Multivariate analyses reveal common and drug-specific genetic influences on responses to four drugs of abuse.
Ontology highlight
ABSTRACT:
SUBMITTER: Belknap JK
PROVIDER: S-EPMC3100800 | biostudies-literature | 2008 Nov
REPOSITORIES: biostudies-literature
Publications
Multivariate analyses reveal common and drug-specific genetic influences on responses to four drugs of abuse.
Belknap John K JK Metten Pamela P Beckley Ethan H EH Crabbe John C JC
Trends in pharmacological sciences 20080904 11
Vulnerability to abused drugs is influenced by multiple genes unique to each drug and to risk genes for polydrug abuse. If several inbred mouse strains respond to different drugs similarly, this implies the action of a common group of genes. Simultaneous analysis of multiple responses to multiple drugs has been attempted infrequently. We performed multivariate analyses of published strain responses to four drugs. Genetic similarity in responses did not simply track pharmacological class. Withdra ...[more]
Similar Datasets
Project description:RationaleAlthough leptin receptors are found in hypothalamic nuclei classically associated with homeostatic feeding mechanisms, they are also present in brain regions known to regulate hedonic-based feeding, natural reward processing, and responses to drugs of abuse. The ob/ob mouse is deficient in leptin signaling, and previous work has found altered mesolimbic dopamine signaling and sensitivity to the locomotor activating effects of amphetamine in these mice.ObjectivesWe directly assessed responses to three drugs of abuse and non-drug rewards in the leptin-deficient ob/ob mouse.MethodsOb/ob mice were tested in assays of sweet preference, novelty seeking, and drug reward/reinforcement.ResultsIn assays of novelty seeking, novel open field activity and operant sensation seeking were reduced in ob/ob mice, although novel object interaction and novel environment preference were comparable to wild types. We also found that ob/ob mice had specific phenotypes in regard to cocaine: conditioned place preference for 2.5 mg/kg was increased, while the locomotor response to 10 mg/kg was reduced, and cocaine self-administration was the same as wild types. Ob/ob mice also acquired self-administration of the potent opioid remifentanil, but breakpoints for the drug were significantly reduced. Finally, we found significant differences in ethanol drinking in ob/ob mice that correlated negatively with body weight and positively with operant sensation seeking.ConclusionsIn conclusion, ob/ob mice displayed task-specific deficits in novelty seeking and dissociable differences in reward/reinforcement associated with cocaine, remifentanil, and ethanol.
| S-EPMC5095929 | biostudies-literature
Project description:ObjectiveThe study evaluated point-of-care resources for scope, completeness, and consistency of information describing interactions between therapeutic drugs and drugs of abuse (DoA).MethodsA cross-sectional evaluation study was conducted focusing on seven resources: Clinical Pharmacology, Facts & Comparisons eAnswers, Lexicomp Online, Micromedex, Drug Interactions Analysis and Management, Drug Interaction Facts, and Stockley's Drug Interactions. A sample of clinically relevant interactions was developed through review of tertiary literature and resources, and input was solicited from subject matter experts. Entries from each resource for each interaction were evaluated for scope (i.e., whether there was an entry for the interaction); completeness (i.e., whether there was information addressing mechanism; clinical effects, severity, course of action, and level of certainty, described as a median rating on a 5-point scale); and consistency (i.e., whether the information in the resource was similar to the majority) among resources with an entry.ResultsFollowing review by subject matter experts, the final sample contained 159 interactions. Scope scores ranged from 0.6% (Drug Interactions Analysis and Management) to 43.4% (Lexicomp Online). Completeness scores ranged from 2 (interquartile range [IQR] 0 to 3, Stockley's Drug Interactions) to 5 (IQR 5 to 5, Drug Interaction Facts, Micromedex, Facts & Comparisons eAnswers). Consistency scores ranged from 30.8% (Stockley's Drug Interactions) to 87.1% (Clinical Pharmacology) for severity and from 15.4% (Facts & Comparisons eAnswers) to 71.4% (Drug Interaction Facts) for course of action.ConclusionsAlthough coverage of drug-DoA interactions was low and content was often inconsistent among resources, the provided information was generally complete.
