Pomegranate seed oil, a rich source of punicic acid, prevents diet-induced obesity and insulin resistance in mice

Background

Pomegranate seed oil has been shown to protect against diet induced obesity and insulin resistance.

Objective

To characterize the metabolic effects of punicic acid on high fat diet induced obesity and insulin resistance.

Design

High-fat diet or high-fat diet with 1% Pomegranate seed oil (PUA) was fed for 12 weeks to induce obesity and insulin resistance. We assessed body weight and composition (pSABRE DEXA-scan), energy expenditure (Columbus Instruments) and insulin sensitivity at the end of the 12 weeks.

Results

PSO intake resulted in a lower body weight, 30.5 ± 2.9 vs 33.8 ± 3.2 g PSO vs HFD respectively, p = 0.02, without affecting food intake or energy expenditure. The lower body weight was fully explained by a decreased body fat mass, 3.3 ± 2.3 vs 6.7 ± 2.7 g for PSO and HFD fed mice, respectively, p = 0.02. Insulin clamps showed that PSO did not affect liver insulin sensitivity but clearly improved peripheral insulin sensitivity, 164 ± 52% vs 92 ± 24% for PSO and HFD fed mice respectively, p = 0.01.

Conclusions

We conclude that dietary PSO ameliorates high-fat diet induced obesity and insulin resistance in mice, independent of changes in food intake or energy expenditure.     

Abstinence and psychological distress in co-morbid smokers using various pharmacotherapies

Background

Existing trials of varenicline have typically excluded smokers with concurrent medical and psychiatric illnesses and no data exist comparing effectiveness of varenicline with combination pharmacotherapy. This study evaluated abstinence and psychiatric outcomes of various tobacco dependence medications, including varenicline.

Methods

Retrospective cohort of 723 smokers, most with significant medical and psychiatric comorbidity, was evaluated at the UMDNJ-Tobacco Dependence Clinic from 2006 to 2008. Demographics, measures of tobacco dependence and co-morbidities, and a validated instrument measuring psychological distress (Kessler-6) were obtained. Primary outcome was 7-day point abstinence at 6 months after target quit date.

Results

Cessation medications used included combination pharmacotherapy (39%), single nicotine replacement therapy (NRT) or bupropion (29%), and varenicline (23%), with 9% using no medications. Overall, 23% of patients were abstinent at 6 months. In an adjusted regression model, smokers using varenicline or combination medications were more likely abstinent at 6 months than those using no medications (adjusted odds ratio = 2.99; 95% confidence interval = 1.20-7.47 and 2.80; 1.15-6.82, respectively), but not statistically higher than those using single medications (AOR = 1.70). Age, gender, education, marital status, cigarettes per day, time to first cigarette, night smoking, and menthol smoking were not significantly related to abstinence. Varenicline or combination medications did not significantly increase serious psychological distress over the treatment period compared to other medication options.

Conclusions

Both varenicline and combination pharmacotherapy were effective and did not increase psychological distress for up to 6 months in smokers with co-morbidities treated at a specialty clinic.     

Ex vivo study of bevacizumab transport through porcine nasal mucosa

Introduction

Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder associated with abnormal angiogenesis and disabling epistaxis, for which bevacizumab is reported to be a new therapeutic option. In the present study, bevacizumab transport in porcine nasal mucosa was investigated to determine antibody bioavailability.

Material and methods

Transmucosal absorption of bevacizumab was examined by using nasal mucosa specimens mounted onto static vertical diffusion cells then treated with bevacizumab solution (25 mg mL⁻¹, 500 μg) for 2.5 h. Bevacizumab concentrations were measured by enzyme-linked immunosorbent assays. Mucosal integrity was examined by histological examination of treated mucosa.

