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1.  Δ9tetrahydrocannabinol impairs reversal learning but not extra-dimensional shifts in rhesus macaques 
Neuroscience  2013;235:51-58.
Expansion of medical marijuana use in the US and the recently successful decriminalization of recreational marijuana in two States elevates interest in the specific cognitive effects of Δ9tetrahydrocannabinol (Δ9THC), the major psychoactive constituent of marijuana. Controlled laboratory studies in nonhuman primates provide mixed evidence for specific effects of Δ9THC in learning and memory tasks, with a suggestion that frontal-mediated tasks may be most sensitive. In this study, adult male rhesus monkeys were trained on tasks which assess reversal learning, extradimensional attentional shift learning and spatial delayed-response. Subjects were challenged with 0.1–0.5 mg/kg Δ9THC, i.m., in randomized order and evaluated on the behavioral measures. Peak plasma levels of Δ9THC were observed 30 min after 0.2 mg/kg (69 ±29 ng/ml) and 60 min after 0.5 mg/kg (121 ±23 ng/ml) was administered and behavioral effects on a bimanual motor task persisted for up to 2 hrs after injection. An increase in errors-to-criterion (ETC) associated with reversal learning was further increased by Δ9THC in a dose-dependent manner. The increase in ETC associated with extradimensional shifts was not affected by Δ9-THC. Spatial delayed-response performance was impaired by Δ9THC in a retention-interval dependent manner. Overall the pattern of results suggest a more profound effect of Δ9THC on tasks mediated by orbitofrontal (reversal learning) versus dorsolateral (extradimensional shifts) prefrontal mechanisms.
doi:10.1016/j.neuroscience.2013.01.018
PMCID: PMC3595391  PMID: 23333671
cannabis; marijuana; Macaca mulatta; extradimensional shift; reversal learning
2.  Measuring Adolescent Boys' Physical Activity: Bout Length and the Influence of Accelerometer Epoch Length 
PLoS ONE  2014;9(3):e92040.
Objectives
Accurate, objective measurement is important for understanding adolescents' physical activity (PA) behaviour. When using accelerometry to objectively measure PA, a decision must be made regarding how frequently data is recorded (i.e., epoch length). The purpose of this study was to examine i) PA bout length, and ii) the effect of variations in accelerometer epoch length on PA estimates during physical education (PE) and leisure time in adolescent boys.
Design
Cross-sectional study.
Methods
Year 9 boys (N = 133; mean age ±SD  = 14.36±0.48 years) wore accelerometers during two PE lessons, and for a period of seven consecutive days. Data were reintegrated from 1s into longer periods of 2, 5, 10, 30, and 60 seconds. ANOVAs were used to test for differences in PA estimates between epochs in leisure time and PE.
Results
The mean length of vigorous PA (VPA) bouts was 3.5±2.0 seconds for PE and 2.5±1.7 seconds for leisure time, and mean length of moderate PA (MPA) bouts was 2.3±0.5 seconds for PE and 2.9±0.5 seconds for leisure time. During PE, estimates of MVPA, MPA, and light PA (LPA) increased as epoch increased from 1 second to 60 seconds, while VPA and sedentary behaviour estimates decreased. During leisure time, estimates of all PA intensities decreased as epoch increased from 1 second to 60 seconds, with the exception of sedentary behaviour, which increased as epoch length increased.
Conclusion
The context in which PA occurs can influence PA bout length measurement and the effect of variations in epoch length on PA estimates. Researchers measuring PA with accelerometry should be conscious of the possible influence of context on PA estimates.
doi:10.1371/journal.pone.0092040
PMCID: PMC3958416  PMID: 24643129
3.  Immunogenicity of Individual Vaccine Components in a Bivalent Nicotine Vaccine Differ According to Vaccine Formulation and Administration Conditions 
PLoS ONE  2013;8(12):e82557.
