Narges Joharchi

Causal considerations on alcohol and HIV/AIDS--a systematic review.

AIM The study aimed to explore the possible causal nature of the association between alcohol consumption and HIV/AIDS. METHODS A review based on meta-analyses and reviews was conducted according to standard epidemiological criteria to distinguish causality from association, examining (i) the potential impact of alcohol on the incidence of HIV and (ii) alcohols impact on worsening the disease course. RESULTS In terms of incidence of HIV, although we found a consistent and strong association with consumption, there was not enough evidence for a causal connection. In particular, it is not clear whether personality traits such as sensation seeking or sexual compulsivity and psychiatric disorders such as antisocial personality disorder impact both alcohol consumption and risky sex, subsequently creating an association between both behaviors. In terms of worsening the disease course of HIV/AIDS, we found enough evidence for a causal impact of alcohol. Alcohol affects the immune system, thus contributing to a worsened course of HIV/AIDS. In addition, alcohol negatively impacts on behaviors that include support seeking and medication adherence. CONCLUSIONS A randomized controlled clinical trial targeted toward at-risk HIV-negative individuals who live in areas with high HIV prevalence is suggested to test the effects of proven effective alcohol interventions on HIV incidence.

Alcohol consumption and the intention to engage in unprotected sex: systematic review and meta-analysis of experimental studies

AIMS To review and analyse in experimentally controlled studies the impact of alcohol consumption on intentions to engage in unprotected sex. To draw conclusions with respect to the question of whether alcohol has an independent effect on the incidence of human immunodeficiency virus (HIV) and other sexually transmitted infections (STIs). METHODS A systematic review and meta-analysis of randomized controlled studies examined the association between blood alcohol content (BAC) and self-perceived likelihood of using a condom during intercourse. The systematic review and meta-analysis were conducted according to internationally standardized protocols (Preferred Reporting Items for Systematic Reviews and Meta-Analyses: PRISMA). The meta-analysis included an estimate of the dose-response effect, tests for publication bias and sensitivity analyses. RESULTS Of the 12 studies included in the quantitative synthesis, our pooled analysis indicated that an increase in BAC of 0.1 mg/ml resulted in an increase of 5.0% (95% CI: 2.8-7.1%) in the indicated likelihood (indicated by a Likert scale) of engaging in unprotected sex. After adjusting for potential publication bias, this estimate dropped to 2.9% (95% CI: 2.0-3.9%). Thus, the larger the alcohol intake and the subsequent level of BAC, the higher the intentions to engage in unsafe sex. The main results were homogeneous, persisted in sensitivity analyses and after correction for publication bias. CONCLUSIONS Alcohol use is an independent risk factor for intentions to engage in unprotected sex, and as risky sex intentions have been shown to be linked to actual risk behavior, the role of alcohol consumption in the transmission of HIV and other STIs may be of public health importance.

Effect of the 5-HT3 receptor antagonists, MDL72222 and ondansetron on morphine place conditioning.

The purpose of the present study was to reassess the original findings of Carboni et al. (1988) who suggested that 5-HT3 receptor antagonists may block morphine-induced place conditioning in rats. These workers used a biased protocol with treatments allocated to compartments based on initial preference. In the present study we have adopted an unbiased approach with treatments randomly assigned to conditioning compartment in a counter-balanced fashion. Thus treatments were equally paired between distinct environmental cues. Using this protocol, morphine produced a dose-related place preference (0.3–3 mg/kg SC). Thirty-minute pretreatment with the selective 5-HT3 antagonists, MDL72222 (1 mg/kg SC) and ondansetron (0.01 mg/kg SC) before morphine (1.5 mg/kg SC), significantly antagonized the place conditioning to this treatment. However, with higher doses of ondansetron (0.1–1 mg/kg SC), the antagonism of morphine-induced place preference became variable and dependent on the conditioning compartment. This was probably a reflection of the fact that ondansetron when administered alone also appeared to produce an environmentally dependent place conditioning at these doses. Therefore it is concluded that at certain doses, 5-HT3 receptor antagonists may antagonize morphine place conditioning in a manner consistent with a blockade of the appetitive effects of this drug. However, at higher doses, at least with ondansetron, this antagonism became non-specific and dependent on the training environment. It is suggested that other animal models of opioid reinforcement (e.g., self-administration) are now needed to validate the hypothesis that 5-HT3 receptor antagonists may modify opioid reward.