Results

Transmucosal transport of bevacizumab followed a Fickian diffusion process (permeability coefficient: [0.63 ± 22] × 10⁻⁶ cm s⁻¹; and steady-state flux: 56.4 ± 19.6 μg cm⁻² h⁻¹). Total recovery of bevacizumab throughout the 2.5 h experiment was 83% of the initial dose distributed (i) at the mucosal surface (263 ± 73 μg; ∼53%) and (ii) into (95 ± 14 μg; ∼19%) and through (56 ± 26 μg; ∼11%) the mucosa. There was no evidence of any noticeable histological effects, confirming the harmlessness of nasal bevacizumab delivery.

Conclusion

In the present study, absorption of bevacizumab into nasal mucosa was demonstrated, providing new fundamentals that are mandatory for further clinical trials in HHT patients.     

Depressive mood and tobacco use: moderating effects of gender and emotional attention

Introduction

Depressive symptomatology is a predictive variable of tobacco use. The objective of the present study was to evaluate the influence that this symptomatology has on tobacco use when moderated by emotional attention.

Methods

A total of 289 participants (127 males, 162 females) completed a survey to measure perceived emotional intelligence, depressive symptomatology, tobacco use and sociodemographic variables. Results were analyzed using a multiple regression model that included self-perceived emotional attention as a moderating variable.

Results

In women, an interaction was found between depressive symptomatology and gender for predicting the number of cigarettes smoked (t = 2.45; p = .01), but not in men (t = −.74; p = .45). This interaction was moderated by emotional attention (t = 2.83; p = .005), such that women with medium and high levels of attention consumed a larger number of cigarettes.

Conclusions

In women, the effect of depressive symptomatology on tobacco use was moderated by the amount of attention that women paid to those symptoms. Such a moderating effect of attention was not observed in men. We recommend that smoking cessation programs incorporate interventions designed specifically for women, in particular to help them manage depressive symptomatology.     

Epidural, intrathecal and plasma pharmacokinetic study of epidural ropivacaine in PLGA-microspheres in sheep model

Background

Microparticulate local anesthetics-loaded delivery systems are known to provide a controlled release of drug and to reduce systemic toxicity resulting from transient high plasma concentrations. The aim of this study was to evaluate epidural, intrathecal and plasma pharmacokinetics of ropivacaine following epidural administrations of repeated boluses or infusions and to compare them with the epidural administration of polylactide-co-glycolide ropivacaine-loaded microspheres.

Methods

In the first step, the epidural and intrathecal pharmacokinetics was evaluated in 3 Lacaunes ewes, receiving epidural continuous infusion of ropivacaine with increasing doses (20, 50 and 100 mg/h). Then, six animals received an epidural administration of ropivacaine-loaded microspheres (500 mg), three others received ropivacaine in epidural bolus (30 mg) followed by infusion (2 mg/ml during 6 h), and the last three animals received three successive epidural boluses of ropivacaine (50 mg) at 2 h interval. A simultaneous microdialysis technique was used to measure epidural and intrathecal concentrations of ropivacaine.

Results

After epidural administration of ropivacaine-loaded microspheres, Cmax in plasma was around 100 ng/ml while epidural and intrathecal Cmax of ropivacaine were close to 600 and 150 μg/ml, respectively. The ratios of intrathecal to epidural AUC (AUCit/AUCepi) for bolus administration, bolus + infusion administration, and for microspheres were 13.4 ± 2.4; 14.1 ± 6.1 and 33.9 ± 22.6%, respectively. This suggested that administration of ropivacaine as microspheres increased the transmeningeal passage of ropivacaine in comparison to other administration regimens.

Conclusions

Epidural administration of ropivacaine-loaded microspheres led to the sustained levels of ropivacaine in the intrathecal space compared to the boluses of ropivacaine solution. Moreover, epidural administration of microspheres resulted in the highest efficiency in intrathecal uptake of ropivacaine compared to administration in solution.     

5-HT induces temporomandibular joint nociception in rats through the local release of inflammatory mediators and activation of local β adrenoceptors

Objectives

The present studies assessed the effects of adolescent and adult ethanol exposure on the rewarding effects of cocaine as measured with the conditioned place preference procedure.

