Effects Of Drug Exposure Research Articles

Prenatal and Postnatal Consequences of Drug Exposure in Pregnancy

Prenatal and Postnatal Consequences of Drug Exposure in Pregnancy

Impaired decision making following escalation of cocaine self-administration predicts vulnerability to relapse in rats.

Impairments in cost‐benefit decision making represent a cardinal feature of drug addiction. However, whether these alterations predate drug exposure, thereby contributing to facilitating loss of control over drug intake, or alternatively arise as a result of drug use and subsequently confer vulnerability to relapse has yet to be determined. Male Sprague‐Dawley rats were trained to self‐administer (SA) cocaine during 19 daily long‐access (12‐h) sessions; conditions reliably shown to promote escalation. One week after cocaine SA, rats underwent an extinction/relapse test immediately followed by conditioned stimuli–, stress‐, and drug‐primed reinstatement challenges. The influence of escalated cocaine intake on decision making was measured over time by four test sessions of a rodent analogue of the Iowa Gambling Task (rGT), once prior to cocaine exposure and then 1 day, 1 week, and 1 month after the last SA session. Substantial individual variability was observed in the influence of escalated cocaine SA on decision‐making performance. A subset of rats displayed pronounced deficits, while others showed unaffected or even improved performance on the rat Gambling Task (rGT) 24 hours after the last SA session. When challenged with a relapse test after 1 week of forced abstinence, animals that showed impaired decision making following SA displayed an increased propensity to respond for cocaine under extinction. These data suggest that decision‐making deficits in individuals with drug addiction are not antecedent to—but arise as a consequence of—drug exposure. Moreover, these data indicate that susceptibility to the deleterious effects of drugs on decision making confers vulnerability toward relapse.

Deletion of Type 2 Metabotropic Glutamate Receptor Decreases Sensitivity to Cocaine Reward in Rats

Cocaine users show reduced expression of the metabotropic glutamate receptor (mGluR2), but it is not clear whether this is a predisposing trait for addiction or a consequence of drug exposure. In this study, we found that a nonsense mutation at the mGluR2 gene decreased mGluR2 expression and altered the seeking and taking of cocaine. mGluR2 mutant rats show reduced sensitivity to cocaine reward, requiring more cocaine to reach satiation when it was freely available and ceasing their drug-seeking behavior sooner than controls when the response requirement was increased. mGluR2 mutant rats also show alower propensity to relapse after a period of cocaine abstinence, an effect associated with reduced cocaine-induced dopamine and glutamate overflow in the nucleus accumbens. These findings suggest that mGluR2 polymorphisms or reduced availability of mGluR2 might be risk factors for the initial development of cocaine use but could actually protect against addiction by reducing sensitivity to cocaine reward.

Long-Term Transcriptional Consequences of Drug Exposure as Cues to Understand Vulnerability to Relapse: Advances and Perspectives.

Quitting drug abuse represents a true challenge for addicted individuals because of the highly persistent vulnerability to relapse. Identifying long-lasting, drug-induced alterations in the brain-including at the transcriptome level-that underlie such vulnerability appears invaluable to improve relapse prevention. Despite substantial technological developments and research effort, however, the picture of drug-induced adaptations provided by high-throughput transcriptomics remains frustratingly partial, notably because of methodological issues. Major advances were made, however, regarding the time course and specificity of long-term transcriptional consequences of drug exposure as well as the recruitment of small, noncoding mRNAs (or miRNAs [microRNAs]) that were previously undetectable. Most importantly, high-throughput studies have benefited from systems biology approaches and shifted their interest toward regulations within functional gene networks rather than individual changes. Such network-based gene discovery approaches have proven informative to delineate the physiological processes, cellular signaling pathways, and neuronal populations altered by drug exposure. Provided the high-throughput effort will be pursued, together with the development of adapted bioinformatics tools, addiction transcriptomics should progressively integrate data across multiple scales (from epigenome to protein), allowing a better understanding of the genetics of drug abuse and opening novel therapeutic trails.