Structurally distinct nicotine immunogens can elicit independent antibody responses against nicotine when administered concurrently. Co-administering different nicotine immunogens together as a multivalent vaccine could be a useful way to generate higher antibody levels than with monovalent vaccines alone. The immunogenicity and additivity of monovalent and bivalent nicotine vaccines was studied across a range of immunogen doses, adjuvants, and routes to assess the generality of this approach. Rats were vaccinated with total immunogen doses of 12.5 - 100 μg of 3′-aminomethyl nicotine conjugated to recombinant Pseudomonas exoprotein A (3′-AmNic-rEPA), 6-carboxymethylureido nicotine conjugated to keyhole limpet hemocyanin (6-CMUNic-KLH), or both. Vaccines were administered s.c. in alum or i.p. in Freund’s adjuvant at matched total immunogen doses. When administered s.c. in alum, the contributions of the individual immunogens to total nicotine-specific antibody (NicAb) titers and concentrations were preserved across a range of doses. Antibody affinity for nicotine varied greatly among individuals but was similar for monovalent and bivalent vaccines. However when administered i.p. in Freund’s adjuvant the contributions of the individual immunogens to total NicAb titers and concentrations were compromised at some doses. These results support the possibility of co-administering structurally distinct nicotine immunogens to achieve a more robust immune response than can be obtained with monovalent immunogens alone. Choice of adjuvant was important for the preservation of immunogen component activity.
doi:10.1371/journal.pone.0082557
PMCID: PMC3846984  PMID: 24312662
4.  Contrasting effects of d-methamphetamine, 3,4-methylenedioxymethamphetamine, 3,4-methylenedioxypyrovalerone, and 4-methylmethcathinone on wheel activity in rats 
Drug and alcohol dependence  2012;126(1-2):168-175.
BACKGROUND
Reports from US, UK and European drug policy entities, and ongoing media accounts, show increasing recreational use of 4-methylmethcathinone (4-MMC, mephedrone) and 3,4-methylenedioxypyrovalerone (MDPV). Severe sympathomimetic symptoms, hallucinations, psychoses, and even deaths have been reported, yet little scientific information is available on the effects of these compounds in laboratory models. Available studies on the neurochemistry of these drugs show that 4-MMC and MDPV enhance DA neurotransmission, while 4-MMC additionally enhances 5-HT neurotransmission- a pattern much like that reported for methamphetamine vs. 3,4-methylenedioxymethamphetamine (MDMA). As is the case for designer amphetamines, these neurochemical distinctions may predict differential potential for repetitive versus episodic abuse and distinct lasting toxicities.
METHODS
This study determined relative locomotor stimulant effects of 4-MMC (1–10 mg/kg, s.c.) and MDPV (0.5–5.6 mg/kg, s.c.), in comparison with d-methamphetamine (MA; 0.5–5.6 mg/kg, s.c.) and MDMA (1–7.5 mg/kg, s.c.) on a measure of locomotor activity – voluntary wheel running – in male Wistar rats (N=8).
RESULTS
Compared to counts of wheel rotations after saline, a biphasic change in the pattern of counts was observed after injections of MA and MDPV, with relatively higher counts following lower doses and lower counts following the highest dose. However, monophasic, dose-dependent reductions in counts were observed in response to injections of MDMA and 4-MMC.
CONCLUSION
Thus, voluntary wheel running yielded the same categorical distinctions for these drugs as did prior experiments testing the effects of these drugs on monoaminergic neurotransmission. These data indicate that MDPV produces prototypical locomotor stimulant effects whereas 4-MMC is more similar to the entactogen MDMA.