Methods

Male rats were exposed to intraperitoneal (IP) injections of ethanol or vehicle for 10 days [postnatal days (PNDs) 30-39 or PNDs 70-79; 2 mg/kg]. Place preference conditioning began on PND 65 or PND 105, respectively, and consisted of a baseline test followed by four conditioning cycles with either 0, 5, 10 or 20 mg/kg cocaine. Following the fourth conditioning cycle a final preference test was performed. Changes in time on the drug-paired side between the baseline and final test were analyzed.

Results

Animals exposed to vehicle (during adolescence or adulthood) showed a significant place preference at 20 mg/kg cocaine. Animals exposed to ethanol (during adolescence or adulthood) showed a significant place preference at 10 mg/kg cocaine.

Conclusions

Exposure to ethanol (adolescents or adults) sensitized the rewarding effects of cocaine. This may indicate an increase in the abuse liability of cocaine following a history of ethanol exposure.     

Fear-potentiated startle, but not light-enhanced startle, is enhanced by anxiogenic drugs

Rationale and objectives

The light-enhanced startle paradigm (LES) is suggested to model anxiety, because of the non-specific cue and the long-term effect. In contrast, the fear-potentiated startle (FPS) is suggested to model conditioned fear. However, the pharmacological profiles of these two paradigms are very similar. The present study investigated the effects of putative anxiogenic drugs on LES and FPS and aimed at determining the sensitivity of LES for anxiogenic drugs and to potentially showing a pharmacological differentiation between these two paradigms.

Methods

Male Wistar rats received each dose of the α₂-adrenoceptor antagonist yohimbine (0.25-1.0 mg/kg), the 5-HT_2C receptor agonist m-chlorophenylpiperazine (mCPP, 0.5-2.0 mg/kg) or the GABA_A inverse receptor agonist pentylenetetrazole (PTZ, 3-30 mg/kg) and were subsequently tested in either LES or FPS.

Results

None of the drugs enhanced LES, whereas mCPP increased percentage FPS and yohimbine increased absolute FPS values. Furthermore, yohimbine increased baseline startle amplitude in the LES, while mCPP suppressed baseline startle in both the LES and FPS and PTZ suppressed baseline startle in the FPS.

Conclusions

In contrast to findings in the FPS paradigm, none of the drugs were able to exacerbate the LES response. Thus, a clear pharmacological differentiation was found between LES and FPS.     

Percutaneous penetration of 5-methoxypsoralen in rhesus monkeys

Objective and design

5-methoxypsoralen (bergapten) has been used in the treatment of psoriasis and vitiligo, and as a sun tanning accelerator. While low plasma concentrations have previously been detected, there is no data on its dermatopharmacokinetics.

Materials and methods

Three rhesus monkeys were used as a model for human skin. [14C]-5-methoxypsoralen, as a parenteral excretion control, was injected in propylene glycol with an activity of 1.12 uCi/ml at a concentration of 80 mcg/ml and urine was collected at 4, 8, 12, 24 h, and then daily for a total of 6 days. [14C]-5-methoxypsoralen was then applied topically in acetone with a dose of 1.19 mc (72 mcg) and urine was collected at 4 and 24 h and then daily for a total of 7 days. The amount excreted was corrected for the previously determined parenteral excretion kinetics.

Results

Intramuscular [14C]-5-methoxypsoralen had an average of 71.87 ± 7.77% of excretion and percutaneously applied [14C]-5-methoxypsoralen had an average of 58.4 ± 11.8% of excretion.

Conclusion

A high percentage of the administered 5-methoxypsoralen was absorbed. This provides a foundation of methodology to evaluate the efficacy of other delivery vehicles for 5-methoxypsoralen and serves as part of its dermatotoxic profile.     