Effect of nephrotoxicants and hepatotoxicants on gene expression profile in human peripheral blood mononuclear cells

Studying peripheral blood transcriptome in the quest for translational markers of toxicity is considered to be an attractive offshoot in the field of toxicogenomics. Moreover, it is acknowledged that, xenobiotics which cause a toxic response through similar mechanisms lead to distinctive gene expression patterns. The current study was undertaken to gauge the response of an accessible surrogate tissue, such as blood, to drug-induced perturbations aimed at deriving gene expression patterns. Human peripheral blood mononuclear cells (hPBMC) were exposed to conventional drugs, with reported kidney and/or liver injury, in order to determine their transcriptomic response. Test drugs were divided into two classes viz., drugs affecting kidney (cyclophosphamide, amphotericin B, gentamicin and cisplatin) and liver (acetaminophen, rosiglitazone, fluconazole and isoniazid). After performing gene expression analysis and hierarchical clustering, signature patterns for the two classes were obtained, with a set of 365 genes that can discriminate the two classes of drugs. Our results imply that transcriptional profile of hPBMC get altered as a consequence of drug exposure and unique patterns indicative of specific organ toxicity can hence be deduced. These signature patterns obtained for drugs could be studied for their qualification to identify drug-induced toxicity.

Abstract LB-286: Use of circulating tumor cells to monitor pharmacodynamic responses of patients in early-stage clinical trials

Abstract Circulating tumor cells (CTCs) in peripheral blood of cancer patients potentially represent a fraction of solid tumor cells available for more frequent pharmacodynamic assessment of drug action than is possible using tumor biopsy. We have developed and validated an assay that directly examines increases in the number of cells positive for the nuclear DNA-damage marker H2AX in individual CTCs of patients treated with DNA-damaging chemotherapeutic agents. The method uses AexaFluor 488-conjugated monoclonal anti- H2AX (JBW301), to stain putative CTCs collected from blood by the CellSearch AutoPrep instrument, followed by enumeration and fluorescence analysis on the CellTracks Analyzer. Patient baselining studies demonstrated that in the absence of treatment the number of CTCs per blood aliquot is relatively constant over short time periods (2 weeks off therapy). CTC measurements are currently in use supporting four NCI new agent trials, two with cytotoxic agents and two with targeted agents (aTOP1 inhibitor and a tyrosine kinase inhibitor, TKI). CTC changes in 40 patients have been monitored on therapy to date. H2AX positive cells increased in 7/14 patients on cytotoxic therapies, 3/14 were unchanged and 4/14 were unevaluable; the fraction of H2AX positive CTCs did not decrease in any patient on cytotoxic therapy, and did not change in patients treated with TKI. The increased H2AX signal in patients on cytotoxic agents appears definitive for the cycle of therapy in which it is measured. Interestingly, 10/40 patients had increased CTC numbers immediately post-therapy, and several of these patients had few or no CTC immediately prior to therapy, suggesting that the cells were mobilized or shed from the tumor as a consequence of drug exposure. Six patients had decreases in CTC number, 12 were unchanged and 12 were unevaluable due to low CTC numbers. These data show promise for monitoring dynamic changes in nuclear biomarkers in CTCs, in addition to a CTC count alone, to rapidly assess drug pharmacodynamic activity, in clinical trials of cytotoxic agents and targeted anti-cancer therapeutics, as well as for translational research. This method may have the potential to inform the development of new anti-cancer agents and enable longitudinal monitoring of target response. Funded by NCI Contract No. HHSN261200800001E. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-286.

Impulsivity and response inhibition in alcohol dependence and problem gambling

IntroductionImpulsivity is a central feature of drug addiction and may arise as a result of impaired inhibitory control. The extent to which inhibitory deficits arise as a consequence of drug exposure or relate to pre-existing addiction vulnerability is unknown.Materials and methodsThis study compared measures of impulsivity in outpatients with alcohol dependence (n = 23) and problem gambling (n = 21), a putative behavioural addiction where direct effects of drug exposure may be minimal. Healthy controls (n = 27) were also tested, in a cross-sectional design. Subjects completed the stop-signal test as a neurocognitive probe of response inhibition, alongside self-report ratings of impulsivity, adult ADHD and OCD.ResultsOn the stop-signal test, Go reaction time and stop-signal reaction time were significantly slower in the alcohol-dependent group, compared with healthy controls. Healthy controls slowed their responding after successful and failed stop trials. Slowing after failed stop trials was significantly attenuated in the alcohol-dependent subjects. Go reaction time and post-error slowing were correlated with chronicity and severity, respectively, in the alcohol-dependent subjects. Problem gamblers did not differ significantly from controls on the stop-signal test, despite trait elevations in impulsivity ratings.ConclusionInhibitory control is impaired in alcohol dependence but occurs in the context of psychomotor slowing. In addition, alcohol-dependent individuals failed to show behavioral adjustment following failed stops. These deficits may represent direct effects of chronic alcohol administration on fronto-striatal circuitry.

