Obesity is a potential risk factor for cognitive deficits in the elder humans. Using a high-fat diet (HFD)–induced obese mouse model, we investigated the impacts of HFD on obesity, metabolic and ...stress hormones, learning performance, and hippocampal synaptic plasticity. Both male and female C57BL/6J mice fed with HFD (3 weeks to 9–12 months) gained significantly more weights than the sex-specific control groups. Compared with the obese female mice, the obese males had similar energy intake but developed more weight gains. The obese male mice developed hyperglycemia, hyperinsulinemia, hypercholesterolemia, and hyperleptinemia, but not hypertriglyceridemia. The obese females had less hyperinsulinemia and hypercholesterolemia than the obese males, and no hyperglycemia and hypertriglyceridemia. In the contextual fear conditioning and step-down passive avoidance tasks, the obese male, but not female, mice showed poorer learning performance than their normal counterparts. These learning deficits were not due to sensorimotor impairment as verified by the open-field and hot-plate tests. Although, basal synaptic transmission characteristics (input–output transfer and paired-pulse facilitation (PPF) ratio) were not significantly different between normal and HFD groups, the magnitudes of synaptic plasticity (long-term potentiation (LTP) and long-term depression (LTD)) were lower at the Schaffer collateral-CA1 synapses of the hippocampal slices isolated from the obese male, but not female, mice, as compared with their sex-specific controls. Our results suggest that male mice are more vulnerable than the females to the impacts of HFD on weight gains, metabolic alterations and deficits of learning, and hippocampal synaptic plasticity.
Methadone maintenance treatment (MMT) is the major tapering therapy for morphine addictive patients. There have gender differences reported in response to MMT. This study discovered that the ...estrogen‐response element single nucleotide polymorphism (ERE‐SNP; rs16974799, C/T) of cytochrome 2B6 gene (cyp2b6; methadone catabolic enzyme) responded differently to MMT dosing. Oestradiol was associated with high MMT dosing, high enantiomer (R‐ or S‐) of 2‐ethylidene‐1,5‐dimethyl‐3,3‐dipheny‐pyrrolidine (EDDP; methadone metabolite) to methadone ratio and increased drug‐seeking behaviour, implicating oestradiol‐CYP‐EDDP/methadone axis decreasing MMT efficacy. In mouse model, oestrogen mitigates methadone antinociceptive response, facilitates methadone catabolism and up‐regulates methadone‐associated metabolizing enzymes. Oestrogen also ablates chronic methadone administration‐induced rewarding response. Mechanism dissection revealed the CC genotype of CYP2B6‐ERE‐SNP exerts higher ERE sequence alignment score, higher estrogenic response as compared to TT genotype. At last, preclinical study via targeting estrogen signal that tamoxifen (TMX; selective estrogen receptor modulator, SERM) could facilitate the tolerance phase rewarding response of methadone. Strikingly, TMX also reduces tapering/abstinence phases methadone liability in mice. In conclusion, this study demonstrates altering methadone metabolism through targeting estrogen signals might be able to free morphine addictive patients from the addiction of opioid replacement therapy. Therefore, the add‐on therapy clinical trial introducing SERM in MMT regimen is suggested.
The retention of patients under methadone maintenance treatment (MMT) is an indication for the effectiveness of the therapy. We aimed to explore the relation between mortality and the cumulative MMT ...duration.
A retrospective cohort analysis was performed using Taiwan Illicit Drug Issue Database (TIDID) and National Health Insurance Research Database (NHIRD) during 2012-2016. We included 9149 and 11 112 MMT patients as the short and long groups according to the length of their cumulative MMT duration, 1-364 and ⩾365 days, respectively. The risk of mortality was calculated by Cox proportional hazards regression model with time-dependent exposure to MMT, and the survival probability was plotted with the Kaplan-Meier curve.
The mortality rates were 2.51 and 1.51 per 100 person-years in the short and long cumulative MMT duration groups, respectively. After adjusting for on or off MMT, age, sex, marital status, education level, maximum methadone dose, and comorbidities (human immunodeficiency virus, depression, hepatitis C virus, hepatitis B virus, alcoholic liver disease, and cardiovascular disease), the long group had a lower risk of death (hazard ratio = 0.67; 95% confidence interval 0.60-0.75) than the short group. Increased risk was observed in patients with advanced age, being male, unmarried, infected by HIV, HCV, and HBV, and diagnosed with depression, ALD, and CVD. Causes of death were frequently related to drug and injury.
Longer cumulative MMT duration is associated with lower all-cause and drug-related mortality rate.