Chronic hepatitis C virus infection and increases in viral load in a prospective cohort of young, HIV-uninfected injection drug users

Background

Chronic hepatitis C (HCV) infection, defined as persistent RNA (viral load) for at least 6 months, accounts for up to 50% of all cirrhosis, end-stage liver disease and liver cancer cases. Moreover, elevated HCV viral load is consistently associated with high infectivity and poor therapy response. This study aims to identify modifiable behavioral correlates both chronic HCV infection and increases in viral load over time among injection drug users (IDUs).

Methods

Cross-sectional and longitudinal analyses were performed using self-interview and serological data from a prospective cohort study (2002-2006) among young (age 18-35), HIV-negative, HCV therapy-naïve IDUs (n = 113) from metropolitan Chicago, Illinois, USA.

Results

After adjustment for age, gender and race/ethnicity, using drugs measured or mixed in someone else's syringe (odds ratio = 2.7, 95% confidence interval: 1.1, 6.7) was associated with chronic (n = 75, 66%) versus resolved (n = 38, 34%) HCV infection status. Among chronically-infected IDUs, injecting with a new, sterile syringe infrequently (<1/2 half the time when injecting) compared to frequently (1/2 the time or more when injecting) was associated with increases in viral load over time after adjusting for age, gender, race/ethnicity and time effects.

Conclusions

Reductions in risky injection-related practices among young IDUs may ameliorate both the burden of chronic HCV infection-related liver disease and elevated viral load-related poor treatment response.     

The reinforcing value of alcohol in a drinking to cope paradigm

Background

Alcohol use is often regarded as a means of coping with sadness and distress. The present research was conducted to explore the relation between negative mood and the reinforcing value of alcohol, while clarifying the role of coping motives.

Methods

Participants with a history of recent alcohol use (N = 44; 72% female) attended a laboratory session and were randomly assigned to either a negative (n = 22) or a neutral (n = 22) mood condition. A manipulation check confirmed that participants in the negative mood condition, but not the neutral mood condition, displayed a significant increase in negative affect. The multiple choice procedure (MCP) was used to measure the reinforcing value of alcohol after the mood manipulation.

Results

Regression models employing the MCP crossover point as the dependent variable and mood condition (neutral or negative) and drinking to cope as predictors indicated that a model with an interaction term accounted for the most variance.

Conclusions

These results suggest that the relation between mood and the reinforcing value of alcohol is moderated by drinking to cope, and help clarify the conditions under which drinking to cope may lead to negative outcomes.     

All-trans retinoic acid protects against arsenic-induced uterine toxicity in female Sprague-Dawley rats

Background and purpose

Arsenic exposure frequently leads to reproductive failures by disrupting the rat uterine histology, hormonal integrity and estrogen signaling components of the rat uterus, possibly by generating reactive oxygen species. All-trans retinoic acid (ATRA) was assessed as a prospective therapeutic agent for reversing reproductive disorders.

Experimental approach

Rats exposed to arsenic for 28 days were allowed to either recover naturally or were treated simultaneously with ATRA for 28 days or treatment continued up to 56 days. Hematoxylin-eosin double staining was used to evaluate changes in the uterine histology. Serum gonadotropins and estradiol were assayed by ELISA. Expression of the estrogen receptor (ERα), an estrogen responsive gene vascular endothelial growth factor (VEGF), and cell cycle regulatory proteins, cyclin D1 and CDK4, was assessed by RT-PCR, immunohistochemistry and western blot analysis.

Key results

ATRA ameliorated sodium arsenite-induced decrease in circulating estradiol and gonadotropin levels in a dose- and time-dependent manner, along with recovery of luminal epithelial cells and endometrial glands. Concomitant up regulation of ERα, VEGF, cyclin D1, CDK4 and Ki-67 was also observed to be more prominent for ATRA-treated rats as compared to the rats that were allowed to recover naturally for 56 days.