doi:10.1016/j.drugalcdep.2012.05.011
PMCID: PMC3439532  PMID: 22664136
cathinones; stimulants; activity wheel; Ecstasy; bath salts
5.  Δ9tetrahydrocannabinol impairs visuo-spatial associative learning and spatial working memory in rhesus macaques 
Cannabis remains the most commonly abused illicit drug and is rapidly expanding in quasi-licit use in some jurisdictions under medical marijuana laws. Effects of the psychoactive constituent Δ9tetrahydrocannabinol (Δ9THC) on cognitive function remain of pressing concern. Prior studies in monkeys have not shown consistent evidence of memory specific effects of Δ9THC on recognition tasks and it remains unclear to what extent Δ9THC causes sedative versus specific cognitive effects. In this study, adult male rhesus monkeys were trained on tasks which assess spatial working memory, visuo-spatial associative memory and learning as well as motivation for food reward. Subjects were subsequently challenged with 0.1-0.3 mg/kg Δ9THC, i.m., in randomized order and evaluated on the behavioral measures. The performance of both vsPAL and SOSS tasks was impaired by Δ9THC in a dose and task-difficulty manner. It is concluded that Δ9THC disrupts cognition in a way that is consistent with a direct effect on memory. There was evidence for interference with spatial working memory, visuo-spatial associative memory and incremental learning in the latter task. These results and the lack of specific effect of Δ9THC in prior visual recognition studies imply a sensitivity of spatial memory processing and/or working memory to endocannabinoid perturbation.
doi:10.1177/0269881112443743
PMCID: PMC3560534  PMID: 22526684
cannabis; marijuana; Macaca mulatta; memory
6.  Attitudes towards Doping and Related Experience in Spanish National Cycling Teams According to Different Olympic Disciplines 
PLoS ONE  2013;8(8):e70999.
Attitudes towards doping are considered an influence of doping intentions. The aims of the present study were 1) to discover and compare the attitudes towards doping among Spanish national team cyclists from different Olympic disciplines, as well as 2) to get some complementary information that could better explain the context. The sample was comprised of seventy-two cyclists: mean age 19.67±4.72 years; 70.8% males (n = 51); from the different Olympic disciplines of Mountain bike -MTB- (n = 18), Bicycle Moto Cross -BMX- (n = 12), Track -TRA- (n = 9) and Road -ROA- (n = 33). Descriptive design was carried out using a validated scale (PEAS). To complement this, a qualitative open-ended questionnaire was used. Overall mean score (17–102) was 36.12±9.39. For different groups, the data were: MTB: 30.28±6.92; BMX: 42.46±10.74; TRA: 43.22±12.00; ROA: 34.91±6.62, respectively. In relation to overall score, significant differences were observed between MTB and BMX (p = 0.002) and between MTB and TRA (p = 0.003). For the open-ended qualitative questionnaire, the most mentioned word associated with “doping” was “cheating” (48.83% of total sample), with “responsible agents of doping” the word “doctor” (52,77%), and with the “main reason for the initiation in doping” the words “sport achievement” (45.83%). The major proposed solution was “doing more doping controls” (43.05%). Moreover, 48.67% stated that there was “a different treatment between cycling and other sports”. This study shows that Spanish national team cyclists from Olympic cycling disciplines, in general, are not tolerant in relation to doping. BMX and Track riders are a little more permissive towards the use of banned substances than MTB and Road. Results from the qualitative open-ended questionnaire showed interesting data in specific questions. These results empower the idea that, apart from maintaining doping controls and making them more efficient, anti-doping education programs are needed from the earliest ages.
doi:10.1371/journal.pone.0070999
PMCID: PMC3749213  PMID: 23990919
7.  Analysis of Cannabis Seizures in NSW, Australia: Cannabis Potency and Cannabinoid Profile 
PLoS ONE  2013;8(7):e70052.
Recent analysis of the cannabinoid content of cannabis plants suggests a shift towards use of high potency plant material with high levels of Δ9-tetrahydrocannabinol (THC) and low levels of other phytocannabinoids, particularly cannabidiol (CBD). Use of this type of cannabis is thought by some to predispose to greater adverse outcomes on mental health and fewer therapeutic benefits. Australia has one of the highest per capita rates of cannabis use in the world yet there has been no previous systematic analysis of the cannabis being used. In the present study we examined the cannabinoid content of 206 cannabis samples that had been confiscated by police from recreational users holding 15 g of cannabis or less, under the New South Wales “Cannabis Cautioning” scheme. A further 26 “Known Provenance” samples were analysed that had been seized by police from larger indoor or outdoor cultivation sites rather than from street level users. An HPLC method was used to determine the content of 9 cannabinoids: THC, CBD, cannabigerol (CBG), and their plant-based carboxylic acid precursors THC-A, CBD-A and CBG-A, as well as cannabichromene (CBC), cannabinol (CBN) and tetrahydrocannabivarin (THC-V). The “Cannabis Cautioning” samples showed high mean THC content (THC+THC-A = 14.88%) and low mean CBD content (CBD+CBD-A = 0.14%). A modest level of CBG was detected (CBG+CBG-A = 1.18%) and very low levels of CBC, CBN and THC-V (<0.1%). “Known Provenance” samples showed no significant differences in THC content between those seized from indoor versus outdoor cultivation sites. The present analysis echoes trends reported in other countries towards the use of high potency cannabis with very low CBD content. The implications for public health outcomes and harm reduction strategies are discussed.