| S-EPMC7524612 | biostudies-literature
Project description:(1) Background: High-altitude hypoxia has been shown to affect the pharmacokinetic properties of drugs. Although there is a high incidence of cardiovascular disease among individuals living in high-altitude areas, studies on the effect of high-altitude hypoxia on the pharmacokinetic properties of cardiovascular drugs are limited. (2) Methods: The aim of this study was to evaluate the pharmacokinetics of nifedipine, bosentan, simvastatin, sildenafil, and their respective main metabolites, dehydronifedipine, hydroxybosentan, simvastatin hydroxy acid, and N-desmethyl sildenafil, in rats exposed to high-altitude hypoxia. Additionally, the protein and mRNA expression of cytochrome P450 3A1 (CYP3A1), a drug-metabolizing enzyme, were examined. (3) Results: There were significant changes in the pharmacokinetic properties of the drugs in rats exposed to high-altitude hypoxia, as evidenced by an increase in the area under the curve (AUC) and the half-life (t1/2z) and a decrease in total plasma clearance (CLz/F). However, most of these changes were reversed when the rats returned to a normoxic environment. Additionally, there was a significant decrease in CYP3A1 expression in rats exposed to high-altitude hypoxia at both the protein and mRNA levels. (4) Conclusions: High-altitude hypoxia suppressed the metabolism of the drugs, indicating that the pharmacokinetics of the drugs should be re-examined, and the optimal dose should be reassessed in patients living in high-altitude areas.
| S-EPMC9612038 | biostudies-literature
Project description:Increase in global population and growing disease burden due to the emergence of infectious diseases (Zika virus), multidrug-resistant pathogens, drug-resistant cancers (cisplatin-resistant ovarian cancer) and chronic diseases (arterial hypertension) necessitate effective therapies to improve health outcomes. However, the rapid increase in drug development cost demands innovative and sustainable drug discovery approaches. Drug repositioning, the discovery of new or improved therapies by reevaluation of approved or investigational compounds, solves a significant gap in the public health setting and improves the productivity of drug development. As the number of drug repurposing investigations increases, a new opportunity has emerged to understand factors driving drug repositioning through systematic analyses of drugs, drug targets and associated disease indications. However, such analyses have so far been hampered by the lack of a centralized knowledgebase, benchmarking data sets and reporting standards. To address these knowledge and clinical needs, here, we present RepurposeDB, a collection of repurposed drugs, drug targets and diseases, which was assembled, indexed and annotated from public data. RepurposeDB combines information on 253 drugs [small molecules (74.30%) and protein drugs (25.29%)] and 1125 diseases. Using RepurposeDB data, we identified pharmacological (chemical descriptors, physicochemical features and absorption, distribution, metabolism, excretion and toxicity properties), biological (protein domains, functional process, molecular mechanisms and pathway cross talks) and epidemiological (shared genetic architectures, disease comorbidities and clinical phenotype similarities) factors mediating drug repositioning. Collectively, RepurposeDB is developed as the reference database for drug repositioning investigations. The pharmacological, biological and epidemiological principles of drug repositioning identified from the meta-analyses could augment therapeutic development.
| S-EPMC6192146 | biostudies-literature
Project description:Histone acetylation and other modifications of the chromatin are important regulators of gene expression and, consequently, may contribute to drug-induced behaviors and neuroplasticity. Previous studies have shown that a reduction on histone deacetylase (HDAC) activity results on the enhancement of some psychostimulant-induced behaviors. In the present study, we extend those seminal findings by showing that the administration of the HDAC inhibitor sodium butyrate enhances morphine-induced locomotor sensitization and conditioned place preference. In contrast, this compound has no effects on the development of morphine tolerance and dependence. Similar effects were observed for cocaine and ethanol-induced behaviors. These behavioral changes were accompanied by a selective boosting of a component of the transcriptional program activated by chronic morphine administration that included circadian clock genes and other genes relevant in addictive behavior. Our results support an specific role for histone acetylation and the epigenetic modulation of transcription at a reduced number of biologically relevant loci on non-homeostatic, long lasting, drug-induced behavioral plasticity. To further investigate the molecular bases of sodium butyrate action on long-lasting behavioral responses to morphine, we screened for potential substrates of their interaction by performing a genome-wide comparison of the striatal transcriptome after chronic administration of morphine in the absence or presence of sodium butyrate.