Conclusions and implications

Collectively, the results reveal that ATRA reverses arsenic-induced disruption of the circulating levels of gonadotropins and estradiol, and degeneration of luminal epithelial cells and endometrial glands of the rat uterus, indicating resumption of their functional status. Since structural and functional maintenance of the pubertal uterus is under the influence of estradiol, ATRA consequently up regulated the estrogen receptor and resumed cellular proliferation, possibly by an antioxidant therapeutic approach against arsenic toxicity.     

Prenatal cocaine exposure and small-for-gestational-age status: effects on growth at 6 years of age

Objective

To evaluate the impact of prenatal cocaine exposure and small-for-gestational-age (SGA) status on childhood growth.

Study design

Cocaine exposure was defined by history or meconium metabolites. Hierarchical linear modeling was used to examine cocaine exposure and SGA status on growth, while controlling for exposure to other drugs and alcohol use.

Results

At birth cocaine-exposed infants (n = 364) had significantly lower growth parameters compared to non-exposed children (n = 771). At 6 years, weight was similar between exposed and unexposed children. SGA infants continued to be growth impaired. There was a significant interaction between prenatal cocaine exposure and SGA status at 6 years. The negative effects of cocaine on weight and height were greater among non-SGA than SGA children (432 vs. 280 gm, and 0.7 and 0.5 cm, respectively) while negative effects of SGA status on weight and height were larger in non-cocaine exposed compared to the exposed children (2.3 kg vs.1.6 kg and 2.2 and 1.0 cm).

Conclusions

Children exposed to prenatal cocaine were similar in weight to non-exposed children at 6 years of age. Cocaine had an unexplained greater detrimental effect on non-SGA than SGA children. SGA status at birth has an independent detrimental effect on childhood growth.     

Internet-based group contingency management to promote abstinence from cigarette smoking: a feasibility study

Background

In contingency management (CM) interventions, monetary consequences are contingent on evidence of drug abstinence. Typically, these consequences are contingent on individual performance. Consequences contingent on group performance may promote social support (e.g., praise).

Methods

Thus, to combine social support with the monetary incentives of CM, we integrated independent and interdependent group contingencies of reinforcement into an Internet-based intervention to promote smoking abstinence. Breath carbon monoxide (CO) measures were compared between treatment conditions and a baseline control condition. Thirteen participants were divided into 5 groups or “teams” (n = 2-3 per team). Each participant submitted video recordings of CO measurement twice daily via the Internet. Teammates could monitor each other's progress and communicate with one another through an online peer support forum. During a 4-day tapering condition, vouchers exchangeable for goods were contingent on gradual reductions in breath CO. During a 10-day abstinence induction condition, vouchers were contingent on abstinence (CO ≤ 4 ppm). In both treatment conditions, concurrent independent and interdependent group contingencies were arranged (i.e., a mixed contingency arrangement).

Results

Less than 1% of CO samples submitted during baseline were ≤ 4 ppm, compared to 57% submitted during abstinence induction. Sixty-five percent of participants’ comments on the online peer support forum were rated as positive by independent observers. Participants rated the intervention favorably on a treatment acceptability questionnaire.

Conclusion

The results suggest that the intervention is feasible and acceptable for promoting abstinence from cigarette smoking.     

Prenatal exposure to multiple toxic heavy metals and neonatal neurobehavioral development in Shanghai, China

Background

Epidemiological studies examining the effects of prenatal toxic heavy metals exposure on neonatal development at the population-based level are limited.

Objective

To explore prenatal exposure levels to toxic heavy metals and examine whether exposure is associated with neonatal development.

Methods

A stratified multi-stage cluster sampling methodology was used to investigate 1652 mother-infant pairs from 2008 through 2009 in Shanghai. Cord blood concentrations of Pb, Hg, Cd, As, Tl and NBNA (Neonatal Behavioral Neurological Assessments) were tested. We defined three different exposure levels (low, medium and high) according to the considered safe values.