doi:10.1371/journal.pone.0070052
PMCID: PMC3722200  PMID: 23894589
8.  The Rationale for Consuming Cognitive Enhancement Drugs in University Students and Teachers 
PLoS ONE  2013;8(7):e68821.
Cognitive enhancement (CE) is the pharmaceutical augmentation of mental abilities (e.g., learning or memory) without medical necessity. This topic has recently attracted widespread attention in scientific and social circles. However, knowledge regarding the mechanisms that underlie the decision to use CE medication is limited. To analyze these decisions, we used data from two online surveys of randomly sampled university teachers (N = 1,406) and students (N = 3,486). Each respondent evaluated one randomly selected vignette with regard to a hypothetical CE drug. We experimentally varied the characteristics of the drugs among vignettes and distributed them among respondents. In addition, the respondent’s internalization of social norms with respect to CE drug use was measured. Our results revealed that students were more willing to enhance cognitive performance via drugs than university teachers, although the overall willingness was low. The probability of side effects and their strength reduced the willingness to use CE drugs among students and university teachers, whereas higher likelihoods and magnitudes of CE increased this propensity. In addition, the internalized norm against CE drug use influenced decision making: Higher internalization decreased the willingness to use such medications. Students’ internalized norms more strongly affected CE abstinence compared with those of university teachers. Furthermore, internalized norms negatively interacted with the instrumental incentives for taking CE medication. This internalization limited the influence of and deliberation on instrumental incentives. This study is the first to provide empirical evidence regarding the importance of social norms and their influence on rational decision making with regard to CE. We identified previously undiscovered decision-making patterns concerning CE. Thus, this study provides insight into the motivators and inhibitors of CE drug use. These findings have implications for contending with CE behavior by highlighting the magnitude of potential side effects and by informing the debate regarding the ethics of CE use.
doi:10.1371/journal.pone.0068821
PMCID: PMC3714277  PMID: 23874778
9.  Intertwined Epidemics: National Demographic Trends in Hospitalizations for Heroin- and Opioid-Related Overdoses, 1993–2009 
PLoS ONE  2013;8(2):e54496.
The historical patterns of opiate use show that sources and methods of access greatly influence who is at risk. Today, there is evidence that an enormous increase in the availability of prescription opiates is fuelling a rise in addiction nationally, drawing in new initiates to these drugs and changing the geography of opiate overdoses. Recent efforts at supply-based reductions in prescription opiates may reduce harm, but addicted individuals may switch to other opiates such as heroin. In this analysis, we test the hypothesis that changes in the rates of Prescription Opiate Overdoses (POD) are correlated with changes in the rate of heroin overdoses (HOD). ICD9 codes from the Nationwide Inpatient Sample and population data from the Census were used to estimate overall and demographic specific rates of POD and HOD hospital admissions between 1993 and 2009. Regression models were used to test for linear trends and lagged negative binomial regression models were used to model the interrelationship between POD and HOD hospital admissions. Findings show that whites, women, and middle-aged individuals had the largest increase in POD and HOD rates over the study period and that HOD rates have increased in since 2007. The lagged models show that increases in a hospitals POD predict an increase in the subsequent years HOD admissions by a factor of 1.26 (p<0.001) and that each increase in HOD admissions increase the subsequent years POD by a factor of 1.57 (p<0.001). Our hypothesis of fungibility between prescription opiates and heroin was supported by these analyses. These findings suggest that focusing on supply-based interventions may simply lead to a shift in use to heroin rather minimizing the reduction in harm. The alternative approach of using drug abuse prevention resources on treatment and demand-side reduction is likely to be more productive at reducing opiate abuse related harm.