Opioids are widely used as the pain reliever and also notorious for being addictive drugs. Sex differences in the opioid analgesia and addiction have been reported and investigated in human subjects ...and animal models. Yet, the molecular mechanism underlying the differences between males and females is still unclear. Here, we reviewed the literature describing the sex differences in analgesic responses and addiction liabilities to clinically relevant opioids. The reported interactions among opioids, estrogens, opioid receptors, and estrogen receptors are also evaluated. We postulate that the sex differences partly originated from the crosstalk among the estrogen and opioid receptors when stimulated by the exogenous opioids, possibly through common secondary messengers and the downstream gene transcriptional regulators.
Methadone maintenance treatment (MMT) is commonly used for controlling opioid dependence, preventing withdrawal symptoms, and improving the quality of life of heroin-dependent patients. A ...steady-state plasma concentration of methadone enantiomers, a measure of methadone metabolism, is an index of treatment response and efficacy of MMT. Although the methadone metabolism pathway has been partially revealed, no genome-wide pharmacogenomic study has been performed to identify genetic determinants and characterize genetic mechanisms for the plasma concentrations of methadone R- and S-enantiomers. This study was the first genome-wide pharmacogenomic study to identify genes associated with the plasma concentrations of methadone R- and S-enantiomers and their respective metabolites in a methadone maintenance cohort. After data quality control was ensured, a dataset of 344 heroin-dependent patients in the Han Chinese population of Taiwan who underwent MMT was analyzed. Genome-wide single-locus and haplotype-based association tests were performed to analyze four quantitative traits: the plasma concentrations of methadone R- and S-enantiomers and their respective metabolites. A significant single nucleotide polymorphism (SNP), rs17180299 (raw p = 2.24 × 10(-8)), was identified, accounting for 9.541% of the variation in the plasma concentration of the methadone R-enantiomer. In addition, 17 haplotypes were identified on SPON1, GSG1L, and CYP450 genes associated with the plasma concentration of methadone S-enantiomer. These haplotypes accounted for approximately one-fourth of the variation of the overall S-methadone plasma concentration. The association between the S-methadone plasma concentration and CYP2B6, SPON1, and GSG1L were replicated in another independent study. A gene expression experiment revealed that CYP2B6, SPON1, and GSG1L can be activated concomitantly through a constitutive androstane receptor (CAR) activation pathway. In conclusion, this study revealed new genes associated with the plasma concentration of methadone, providing insight into the genetic foundation of methadone metabolism. The results can be applied to predict treatment responses and methadone-related deaths for individualized MMTs.
Prenatal exposure to buprenorphine renders offspring vulnerable to cerebral impairments. In this study, our data demonstrate, for the first time, that prenatal exposure to buprenorphine escalates ...astrocyte activation concurrent with indications of endoplasmic reticulum (ER) stress in the hippocampi of neonates, and this can be prevented by the coadministration of dextromethorphan with buprenorphine. Furthermore, dextromethorphan can inhibit the accumulation of GPR37 in the hippocampus of newborns caused by buprenorphine and is accompanied by the proapoptotic ER stress response that involves the procaspase-3/CHOP pathway. Primary astrocyte cultures derived from the neonates of the buprenorphine group also displayed aberrant ER calcium mobilization and elevated basal levels of cyclooxygenase-2 (COX-2) at 14 days in vitro while showing sensitivity to lipopolysaccharide-activated expression of COX-2. Similarly, these long-lasting defects in the hippocampus and astrocytes were abolished by dextromethorphan. Our findings suggest that prenatal exposure to buprenorphine might instigate long-lasting effects on hippocampal and astrocytic functions. The beneficial effects of prenatal coadministration of dextromethorphan might be, at least in part, attributed to its properties in attenuating astrocyte activation and hippocampal ER stress in neonates.
Addiction is characterized by drug-craving, compulsive drug-taking, and relapse, and results from the interaction between multiple genetic and environmental factors. Reward pathways play an important ...role in mediating drug-seeking and drug-taking behaviors, and relapse. The objective of this study was to identify heroin addicts who carry specific genetic variants in their dopaminergic reward systems. A total of 326 heroin-dependent patients undergoing methadone maintenance therapy (MMT) were recruited from the Addiction Center of the China Medical University Hospital. A heroin-use and craving questionnaire was used to evaluate the urge for heroin, the daily or weekly frequency of heroin usage, daily life disturbance, anxiety, and the ability to overcome heroin use. A general linear regression model was used to assess the associations of genetic polymorphisms in one's dopaminergic reward system with heroin-use and craving scores. Results: The most significant results were obtained for rs2240158 in
(
= 0.021), rs3983721 in
(
= 0.00326), rs2129575 in
(
= 0.033), rs6583954 in
(
= 0.033), and rs174699 in
(
= 0.036). These were all associated with heroin-using and craving scores with and without adjustments for age, sex, and body mass index. We combined five variants, and the ensuing dose-response effect indicated that heroin-craving scores increased with the numbers of risk alleles (
for trend = 0.0008). These findings will likely help us to understand the genetic mechanism of craving, which will help in predicting the risk of relapse in clinical practice and the potential for therapies to target craving in heroin addiction.
