Decreased Mitochondrial DNA Copy Number in the Hippocampus and Peripheral Blood During Opiate Addiction Is Mediated by Autophagy and Can Be Salvaged by Melatonin.

Decreased mitochondrial DNA copy number in the hippocampus and peripheral blood during opiate addiction is mediated by autophagy and can be salvaged by melatonin.

Autophagy. 2013 Jun 20; 9(9):
Feng YM, Jia YF, Su LY, Wang D, Lv L, Xu L, Yao YG

Drug addiction is a chronic brain disease that is a serious social problem and causes enormous financial burden. Because mitochondrial abnormalities have been associated with opiate addiction, we examined the effect of morphine on mtDNA levels in rat and mouse models of addiction and in cultured cells. We found that mtDNA copy number was significantly reduced in the hippocampus and peripheral blood of morphine-addicted rats and mice compared with control animals. Concordantly, decreased mtDNA copy number and elevated mtDNA damage were observed in the peripheral blood from opiate-addicted patients, indicating detrimental effects of drug abuse and stress. In cultured rat pheochromocytoma (PC12) cells and mouse neurons, morphine treatment caused many mitochondrial defects, including a reduction in mtDNA copy number that was mediated by autophagy. Knockdown of the Atg7 gene was able to counteract the loss of mtDNA copy number induced by morphine. The mitochondria-targeted antioxidant melatonin restored mtDNA content and neuronal outgrowth and prevented the increase in autophagy upon morphine treatment. In mice, coadministration of melatonin with morphine ameliorated morphine-induced behavioral sensitization, analgesic tolerance and mtDNA content reduction. During drug withdrawal in opiate-addicted patients and improvement of protracted abstinence syndrome, we observed an increase of serum melatonin level. Taken together, our study indicates that opioid addiction is associated with mtDNA copy number reduction and neurostructural remodeling. These effects appear to be mediated by autophagy and can be salvaged by melatonin. HubMed – addiction


Drug exposure: inclusion of dispensed drugs before pregnancy may lead to underestimation of risk associations.

J Clin Epidemiol. 2013 Jun 22;
Skurtveit S, Selmer R, Tverdal A, Furu K, Nystad W, Handal M

To assess the impact of exposure misclassification on risk associations when using prescription databases as the source for drug exposure in pregnancy by applying results from a validation analysis of exposure classification.Linkage of data on 27,656 participants in the Norwegian Mother and Child Cohort Study (MoBa) with the Norwegian Prescription Database (NorPD). Exposure to selective serotonin reuptake inhibitors (SSRIs) was defined by dispensed drugs during pregnancy including different time windows before pregnancy. The validity of NorPD data was estimated using self-reported use in MoBa as the reference standard. We applied the results from the validation analysis on data from a Nordic study on SSRI use in pregnancy and risk of persistent pulmonary hypertension in the newborn.Sensitivity increased and specificity decreased when the time window in NorPD was expanded before pregnancy. Using the same time window as in the Nordic study (+90 days before pregnancy), for use in early pregnancy, the odds ratio (OR) corrected for misclassification was 2.6 compared with the OR of 1.6 in the Nordic study.Expansion of the time window to include intervals before pregnancy can lead to lower specificity and underestimation of risk associations. HubMed – addiction


Inhibitory effects of forced swim stress and corticosterone on the acquisition but not expression of morphine-induced conditioned place preference: involvement of glucocorticoid receptor in the basolateral amygdala.

Behav Brain Res. 2013 Jun 22;
Attarzadeh-Yazdi G, Karimi S, Azizi P, Yazdi-Ravandi S, Hesam S, Haghparast A

Addiction is a common chronic psychiatric disease which represents a global problem and stress has an important role to increase drug addiction and relapse. In the present study, we investigated the effects of physical stress and exogenous corticosterone on the acquisition and expression of morphine-induced conditioned place preference (CPP). Also, we tried to find out the role of glucocorticoid receptors (GRs) of basolateral amygdala (BLA) in this regard. In the CPP paradigm, conditioning score and locomotion activity were recorded by Ethovision software. Male adult rats received forced swim stress (FSS) as a physical stress or corticosterone (10mg/kg;ip) as a dominant stress hormone in rodents, 10min before morphine injection (5mg/kg;sc) during three conditioning days (acquisition) or just prior to CPP test in the post-conditioning day (expression). In FSS procedure, animals were forced to swim for 6min in cylinder filled with water (24-27°(C)). To evaluate the role of glucocorticoid receptors in the BLA, different doses of mifepristone (RU38486) as a GR antagonist were injected into the BLA (0.3, 3 and 30ng/side) during 3-day conditioning phase before FSS or injection of corticosterone in morphine-CPP paradigm. The results showed that FSS and corticosterone reduce the acquisition but not expression of morphine-induced CPP. Moreover, blockade of GRs in the BLA could diminish the inhibitory effects of FSS or corticosterone on the acquisition of morphine-induced CPP. It seems that stress exerts its effect on reward pathway via glucocorticoid receptors in the BLA. HubMed – addiction


Loss of Control of Alcohol Use and Severity of Alcohol Dependence in Non-Treatment-Seeking Heavy Drinkers Are Related to Lower Glutamate in Frontal White Matter.

Alcohol Clin Exp Res. 2013 Jun 25;
Ende G, Hermann D, Demirakca T, Hoerst M, Tunc-Skarka N, Weber-Fahr W, Wichert S, Rabinstein J, Frischknecht U, Mann K, Vollstädt-Klein S

The development and maintenance of alcohol use disorders (AUD) have been hypothesized to be associated with an imbalance of glutamate (GLU) homeostasis. White matter (WM) loss, especially in anterior brain regions, has been reported in alcohol dependence, which may involve disturbances in both myelin and axonal integrity. Frontal lobe dysfunction plays an important role in addiction, because it is suggested to be associated with the loss of control over substance use. This study investigated magnetic resonance spectroscopy (MRS)-detectable Glu levels in frontal WM of non-treatment-seeking heavy drinkers and its associations with AUD symptoms.Single-voxel MR spectra optimized for Glu assessment (TE 80 ms) were acquired at 3T from a frontal WM voxel in a group of heavy drinking, non-treatment-seeking subjects in comparison with a group of subjects with only light alcohol consumption.The results corroborate previous findings of increased total choline in heavy drinking subjects. A negative association of Glu levels with severity of alcohol dependence and especially loss of control over time and amount of alcohol intake was observed.In contrast to the rather unspecific rise in choline-containing compounds, low Glu in frontal WM may be specific for the shift from nondependent heavy drinking to dependence and does not reflect a simple effect of the amount of alcohol consumption alone. HubMed – addiction