Results

The median blood Pb, Hg, Cd, As and Tl concentrations were 41 μg/L, 1.88 μg/L, 0.03 μg/L, 0.86 μg/L and 0.02 μg/L, respectively, which all were in the level considered safe. Increasing exposure to Cd, Hg, As and Tl during pregnancy was associated with decreasing NBNA scores. High level-exposure (exceeding the level considered safe) of Hg, Cd and Tl had lower NBNA scores compared to medium and low levels (both in the level considered safe), which implied that the level considered safe of these heavy metals was safe for the newborns' development. The mean decreasing scores of NBNA was 0.61, 1.50 and 0.84 (total score = 40) with high-level exposure of Hg, Cd and Tl, respectively. The medium-level exposure (in the level considered safe) to As had lower NBNA scores compared to low-level exposure, which implied that level of considered safe for As was not safe to the newborns' development. However, prenatal Pb high-exposure did not affect NBNA scores either by single or multiple factor analysis. In addition, important contribution factors for heavy metals pollutants were diet, lifestyle and housing renovation.

Conclusions

Prenatal heavy metals except Pb exposures were associated with NBNA. The adverse effect of medium-level As warrants the need to further investigate the safe range of As.     

A systematic review of the impact of alcohol use disorders on HIV treatment outcomes, adherence to antiretroviral therapy and health care utilization

Background

Alcohol use disorders (AUDs) are highly prevalent and associated with non-adherence to antiretroviral therapy, decreased health care utilization and poor HIV treatment outcomes among HIV-infected individuals.

Objectives

To systematically review studies assessing the impact of AUDs on: (1) medication adherence, (2) health care utilization and (3) biological treatment outcomes among people living with HIV/AIDS (PLWHA).

Data sources

Six electronic databases and Google Scholar were queried for articles published in English, French and Spanish from 1988 to 2010. Selected references from primary articles were also examined.

Review methods

Selection criteria included: (1) AUD and adherence (N = 20); (2) AUD and health services utilization (N = 11); or (3) AUD with CD4 count or HIV-1 RNA treatment outcomes (N = 10). Reviews, animal studies, non-peer reviewed documents and ongoing studies with unpublished data were excluded. Studies that did not differentiate HIV+ from HIV− status and those that did not distinguish between drug and alcohol use were also excluded. Data were extracted, appraised and summarized.

Data synthesis and conclusions

Our findings consistently support an association between AUDs and decreased adherence to antiretroviral therapy and poor HIV treatment outcomes among HIV-infected individuals. Their effect on health care utilization, however, was variable.     

Activation of α7 nicotinic receptors improves phencyclidine-induced deficits in cognitive tasks in rats: Implications for therapy of cognitive dysfunction in schizophrenia

Rationale

Nicotinic α7 acetylcholine receptors (nAChRs) have been highlighted as a target for cognitive enhancement in schizophrenia.

Aim

To investigate whether the deficits induced by sub-chronic phencyclidine (PCP) in reversal learning and novel object recognition could be attenuated by the selective α7 nAChR full agonist, PNU-282987.

Methods

Adult female hooded-Lister rats received sub-chronic PCP (2 mg/kg) or vehicle i.p. twice daily for 7 days, followed by 7 days washout. In cohort 1, PCP-treated rats then received PNU-282987 (5, 10, 20 mg/kg; s.c.) or vehicle and were tested in the reversal-learning task. In cohort 2, PCP-treated rats received PNU-282987 (10 mg/kg; s.c.) or saline for 15 days and were tested in the novel object recognition test on day 1 and on day 15, to test for tolerance.

Results

Sub-chronic PCP produced significant deficits in both cognitive tasks (P < 0.01-0.001). PNU-282987 attenuated the PCP-induced deficits in reversal learning at 10 mg/kg (P < 0.01) and 20 mg/kg (P < 0.001), and in novel object recognition at 10 mg/kg on day 1 (P < 0.01) and on day 15 (P < 0.001).