The purpose of this study was to determine whether a specific threshold per lifting movement, the accumulation above which best predicts lumbar disk protrusion, exists or the total lifting load ...should be considered.
This was a retrospective study. Subjects with various lifting exposures were recruited. Disk protrusion was assessed by magnetic resonance imaging. The cumulative lifting load was defined as the sum of the time-weighed lumbar load for each job and was calculated using a biomechanical software system. The effectiveness of accumulation above different thresholds in predicting disk protrusion were compared using four statistical methods.
A total of 252 men and 301 women were included in the final analysis. For the men, 3000 Newtons for each lifting task was the optimal threshold for predicting L4-S1 disk protrusion, whereas for the women, 2800 Newtons was optimal.
Our findings suggested that for cumulative lifting exposure, including the total lifting load without defining a minimal exposure limit might not be the optimal method for predicting disk protrusion. The NIOSH 3400 Newton recommended limits do not appear to be the optimal thresholds for preventing disk protrusion. Different lifting thresholds might be needed for men and women in the workplace for their safety.
Heroin use among young women of reproductive age has drawn much attention around the world. However, there is lack of information on the long‐term effects of prenatal exposure to opioids on their ...offspring. Our previous study demonstrated that prenatally buprenorphine‐exposed offspring showed a marked change in the cross‐tolerance to morphine compared with other groups. In the current study, this animal model was used to study effects of methamphetamine (METH)‐induced behavioral sensitization in the offspring at their adulthood. The results showed no differences in either basal or acute METH‐induced locomotor activity in any of the groups of animals tested. When male offspring received METH injections of 2 mg/kg, i.p., once a day for 5 days, behavioral sensitization was induced, as determined by motor activity. Furthermore, the distance and rate of development (slope) of locomotor activity and conditioned place preference induced by METH were significantly increased in the prenatally buprenorphine‐exposed animals compared with those in other groups. The dopamine D1R in the nucleus accumbens of the prenatally buprenorphine‐exposed offspring had lower mRNA expression; but no significant changes in the μ‐, κ‐opioid, nociceptin, D2R and D3R receptors were noted. Furthermore, significant alterations were observed in the basal level of cAMP and the D1R agonist enhanced adenylyl cyclase activity in the prenatally buprenorphine‐exposed group. Overall, the study demonstrates that D1R and its downregulated cAMP signals are involved in enhancing METH‐induced behavioral sensitization in prenatally buprenorphine‐exposed offspring. The study reveals that prenatal exposure to buprenorphine caused long‐term effects on offspring and affected the dopaminergic system‐related reward mechanism.
Heroin use among young women of reproductive age has drawn much attention around the world, but there is lack of information on the long‐term effects of them. The current study demonstrates that dopamine D1R and its down‐regulated cAMP signals in the nucleus accumbens are involved in enhancing METH‐induced behavioral sensitization and conditioned place preference in the prenatally buprenorphine‐exposed offspring. The study reveals that prenatal exposure to buprenorphine caused long‐term effects on offspring and affected the dopaminergic system‐related reward mechanism.
Buprenorphine, a maintenance drug for heroin addicts, exerts its pharmacological function via κ‐ (KOP), μ‐opioid (MOP) and nociceptin/opioid receptor‐like 1 (NOP) receptors. Previously, we ...investigated its effects in an in vitro model expressing human MOP and NOP receptors individually or simultaneously (MOP, NOP, and MOP+NOP) in human embryonic kidney 293 cells. Here, we expanded this cell model by expressing human KOP, MOP and NOP receptors individually or simultaneously (KOP, KOP+MOP, KOP+NOP and KOP+MOP+NOP). Radioligand binding with tritium‐labelled diprenorphine confirmed the expression of KOP receptors. Immunoblotting and immunocytochemistry indicated that the expressed KOP, MOP and NOP receptors are N‐linked glycoproteins and colocalized in cytoplasmic compartments. Acute application of the opioid receptor agonists— U‐69593, DAMGO and nociceptin— inhibited adenylate cyclase (AC) activity in cells expressing KOP, MOP and NOP receptors respectively. Buprenorphine, when applied acutely, inhibited AC activity to ~90% in cells expressing KOP+MOP+NOP receptors. Chronic exposure to buprenorphine induced concentration‐dependent AC superactivation in cells expressing KOP+NOP receptors, and the level of this superactivation was even higher in KOP+MOP+NOP‐expressing cells. Our study demonstrated that MOP receptor could enhance AC regulation in the presence of coexpressed KOP and NOP receptors, and NOP receptor is essential for concentration‐dependent AC superactivation elicited by chronic buprenorphine exposure.
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