doi:10.1371/journal.pone.0054496
PMCID: PMC3566161  PMID: 23405084
10.  Δ9-Tetrahydrocannabinol attenuates MDMA-induced hyperthermia in rhesus monkeys 
Neuroscience  2011;201:125-133.
Background
Cannabis is commonly consumed by Ecstasy (3,4-methylenedioxymethamphetamine; MDMA) users, including as an intentional strategy to manipulate the drug experience. The most active psychoactive constituent in cannabis, Δ9-tetrahydrocannabinol (THC), and other drugs with partial or full agonist activity at the CB1 receptor, produces a reduction of body temperature in rodents. Reports show that administration of THC can attenuate temperature increases caused by MDMA in mice or rats however a recent study in humans shows that THC potentiates MDMA-induced temperature elevations. Relatively little scientific evidence on the thermoregulatory effects of THC in monkeys is available.
Methods
The body temperature of male rhesus macaques was recorded after challenge with THC (0.1–0.3 mg/kg, i.m.) or combined challenge of THC with the CB1 receptor antagonist SR141716 (Rimonabant; 0.3 mg/kg, i.m.) or combined challenge of THC (0.1, 0.3 m/gkg, i.m.) with 3,4-methylenedioxymethamphetamine (MDMA; 1.78 mg/kg p.o.) using minimally-invasive, implanted radiotelemetry techniques.
Results
THC reduced the body temperature of monkeys in a dose-dependent manner with the nadir observed 3–5 hrs post-injection, however an attenuation of normal circadian cooling was also produced overnight following dosing. Hypothermia induced by THC (0.3 mg/kg, i.m.) was prevented by Rimonabant (0.3 mg/kg, i.m.). Finally, 0.3 mg/kg THC (i.m.) attenuated the elevation of body temperature produced by MDMA for about 4 hours after oral dosing.
Conclusions
As with rodents THC produces a robust and lasting decrement in the body temperature of rhesus monkeys; this effect is mediated by the CB1 receptor. THC also protects against the immediate hyperthermic effects of MDMA in monkeys in a dose-dependent manner. Nevertheless, a paradoxical attenuation of circadian cooling overnight after the THC/MDMA combination cautions that longer term effects may be critical in assessing risks for the recreational user of cannabis in combination with MDMA.
doi:10.1016/j.neuroscience.2011.11.040
PMCID: PMC3258357  PMID: 22138434
Ecstasy; hypothermia; endocannabinoid; thermoregulation; nonhuman primate; radiotelemetry
11.  Psychomotor Function in Chronic Daily Cannabis Smokers during Sustained Abstinence 
PLoS ONE  2013;8(1):e53127.
Background
The present study assessed psychomotor function in chronic, daily cannabis smokers during 3 weeks continuously monitored abstinence on a secure research unit. We hypothesized that psychomotor performance would improve during abstinence of chronic, daily cannabis smokers.
Methodology/Principal Findings
Performance on the critical tracking (CTT) and divided attention (DAT) tasks was assessed in 19 male chronic, daily cannabis smokers at baseline and after 8, 14–16 and 21–23 days of continuously monitored abstinence. Psychomotor performance was compared to a control group of non-intoxicated occasional drug users. Critical frequency (λc) of the CTT and tracking error and control losses of the DAT were the primary outcome measures. Results showed that chronic cannabis smokers’ performance on the CTT (p<0.001) and the DAT (p<0.001) was impaired during baseline relative to the comparison group. Psychomotor performance in the chronic cannabis smokers improved over 3 weeks of abstinence, but did not recover to equivalent control group performance.