2009-08-22 | GSE17731 | GEO
Project description:Histone acetylation and other modifications of the chromatin are important regulators of gene expression and, consequently, may contribute to drug-induced behaviors and neuroplasticity. Previous studies have shown that a reduction on histone deacetylase (HDAC) activity results on the enhancement of some psychostimulant-induced behaviors. In the present study, we extend those seminal findings by showing that the administration of the HDAC inhibitor sodium butyrate enhances morphine-induced locomotor sensitization and conditioned place preference. In contrast, this compound has no effects on the development of morphine tolerance and dependence. Similar effects were observed for cocaine and ethanol-induced behaviors. These behavioral changes were accompanied by a selective boosting of a component of the transcriptional program activated by chronic morphine administration that included circadian clock genes and other genes relevant in addictive behavior. Our results support an specific role for histone acetylation and the epigenetic modulation of transcription at a reduced number of biologically relevant loci on non-homeostatic, long lasting, drug-induced behavioral plasticity. To further investigate the molecular bases of sodium butyrate action on long-lasting behavioral responses to morphine, we screened for potential substrates of their interaction by performing a genome-wide comparison of the striatal transcriptome after chronic administration of morphine in the absence or presence of sodium butyrate. Striatal tissue was dissected from two months-old Swiss-Albino male mice subjected to behavioral sensitization. Behavioural sensitization: Locomotor sensitization induced by morphine was evaluated using a protocol divided into two phases: induction and challenge. The induction phase involved six trials on alternate days, one trial per day. On each one of these trials, mice received and injection of saline or sodium butyrate (300 mg/kg) immediatedly followed by a second injection of morphine (20 mg/kg). The challenge phases consisted of a single trial conducted 7 days after the last test of the induction phase. In this case, all animals received a single injection of morphine (20 mg/kg). Striatal RNA was extracted 1h after the morphine challenge in groups of four animals that received either saline (N=6) or morphine (N=3), or the sodium butyrate-morphine (N=3) co-treatment during the sensitization induction phase.
2010-09-17 | E-GEOD-17731 | biostudies-arrayexpress
Project description:Drugs of abuse produce rearrangements at glutamatergic synapses thought to contribute to drug-reinforced behaviors. Acid-Sensing Ion Channels (ASICs) have been suggested to oppose these effects, largely due to observations in mice lacking the ASIC1A subunit. However, the ASIC2A and ASIC2B subunits are known to interact with ASIC1A, and their potential roles in drugs of abuse have not yet been investigated. Therefore, we tested the effects of disrupting ASIC2 subunits in mice exposed to drugs of abuse. We found conditioned place preference (CPP) to both cocaine and morphine were increased in Asic2 -/- mice, which is similar to what was observed in Asic1a -/- mice. Because nucleus accumbens core (NAcc) is an important site of ASIC1A action, we examined expression of ASIC2 subunits there. By western blot ASIC2A was readily detected in wild-type mice, while ASIC2B was not, suggesting ASIC2A is the predominant subunit in nucleus accumbens core. An adeno-associated virus vector (AAV) was used to drive recombinant ASIC2A expression in nucleus accumbens core of Asic2 -/- mice, resulting in near normal protein levels. Moreover, recombinant ASIC2A integrated with endogenous ASIC1A subunits to form functional channels in medium spiny neurons (MSNs). However, unlike ASIC1A, region-restricted restoration of ASIC2A in nucleus accumbens core was not sufficient to affect cocaine or morphine conditioned place preference, suggesting effects of ASIC2 differ from those of ASIC1A. Supporting this contrast, we found that AMPA receptor subunit composition and the ratio of AMPA receptor-mediated current to NMDA receptor-mediated current (AMPAR/NMDAR) were normal in Asic2 -/- mice and responded to cocaine withdrawal similarly to wild-type animals. However, disruption of ASIC2 significantly altered dendritic spine morphology, and these effects differed from those reported previously in mice lacking ASIC1A. We conclude that ASIC2 plays an important role in drug-reinforced behavior, and that its mechanisms of action may differ from ASIC1A.