Effects of 5-HT3 receptor antagonists on behavioural measures of naloxone-precipitated opioid withdrawal*

The effect of the selective 5-HT3 receptor antagonists, ondansetron and MDL 72222, against various behaviours elicited by naloxone-precipitated morphine withdrawal were examined. Rats made dependent upon morphine by the subcutaneous implantation of a 75 mg pellet, when challenged with naloxone (0.5 mg/kg SC), 3 or 4 days later exhibited a wide range of behaviours including wet dog shakes, paw shakes, salivation and a marked weight loss. Pre-treatment with ondansetron (0.01–1 mg/kg SC) or MDL 72222 (1–3 mg/kg SC) failed to affect the incidence of these responses except weight loss, which was attenuated by both treatments. At doses similar to and below those required to elicit the withdrawal syndrome, naloxone produced a single-trial place aversion in morphine dependent rats. The place aversion produced by naloxone (0.05 mg/kg SC) was antagonized by pre-treatment of ondansetron (0.1–1 mg/kg SC) and MDL 72222 (1 mg/kg SC) prior to conditioning. Chlordiazepoxide (10 mg/kg IP) but not gepirone (3–10 mg/kg SC) was similarly effective. It is concluded that 5-HT3 antagonists may attenuate some but not all behavioural signs associated with morphine withdrawal. Reasons for this apparent selectivity are discussed.

Further studies to examine the nature of dexfenfluramine-induced suppression of heroin self-administration

The present series of experiments sought to investigate further the mechanism by which dexfenfluramine, a selective 5-HT releaser/reuptake inhibitor, reduces heroin self-administration by male Wistar rats. In experiment 1, the effect of combined intravenous heroin and intraperitoneal dexfenfluramine injections on operant responding for food was examined. In experiment 2, the maintenance of dexfenfluramine suppression of heroin self-administration following chronic (7 day) treatment was evaluated. Finally, in experiment 3, the ability of various 5-HT antagonists to block the dexfenfluramine suppression was examined. The results from experiment 1 suggest that sensorimotor deficits/malaise potentially associated with heroin/dexfenfluramine combinations are unlikely to account for the reductions in heroin self-administration. Experiment 2 suggested that the suppressant effect of dexfenfluramine on heroin responding may diminish rapidly following chronic treatment. Finally, central 5-HT1 and/or 5-HT2, but not 5-HT3, receptors may underlie the suppressant effects of dexfenfluramine on heroin self-administration.

The CCKA receptor antagonist devazepide does not modify opioid self-administration or drug discrimination: comparison with the dopamine antagonist haloperidol.

We previously reported that the selective cholecystokininA (CCKA) receptor antagonist, devazepide, blocked the acquisition of a morphine conditioned place preference (ref 28). An interpretation of this finding is that devazepide may either affect an opioid discriminative stimulus and/or modify the rewarding properties of opioids. The present study was designed to investigate these issues by determining the effect of equivalent doses of devazepide in a morphine drug discrimination paradigm and a model of heroin self-administration. In each case, devazepide (0.001-1 mg/kg) was ineffective, i.e there was no antagonism of a morphine discriminative cue, and in a separate group of rats trained to self-administer heroin (0.03 mg/kg/infusion, FR5 schedule, 1h per day), devazepide did not alter the pattern of heroin responding. Because of evidence implicating an interaction between accumbens CCK and dopamine (DA) systems and evidence suggesting an apparent differential involvement of DA in opioid place conditioning, self-administration and drug discrimination behaviour, the effect of the DA antagonist haloperidol was examined in the latter two paradigms. In each test, haloperidol produced an effect inconsistent with a direct DAergic involvement. In a final study the CCKB antagonist L365-260 was also found not to affect an opioid discriminative cue. The present results therefore cast doubt on the potential utility of selective CCKA antagonists as treatments for opioid abuse, and further suggest that CCKB antagonists may not potentiate the subjective effects of opioids, an important finding considering that such drugs have been proposed as adjuncts to opioid therapy for the treatment of pain relief.

Personality as a Predictor of Unprotected Sexual Behavior Among People Living with HIV/AIDS: A Systematic Review

The present investigation involved a systematic literature review to (1) identify associations between personality constructs and unprotected sex among people living with HIV/AIDS (PLWH); (2) assess patterns of direct versus indirect personality-risky sex associations; and (3) explore possible differences in personality-risky sex associations among PLWH versus non-infected populations. Among the 26 studies yielded through the systematic search, sensation seeking and sexual compulsivity were the constructs most frequently examined, with fewer studies investigating traditional personality typologies. Personality constructs that were more conceptually proximal to the sexual act, such as sexual compulsivity and sex-related sub-components of sensation seeking, showed relatively direct associations with unprotected sex, whereas more conceptually distal constructs such as generalized impulsivity demonstrated only weak or indirect associations. Associations were also frequently mediated by other risk factors, including perceived responsibility and substance use. These findings have implications for the development of interventions to reduce high risk sexual behavior among PLWH.