Conclusions

These data show that PNU-282987 has efficacy to reverse PCP-induced deficits in two paradigms of relevance to schizophrenia. Results further suggest that 15-day once daily dosing of PNU-282987 (10 mg/kg s.c.) does not cause tolerance in the rat. This study suggests that activation of α7 nAChRs, may represent a suitable strategy for improving cognitive deficits of relevance to schizophrenia.     

Low-dose naltrexone augmentation of nicotine replacement for smoking cessation with reduced weight gain: A randomized trial

Background

Fear of weight gain is a significant obstacle to smoking cessation, preventing some smokers from attempting to quit. Several previous studies of naltrexone yielded promising results for minimization of post-quit weight gain. Given these encouraging findings, we endeavored to test whether minimization of weight gain might translate to better quit outcomes for a population that is particularly concerned about gaining weight upon quitting.

Methods

Smokers (N = 172) in this investigation were prospectively randomized to receive either 25 mg naltrexone or placebo for 27 weeks (1 week pre-, 26 weeks post-quit) for minimization of post-quit weight gain and smoking cessation. All participants received open label therapy with the nicotine patch for the first 8 weeks post-quit and behavioral counseling over the 27-week treatment. The 2 pre-specified primary outcomes were change in weight for continuously abstinent participants and biologically verified end-of-treatment 7-day point-prevalence abstinence at 26 weeks after the quit date.

Results

The difference in weight at 26 weeks post-quit between the naltrexone and placebo groups (naltrexone: 6.8 lbs ± 8.94 vs placebo: 9.7 lbs ± 9.19, p = 0.45) was not statistically different. Seven-day point-prevalence smoking abstinence rates at 26 weeks post-quit was not significantly different between the 2 groups (naltrexone: 22% vs placebo: 27%, p = 0.43).

Conclusions

For smokers high in weight concern, the relatively small reduction in weight gain with low-dose naltrexone is not worth the potential for somewhat lower rates of smoking abstinence.     

Chronic treatment with curcumin enhances methamphetamine locomotor sensitization and cue-induced reinstatement of methamphetamine self-administration

Objectives

Curcumin, a major active component of Curcuma longa, possesses antidepressant effects that are mediated by the 5-HT system. However, little is known about the effect of curcumin on the behavioral consequences of methamphetamine (METH).

Methods

The subjects were male, adult Sprague-Dawley rats. In Experiment 1, the effects of 20 and 40 mg/kg curcumin (i.p.) on response rates and breakpoints of 0.06 mg/kg/infusion METH were evaluated. In Experiment 2, rats were self-administering METH for 10 days followed by a 14-day abstinence period. During the abstinence period, the animals were treated with DMSO, 20 or 40 mg/kg curcumin. All rats were then tested for extinction responding and cue-induced reinstatement. In Experiment 3, rats were treated with DMSO, 20, or 40 mg/kg curcumin15 min before a METH-induced locomotor activity test for 14 consecutive days. In Experiment 4, rats were pretreated with DMSO or curcumin (20 mg/kg or 40 mg/kg) for 13 days and were subsequently tested for METH-induced locomotor activity on the 14th day. In Experiment 5, three groups were tested for locomotor activity after an injection of DMSO, 20, or 40 mg/kg curcumin. The test was repeated for 14 days.

Results

Curcumin produced little effect on response rates and breakpoints maintained by METH. Chronic treatment of only 40 mg/kg curcumin during the abstinence phase enhanced cue-induced reinstatement of METH self-administration. Chronic administration of curcumin increased METH-induced sensitization of locomotor activity at the lower (20 mg/kg) but not higher (40 mg/kg) dose. However pretreatment of curcumin alone showed no significant effect on acute locomotor responses to METH and locomotor responses per se.

Conclusions

Curcumin enhanced, rather than inhibited the behavioral effects of METH.     