| S-EPMC9923001 | biostudies-literature
Project description:Rice provides more than one fifth of daily calories for half of the world's human population, and is a major dietary source of both essential mineral nutrients and toxic elements. Rice grains are generally poor in some essential nutrients but may contain unsafe levels of some toxic elements under certain conditions. Identification of quantitative trait loci (QTLs) controlling the concentrations of mineral nutrients and toxic trace metals (the ionome) in rice will facilitate development of nutritionally improved rice varieties. However, QTL analyses have traditionally considered each element separately without considering their interrelatedness. In this study, we performed principal component analysis (PCA) and multivariate QTL analyses to identify the genetic loci controlling the covariance among mineral elements in the rice ionome. We resequenced the whole genomes of a rice recombinant inbred line (RIL) population, and performed univariate and multivariate QTL analyses for the concentrations of 16 elements in grains, shoots and roots of the RIL population grown in different conditions. We identified a total of 167 unique elemental QTLs based on analyses of individual elemental concentrations as separate traits, 53 QTLs controlling covariance among elemental concentrations within a single environment/tissue (PC-QTLs), and 152 QTLs which determined covariation among elements across environments/tissues (aPC-QTLs). The candidate genes underlying the QTL clusters with elemental QTLs, PC-QTLs and aPC-QTLs co-localized were identified, including OsHMA4 and OsNRAMP5. The identification of both elemental QTLs and PC QTLs will facilitate the cloning of underlying causal genes and the dissection of the complex regulation of the ionome in rice.
| S-EPMC7868434 | biostudies-literature
Project description:Adolescent drug misuse represents a major risk factor for long-term drug use disorders. However, wide individual differences in responses to first-line behavioral therapies targeting adolescent drug misuse limit critical early intervention. Identifying the neural signatures of those adolescents most likely to respond to an intervention would potentially guide personalized strategies for reducing drug misuse. Prior to a 14-week evidence-based intervention involving combinations of contingency management, motivational enhancement, and cognitive behavioral therapy, thirty adolescent alcohol and/or cannabis users underwent fMRI while performing a reward delay discounting (DD) task tapping an addiction-related cognition. Intervention responses were longitudinally characterized by both urinalysis and self-report measures of the percentage of days used during treatment and in post-treatment follow-up. Group independent component analysis (ICA) of task fMRI data identified neural processing networks related to DD task performance. Separate measures of wholesale recruitment during immediate reward choices and within-network functional connectivity among selective networks significantly predicted intervention-related changes in drug misuse frequency. Specifically, heightened pre-intervention engagement of a temporal lobe "reward motivation" network for impulsive choices on the DD task predicted poorer intervention outcomes, while modes of functional connectivity within the reward motivation network, a prospection network, and a posterior insula network demonstrated robust associations with intervention outcomes. Finally, the pre-intervention functional organization of the prospection network also predicted post-intervention drug use behaviors for up to 6 months of follow-up. Multiple functional variations in the neural processing networks supporting preference for immediate and future rewards signal individual differences in readiness to benefit from an effective behavioral therapy for reducing adolescent drug misuse. The implications for efforts to boost therapy responses are discussed.
| S-EPMC6699467 | biostudies-literature
Project description:Many drugs act very rapidly - they can turn on or off their targets within minutes in a whole animal. What are the acute effects of drug treatment and how does an animal respond to these? We developed a simple assay to measure the acute effects of drugs on C. elegans movement and examined the effects of a range of compounds including neuroactive drugs, toxins, environmental stresses and novel compounds on worm movement over a time period of 3 hr. We found a wide variety of acute responses. Many compounds cause rapid paralysis which may be permanent or followed by one or more recovery phases. The recoveries are not the result of some generic stress response but are specific to the drug e.g., recovery from paralysis due to a neuroactive drug requires neurotransmitter pathways whereas recovery from a metabolic inhibitor requires metabolic changes. Finally, we also find that acute responses can vary greatly across development and that there is extensive natural variation in acute responses. In summary, acute responses are sensitive probes of the ability of biological networks to respond to drug treatment and these responses can reveal the action of unexplored pathways.
| S-EPMC6118317 | biostudies-other