respectively). This study provides evidence of common genetic variants within the PDLIM5 gene and interactions between PLDIM5 gene polymorphisms and steroid use influencing cancer

Peripheral PDLIM5 expression in bipolar disorder and the effect of olanzapine administration

<p>Abstract</p> <p>Background</p> <p>One of the genes suggested to play an important role in the pathophysiology of bipolar disorder (BPD) is <it>PDLIM5</it>, which encodes LIM domain protein. Our main objective was to examine the effect of olanzapine treatment on <it>PDLIM5</it> mRNA expression in the peripheral blood leukocytes of BPD patients.</p> <p>Methods</p> <p>We measured the expression of <it>PDLIM5</it> mRNA from 16 patients with BPD Type I after 0, 4, and 8 weeks of treatment with olanzapine using quantitative real-time PCR. The Young Mania Rating Scale was used to evaluate the severity of manic symptoms in BPD patients. We also compared <it>PDLIM5</it> mRNA expression in treatment-naïve BPD patients with that in healthy control subjects.</p> <p>Results</p> <p>No significant difference was found in <it>PDLIM5</it> mRNA expression between patients before olanzapine treatment and following 4 and 8 weeks of treatment (<it>p</it>>0.05). Although we observed a significant reduction in the severity of manic symptoms in all BPD patients (<it>p</it><0.05), the effectiveness of the medication did not significantly correlate with the expression of <it>PDLIM5</it> mRNA (<it>p</it>>0.05). Interestingly, <it>PDLIM5</it> mRNA expression differed significantly between treatment-naïve BPD patients and healthy control subjects (<it>p</it>=0.002).</p> <p>Conclusion</p> <p><it>PDLIM5</it> mRNA expression did not appear to be a reflection of the efficacy of olanzapine in reducing the manic symptoms of BPD. The significant difference in expression of <it>PDLIM5</it> mRNA in the peripheral blood leukocytes of treatment-naïve BPD patients versus that of healthy control subjects, however, suggests that it may be a good biological marker for BPD.</p