Motor and cognitive outcomes through three years of age in children exposed to prenatal methamphetamine

Background

Methamphetamine (MA) use among pregnant women is an increasing problem in the United States. The impact of prenatal MA exposure on development in childhood is unknown.

Objective

To examine the effects of prenatal MA exposure on motor and cognitive development in children at 1, 2, and 3 years of age.

Design/methods

IDEAL enrolled 412 mother-infant pairs at four sites (Tulsa OK, Des Moines IA, Los Angeles CA, and Honolulu HI). MA subjects (n = 204) were identified by self report or GC/MS confirmation of amphetamine and metabolites in infant meconium. Comparison subjects (n = 208) were matched (race, birth weight, maternal education, and type of insurance), denied amphetamine use, and had a negative meconium screen. Both groups included prenatal alcohol, tobacco and marijuana use, but excluded use of opiates, lysergic acid diethylamide, phencyclidine or cocaine only. The Peabody Developmental Motor Scales (PDMS-2) were administered to the infants at the 1 and 3 year visits. This analysis includes a subsample (n = 350) of the IDEAL study with completed 1 and/or 3 year visits (n = 330 and 281, respectively). At each annual visit we also conducted the Bayley Scales of Infant Development (BSID-II) as a general evaluation of mental and motor development. The BSID-II analysis includes a subsample (n = 356) of the IDEAL study with completed 1, 2, and/or 3 year visits (n = 331, 288, and 278 respectively). GLM analysis conducted on the PDMS-2 and BSID-II examined the effects of MA exposure and heavy MA exposure (≥ 3 days of use/week), with and without covariates. Longitudinal analyses were used to examine the effects of MA exposure on changes in motor and cognitive performance over time.

Results

Heavy MA exposure was associated with significantly lower grasping scores than some and no use at 1 year (P = 0.018). In longitudinal analysis, lower grasping scores associated with any MA exposure and heavy exposure persisted to 3 years. There were no effects of MA exposure, including heavy exposure, on the Bayley Mental Development Index (MDI) or Psychomotor Development Index (PDI) at any or across age.

Conclusions

There were no differences in cognition as assessed by the BSID-II between the groups. There was a subtle MA exposure effect on fine motor performance at 1 year with the poorest performance observed in the most heavily exposed children. By 3 years, no differences in fine motor performance were observed. These findings suggest MA exposure has modest motor effects at 1 year that are mostly resolved by 3 years.     

Oral and transdermal DL-methylphenidate-ethanol interactions in C57BL/6J mice: potentiation of locomotor activity with oral delivery

Purpose

Many abusers of dl-methylphenidate co-abuse ethanol. The present animal study examined behavioral effects of oral or transdermal dl-methylphenidate in combination with a high, depressive dose of ethanol to model co-abuse.

Methods

Locomotor activity of C57BL/6J mice was recorded for 3 h following dosing with either oral dl-methylphenidate (7.5 mg/kg) or transdermal dl-methylphenidate (Daytrana®;1/4 of a 12.5 cm² patch; mean dose 7.5 mg/kg), with or without oral ethanol (3 g/kg). Brains were enantiospecifically analyzed for the isomers of methylphenidate and the transesterification metabolite ethylphenidate.

Results

An otherwise depressive dose of ethanol significantly potentiated oral dl-methylphenidate induced increases in total distance traveled for the first 100 min (p < 0.05). Transdermal dl-methylphenidate increased total distance traveled after a latency of 80 min, though this effect was not potentiated by concomitant ethanol. Mean 3 h brain d-methylphenidate concentrations were significantly elevated by ethanol in both the oral (65% increase) and transdermal (88% increase) groups. The corresponding l-ethylphenidate concentrations were 10 ng/g and 130 ng/g.

Conclusions

Stimulant induced motor activity in rodents may correlate with abuse liability. Potentiation of dl-methylphenidate motor effects by concomitant ethanol carries implications regarding increased abuse potential of dl-methylphenidate when combined with ethanol.