Conclusions/Significance
Sustained cannabis abstinence moderately improved critical tracking and divided attention performance in chronic, daily cannabis smokers, but impairment was still observable compared to controls after 3 weeks of abstinence. Between group differences, however, need to be interpreted with caution as chronic smokers and controls were not matched for education, social economic status, life style and race.
doi:10.1371/journal.pone.0053127
PMCID: PMC3534640  PMID: 23301031
12.  Social Rewards Enhance Offline Improvements in Motor Skill 
PLoS ONE  2012;7(11):e48174.
Motor skill memory is first encoded online in a fragile form during practice and then converted into a stable form by offline consolidation, which is the behavioral stage critical for successful learning. Praise, a social reward, is thought to boost motor skill learning by increasing motivation, which leads to increased practice. However, the effect of praise on consolidation is unknown. Here, we tested the hypothesis that praise following motor training directly facilitates skill consolidation. Forty-eight healthy participants were trained on a sequential finger-tapping task. Immediately after training, participants were divided into three groups according to whether they received praise for their own training performance, praise for another participant's performance, or no praise. Participants who received praise for their own performance showed a significantly higher rate of offline improvement relative to other participants when performing a surprise recall test of the learned sequence. On the other hand, the average performance of the novel sequence and randomly-ordered tapping did not differ between the three experimental groups. These results are the first to indicate that praise-related improvements in motor skill memory are not due to a feedback-incentive mechanism, but instead involve direct effects on the offline consolidation process.
doi:10.1371/journal.pone.0048174
PMCID: PMC3492334  PMID: 23144855
13.  Clinical Pharmacology of 3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”): The Influence of Gender and Genetics (CYP2D6, COMT, 5-HTT) 
PLoS ONE  2012;7(10):e47599.
The synthetic psychostimulant MDMA (±3,4-methylenedioxymethamphetamine, ecstasy) acts as an indirect serotonin, dopamine, and norepinephrine agonist and as a mechanism-based inhibitor of the cytochrome P-450 2D6 (CYP2D6). It has been suggested that women are more sensitive to MDMA effects than men but no clinical experimental studies have satisfactorily evaluated the factors contributing to such observations. There are no studies evaluating the influence of genetic polymorphism on the pharmacokinetics (CYP2D6; catechol-O-methyltransferase, COMT) and pharmacological effects of MDMA (serotonin transporter, 5-HTT; COMT). This clinical study was designed to evaluate the pharmacokinetics and physiological and subjective effects of MDMA considering gender and the genetic polymorphisms of CYP2D6, COMT, and 5-HTT. A total of 27 (12 women) healthy, recreational users of ecstasy were included (all extensive metabolizers for CYP2D6). A single oral weight-adjusted dose of MDMA was administered (1.4 mg/kg, range 75–100 mg) which was similar to recreational doses. None of the women were taking oral contraceptives and the experimental session was performed during the early follicular phase of their menstrual cycle. Principal findings show that subjects reached similar MDMA plasma concentrations, and experienced similar positive effects, irrespective of gender or CYP2D6 (not taking into consideration poor or ultra-rapid metabolizers) or COMT genotypes. However, HMMA plasma concentrations were linked to CYP2D6 genotype (higher with two functional alleles). Female subjects displayed more intense physiological (heart rate, and oral temperature) and negative effects (dizziness, sedation, depression, and psychotic symptoms). Genotypes of COMT val158met or 5-HTTLPR with high functionality (val/val or l/*) determined greater cardiovascular effects, and with low functionality (met/* or s/s) negative subjective effects (dizziness, anxiety, sedation). In conclusion, the contribution of MDMA pharmacokinetics following 1.4 mg/kg MDMA to the gender differences observed in drug effects appears to be negligible or even null. In contrast, 5-HTTLPR and COMT val158met genotypes play a major role.
Trial Registration
ClinicalTrials.gov NCT01447472
doi:10.1371/journal.pone.0047599
PMCID: PMC3480420  PMID: 23112822
14.  Modafinil Abrogates Methamphetamine-Induced Neuroinflammation and Apoptotic Effects in the Mouse Striatum 
PLoS ONE  2012;7(10):e46599.