Effect of 5-HT3 receptor antagonists on the discriminative stimulus properties of morphine in rats

Abstract5-HT3 receptor antagonists, e.g. MDL72222, ondansetron and ICS205-930, have been previously reported to block a morphine (1.5 mg/kg)-induced conditioned place preference in rats. This finding suggests that these drugs may modify the morphine discriminative stimulus which underlies place conditioning. To study this further we have examined the effects of MDL72222, ondansetron and ICS205-930 against a morphine discriminative stimulus using a two-choice, food reinforced, operant paradigm. In an attempt to provide consistency with previous place conditioning studies, a morphine training dose of 1.5 mg/kg was used in addition to a higher 3 mg/kg dose which was studied in separate animals. Stimulus control of behaviour was attained at both morphine training doses, the characteristics of each being consistent with an effect at the mu opioid receptor. Ondansetron (0.001–1 mg/kg), MDL72222 (0.1–3 mg/kg), and ICS205-930 (0.001–1 mg/kg) all failed to consistently antagonise the morphine cue at both training doses, although a mild attenuation was seen in the 1.5 mg/kg group following pretreatment with an intermediate dose of ondansetron and ICS205-930 (both 0.01 mg/kg). The present results therefore suggest hat 5-HT3 antagonists do not block a morphine discriminative state, at least in rats.

The anti-epileptic drug lacosamide (Vimpat) has anxiolytic property in rodents.

Lacosamide ((R)-2-acetamido-N-benzyl-3-methoxypropionamide; formerly harkoseride, SPM 927; Vimpat), has been recently approved by US and European regulatory authorities for use as add-on therapy for partial-onset seizures in adults. Because a number of anti-epileptic drugs are used to treat conditions beyond epilepsy, including anxiety, in the present study we investigated the anxiolytic potential of lacosamide in a conditioned emotional response (CER) model in rat, and the mouse marble burying assay. In each test lacosamide produced a significant effect consistent with anxiolysis, i.e. lacosamide increased suppression ratio in the CER test, and reduced the number of marbles buried in the marble burying assay. The doses necessary for an anxiolytic effect were higher than those necessary for efficacy in seizure tests conducted in the same species. For example in the mouse, the lacosamide oral ED(50) in the maximal electroshock seizure (MES) and 6 Hz tests was 5.3 and 9.6 mg/kg respectively, and the minimal effective dose in the marble burying assay was 30 mg/kg. In both seizure and anxiety tests, the (S)-enantiomer of lacosamide was inactive suggesting a similar mechanism of action, possibly use-dependent inhibition of sodium channel function (Errington et al., 2008). Efficacy in the CER model was equivalent to diazepam and pregabalin (Lyrica). In tests of side-effects, lacosamide had no effect on choice accuracy in the delayed match to position task of working memory, although at the 30 mg/kg dose, response rates and response latencies were significantly affected. In sum, the present results identify for the first time, an anxiolytic potential of lacosamide.

Protocol for a Controlled Experiment to Identify the Causal Role of Acute Alcohol Consumption in Condomless Sex among HIV-Positive MSM: Study Procedures, Ethical Considerations, and Implications for HIV Prevention.

AbstractAlthough alcohol consumption is frequently perceived as a driver of condomless sex and subsequent HIV acquisition, the causal nature of this relationship remains unclear, and little is known about alcohol’s direct versus indirect impact on the sexual risk dynamics of those who are HIV-positive. To address this gap, we present the protocol for an in-progress NIAAA-funded controlled experiment, wherein a sample of HIV-positive men-who-have-sex-with-men (MSM) undergoes an alcohol consumption manipulation (alcohol/placebo/control) and sexual arousal induction (sexually aroused/non-aroused), and then reports intentions to engage in condom-protected and condomless sexual acts with hypothetical sexual partners differing in HIV serostatus (HIV+/HIV−/HIV status unknown), condom use preference (use/don’t use/not stated), and physical attractiveness (attractive/unattractive). Study outcomes will identify alcohol’s impact on HIV-positive MSM’s condomless sex intentions in the context of experimentally-manipulated factors as well as risk-relevant personality traits and alcohol-related expectancies. Detailed experimental procedures, ethical considerations, and potential implications for HIV prevention are discussed.