O221 Optimising paediatric treatment for long term survival. Adult survivors of congenital HIV infection – what problems will they have?

During 10 years of HAART potency, efficacy and adherence have markedly improved, and morbidity and mortality from paediatric HIV has fallen dramatically in cohorts with access to treatment. Short-term side-effects of HAART in children mirrored those seen in adults. Assessment of long-term side-effects and treatment outcomes will depend on following this congenitally infected cohort into adult life, as has been undertaken with other congenital infections (e.g. rubella) or abnormalities (e.g. congenital heart disease). Long-term follow up of the first adult survivor cohorts in resource rich setting will help to inform the management of much larger cohorts in resource-poor settings. Neuro-cognitive function, behaviour and learning is affected in a significant proportion of children and adolescents with HIV, and long-term follow up is required to monitor ongoing viral effects on the CNS. Growth, puberty, bones and kidneys: current survivors are shorter than average and delayed sexual maturation is recognised; abnormalities of bone and renal metabolism are common, both HIV and drugs may contribute. Fertility and teratogenicity: both drugs and/or HIV may have long-term effects on gonadal function. Cardiovascular health and lipids: children with HIV have very low HDL blood levels which improve on HAART, but some on HAART have high LDL levels, which will be more deleterious in the long-term? Malignancy in adult life may be the consequence of drug exposure, immune deficiency, or co-infections (HPV, HBV etc). When to start HAART: interim data from the CHER trial has confirmed that all infants diagnosed with HIV should be started urgently on HAART to reduce the risk of death or disease progression in the first year of life. Whether this treatment needs to be continued life long or not, is still under investigation in the trial. For older children diagnosed with HIV, when to start HAART remains untested by randomised controlled trial and 2008 guidelines, as for adults, have revised the CD4 starting thresholds upwards. The complex balance here is between the long-term viral-toxicity of untreated HIV with a currently acceptable CD4 count, versus the long-term drug-toxicity of HAART exposure with full HIV suppression during growth and development. It is unlikely that a simple answer will found as to which more deleterious in the long-term, for the cumulative noxious effects of HIV or drugs over time in the organ systems (e.g. brain, bones, gonads etc) will be different. In the short term, this question has been addressed in PENTA 11 (paediatric structured treatment interruption trial – data to be presented at HIV9); long-term follow up of these trial patients and national cohorts will be very important in helping to elucidate this question of competing long-term drug and/or HIV effects. from Ninth International Congress on Drug Therapy in HIV Infection Glasgow, UK. 9–13 November 2008

Behavioural teratology: post-natal consequences of drug exposure in utero.

The effects of pre-natal exposure to drugs that subsequently affect the post-natal behaviour without apparently causing noticeable brain damage forms the subject of behavioural teratology. This review summarizes the experimental studies of several investigators who showed that pre-natal administration of such psychotropic drugs as meprobamate, isocarboxazid and reserpine reduced the maze-learning ability of the mature offspring. A more detailed survey of the effects of D-amphetamine and diazepam is then given. Both drugs were not foetotoxic and only caused appreciable changes in locomotor activity of the offspring at least 14 days after birth. With the amphetamine treated rats, these changes were biphasic (elevated at 15 days and reduced at 21 days) whereas the diazepam treated animals showed a reduction in locomotor activity for at least 21 days after birth. The results of our own studies, and those of others, do not enable a correlation to be made between the effects of the various drugs on the development of specific central neurotransmitters and the behavioural deficits noticed. The review concludes with an outline proposal for screening drugs for their potential as behavioural teratogens. The possible mechanisms whereby behavioural teratogens may cause subtle changes in the maturation of the brain are also outlined.