Methamphetamine is a drug of abuse that can cause neurotoxic damage in humans and animals. Modafinil, a wake-promoting compound approved for the treatment of sleeping disorders, is being prescribed off label for the treatment of methamphetamine dependence. The aim of the present study was to investigate if modafinil could counteract methamphetamine-induced neuroinflammatory processes, which occur in conjunction with degeneration of dopaminergic terminals in the mouse striatum. We evaluated the effect of a toxic methamphetamine binge in female C57BL/6 mice (4×5 mg/kg, i.p., 2 h apart) and modafinil co-administration (2×90 mg/kg, i.p., 1 h before the first and fourth methamphetamine injections) on glial cells (microglia and astroglia). We also evaluated the striatal expression of the pro-apoptotic BAX and anti-apoptotic Bcl-2 proteins, which are known to mediate methamphetamine-induced apoptotic effects. Modafinil by itself did not cause reactive gliosis and counteracted methamphetamine-induced microglial and astroglial activation. Modafinil also counteracted the decrease in tyrosine hydroxylase and dopamine transporter levels and prevented methamphetamine-induced increases in the pro-apoptotic BAX and decreases in the anti-apoptotic Bcl-2 protein expression. Our results indicate that modafinil can interfere with methamphetamine actions and provide protection against dopamine toxicity, cell death, and neuroinflammation in the mouse striatum.
doi:10.1371/journal.pone.0046599
PMCID: PMC3464292  PMID: 23056363
15.  Rhesus monkeys employ a procedural strategy to reduce working memory load in a self-ordered spatial search task 
Brain research  2011;1413C:43-50.
Several nonhuman primate species have been reported to employ a distance-minimizing, traveling salesman-like, strategy during foraging as well as in experimental spatial search tasks involving lesser amounts of locomotion. Spatial sequencing may optimize performance by reducing reference or episodic memory loads, locomotor costs, competition or other demands. A computerized self-ordered spatial search (SOSS) memory task has been adapted from a human neuropsychological testing battery (CANTAB, Cambridge Cognition, Ltd) for use in monkeys. Accurate completion of a trial requires sequential responses to colored boxes in two or more spatial locations without repetition of a previous location. Marmosets have been reported to employ a circling pattern of search, suggesting spontaneous adoption of a strategy to reduce working memory load. In this study the SOSS performance of rhesus monkeys was assessed to determine if the use of a distance-minimizing search path enhances accuracy. A novel strategy score, independent of the trial difficulty and arrangement of boxes, has been devised. Analysis of the performance of 21 monkeys trained on SOSS over two years shows that a distance-minimizing search strategy is associated with improved accuracy. This effect is observed within individuals as they improve over many cumulative sessions of training on the task and across individuals at any given level of training. Erroneous trials were associated with a failure to deploy the strategy. It is concluded that the effect of utilizing the strategy on this locomotion-free, laboratory task is to enhance accuracy by reducing demands on spatial working memory resources.
doi:10.1016/j.brainres.2011.07.048
PMCID: PMC3167000  PMID: 21840507
16.  Effect of Ambient Temperature on the Thermoregulatory and Locomotor Stimulant Effects of 4-Methylmethcathinone in Wistar and Sprague-Dawley Rats 
PLoS ONE  2012;7(8):e44652.
