Detection of Epigenetic Changes Using ANOVA With Spatially Varying Coefficients.

Detection of epigenetic changes using ANOVA with spatially varying coefficients.

Stat Appl Genet Mol Biol. 2013 Mar 13; 1-17
Guanghua X, Xinlei W, Quincey L, Nestler EJ, Xie Y

Abstract Identification of genome-wide epigenetic changes, the stable changes in gene function without a change in DNA sequence, under various conditions plays an important role in biomedical research. High-throughput epigenetic experiments are useful tools to measure genome-wide epigenetic changes, but the measured intensity levels from these high-resolution genome-wide epigenetic profiling data are often spatially correlated with high noise levels. In addition, it is challenging to detect genome-wide epigenetic changes across multiple conditions, so efficient statistical methodology development is needed for this purpose. In this study, we consider ANOVA models with spatially varying coefficients, combined with a hierarchical Bayesian approach, to explicitly model spatial correlation caused by location-dependent biological effects (i.e., epigenetic changes) and borrow strength among neighboring probes to compare epigenetic changes across multiple conditions. Through simulation studies and applications in drug addiction and depression datasets, we find that our approach compares favorably with competing methods; it is more efficient in estimation and more effective in detecting epigenetic changes. In addition, it can provide biologically meaningful results. HubMed – addiction


Differential development of tolerance to the functional and behavioral effects of repeated baclofen treatment in rats.

Pharmacol Biochem Behav. 2013 Mar 11;
Beveridge TJ, Smith HR, Porrino LJ

Baclofen, a gamma-aminobutyric acid (GABA)B receptor agonist, has been used clinically to treat muscle spasticity, rigidity and pain. More recently, interest in the use of baclofen as an addiction medicine has grown, with promising preclinical cocaine and amphetamine data and demonstrated clinical benefit from alcohol and nicotine studies. Few preclinical investigations, however, have utilized chronic dosing of baclofen, which is important given that tolerance can occur to many of its effects. Thus the question of whether chronic treatment of baclofen maintains the efficacy of acute doses is imperative. The neural substrates that underlie the effects of baclofen, particularly those after chronic treatment, are also not known. In the present study, therefore, rats were treated with either a) vehicle, b) acute baclofen (5mg/kg) or c) chronic baclofen (5mg/kg, t.i.d. for 5days). The effects of acute and chronic baclofen administration, compared to vehicle, were assessed using locomotor activity and changes in brain glucose metabolism (a measure of functional brain activity). Acute baclofen significantly reduced locomotor activity (horizontal and total distance traveled), while chronic baclofen failed to affect locomotor activity. Acute baclofen resulted in significantly lower rates of local cerebral glucose utilization throughout many areas of the brain, including the prefrontal cortex, caudate putamen, septum and hippocampus. The majority of these functional effects, with the exception of the caudate putamen and septum, were absent in animals chronically treated with baclofen. Despite the tolerance to the locomotor and functional effects of baclofen following repeated treatment, these persistent effects on functional activity in the caudate putamen and septum may provide insights into the way in which baclofen alters the reinforcing effects of abused substances such as cocaine, alcohol, and methamphetamine both in humans and animal models. HubMed – addiction


Intrahippocampal administration of D2 but not D1 dopamine receptor antagonist suppresses the expression of conditioned place preference induced by morphine in the ventral tegmental area.

Neurosci Lett. 2013 Mar 7;
Haghparast A, Esmaeili MH, Taslimi Z, Kermani M, Yazdi-Ravandi S, Alizadeh AM

The ventral tegmental area (VTA) as a major source of dopamine neurons projecting to cortical and limbic regions has a crucial role in reward and addiction. The current study assessed the role of D1 and D2 receptors within the dorsal hippocampus (CA1) in the expression of conditioned place preference (CPP) by intra-VTA morphine in the rats. In the present study, 160 adult male albino Wistar rats weighing 220-290g were bilaterally implanted by two cannulae into the CA1 and VTA. The CPP paradigm was done and animal displacement, conditioning score and locomotor activity were recorded. For blocking the dopamine D1/D2 receptors in the dorsal hippocampus, SCH23390 (0.02, 0.05, 0.2 and 0.5?g per side) or sulpiride (0.25, 0.75, 1.5 and 3?g per side) were microinjected into the CA1, just 5min before the CPP test on the post-conditioning day. All animals received intra-VTA morphine (1?g per side) during 3-days conditioning phase. Our results showed that sulpiride (1.5 and 3?g) but not SCH23390 in the dorsal hippocampus significantly decreased the expression of CPP induced by intra-VTA morphine (p<0.001). Intra-CA1 administration of these antagonists alone, in all doses, could not induce CPP. We suggest that D2 receptors in the CA1 region of hippocampus have a key role in the expression of CPP induced by morphine at the level of the VTA and there is a relationship between dopaminergic D2 receptors and opioidergic systems in these areas in reward circuit. HubMed – addiction


Acute effects of resveratrol to enhance cocaine-induced dopamine neurotransmission in the striatum.

Neurosci Lett. 2013 Mar 7;
Shuto T, Kuroiwa M, Koga Y, Kawahara Y, Sotogaku N, Toyomasu K, Nishi A

Resveratrol is known as an activator of SIRT1, which leads to the deacetylation of histone and non-histone protein substrates, but also has other pharmacological profiles such as the inhibition of monoamine oxidase (MAO)-A and MAO-B. Resveratrol was previously demonstrated to potentiate the rewarding effects of chronic cocaine via activation of SIRT1. However, the role of resveratrol in cocaine responses in the acute phase remains unexplored. Therefore, we investigated the acute effects of resveratrol on cocaine-stimulated dopamine neurotransmission by analyzing protein phosphorylation in neostriatal slices. Treatment with resveratrol (50?M for 30min) enhanced cocaine-induced increases in the phosphorylation of DARPP-32 at Thr34 and GluA1 at Ser845, postsynaptic substrates for dopamine/D1 receptor/PKA signaling, and a cocaine-induced decrease in the phosphorylation of tyrosine hydroxylase at Ser40, a presynaptic substrate for dopamine/D2 receptor signaling. The inhibition of both MAO-A and MAO-B by clorgyline and pargyline, respectively, enhanced the effects of cocaine on DARPP-32 phosphorylation. The acute effect of resveratrol on cocaine-induced DARPP-32 phosphorylation was occluded with inhibition of MAO-A and MAO-B. In behavioral studies, resveratrol (40mg/kg, s.c.) enhanced the increase in locomotor activity induced by acute cocaine administration (10mg/kg, i.p.). Thus, this study provides pharmacological evidence that acute resveratrol enhances cocaine-induced dopamine neurotransmission and behavioral responses, presumably via mechanisms involving the inhibition of dopamine catabolism by MAO-A and MAO-B. Resveratrol may be useful to treat dysregulated dopamine neurotransmission, but it may enhance the risk of developing drug addiction. HubMed – addiction