The drug 4-methylmethcathinone (4-MMC; aka, mephedrone, MMCAT, “plant food”, “bath salts”) is a recent addition to the list of popular recreational psychomotor-stimulant compounds. Relatively little information about this drug is available in the scientific literature, but popular media reports have driven recent drug control actions in the UK and several US States. Online user reports of subjective similarity to 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) prompted the current investigation of the thermoregulatory and locomotor effects of 4-MMC. Male Wistar and Sprague-Dawley rats were monitored after subcutaneous administration of 4-MMC (1–10 mg/kg ) using an implantable radiotelemetry system under conditions of low (23°C) and high (27°C) ambient temperature. A reliable reduction of body temperature was produced by 4-MMC in Wistar rats at 23°C or 27°C with only minimal effect in Sprague-Dawley rats. Increased locomotor activity was observed after 4-MMC administration in both strains with significantly more activity produced in the Sprague-Dawley strain. The 10 mg/kg s.c. dose evoked greater increase in extracellular serotonin, compared with dopamine, in the nucleus accumbens. Follow-up studies confirmed that the degree of locomotor stimulation produced by 10 mg/kg 4-MMC was nearly identical to that produced by 1 mg/kg d-methamphetamine in each strain. Furthermore, hypothermia produced by the serotonin 1A/7 receptor agonist 8-hydroxy-N,N-dipropyl-2-aminotetralin (8-OH-DPAT) was similar in each strain. These results show that the cathinone analog 4-MMC exhibits thermoregulatory and locomotor properties that are distinct from those established for methamphetamine or MDMA in prior work, despite recent evidence of neuropharmacological similarity with MDMA.
doi:10.1371/journal.pone.0044652
PMCID: PMC3432134  PMID: 22952999
17.  A Case-Control Study Estimating Accident Risk for Alcohol, Medicines and Illegal Drugs 
PLoS ONE  2012;7(8):e43496.
Background
The aim of the present study was to assess the risk of having a traffic accident after using alcohol, single drugs, or a combination, and to determine the concentrations at which this risk is significantly increased.
Methods
A population-based case-control study was carried out, collecting whole blood samples of both cases and controls, in which a number of drugs were detected. The risk of having an accident when under the influence of drugs was estimated using logistic regression adjusting for gender, age and time period of accident (cases)/sampling (controls). The main outcome measures were odds ratio (OR) for accident risk associated with single and multiple drug use. In total, 337 cases (negative: 176; positive: 161) and 2726 controls (negative: 2425; positive: 301) were included in the study.
Results
Main findings were that 1) alcohol in general (all the concentrations together) caused an elevated crash risk; 2) cannabis in general also caused an increase in accident risk; at a cut-off of 2 ng/mL THC the risk of having an accident was four times the risk associated with the lowest THC concentrations; 3) when ranking the adjusted OR from lowest to highest risk, alcohol alone or in combination with other drugs was related to a very elevated crash risk, with the highest risk for stimulants combined with sedatives.
Conclusion
The study demonstrated a concentration-dependent crash risk for THC positive drivers. Alcohol and alcohol-drug combinations are by far the most prevalent substances in drivers and subsequently pose the largest risk in traffic, both in terms of risk and scope.
doi:10.1371/journal.pone.0043496
PMCID: PMC3429508  PMID: 22952694
18.  A Comparison of Intraperitoneal and Subcutaneous Temperature in Freely Moving Rhesus Macaques 
Physiology & behavior  2011;103(5):440-444.
Rationale
The remote measurement of body temperature with radiotelemetry provides a minimally invasive and robust method for larger experimental animals such as Old World monkeys. Existing literature encompasses data using intraperitoneal (IP) and subcutaneous (SC) implantation locations which may affect inferences about body temperature.
Methods
The body temperature of four adult male rhesus monkeys was monitored with radiotelemetry devices implanted both IP and SC in each subject. Animals were recorded at 5 minute intervals for five months with the two transmitters being used in sequence on a weekly basis. Additional challenge with d-methamphetamine (0.32 mg/kg ; i.m.) was conducted to compare the magnitude of the hyperthermic response measured IP and SC.
Results
Normal daily temperatures differed by about 0.5–0.8°C across implant locations with IP temperature consistently higher. The difference was consistent across the circadian cycle and when compared 1, 3 or 5 months after surgical implantation. The magnitude of the hyperthermia response to methamphetamine was about 0.75°C when measured with either IP or SC implants.
Conclusions
The study shows that data derived from the two major implantation locations used in existing literature are likely to be comparable.
doi:10.1016/j.physbeh.2011.03.023
PMCID: PMC3107936  PMID: 21443893
Macaca mulatta; circadian; temperature; hyperthermia; hypothermia
19.  What Users Think about the Differences between Caffeine and Illicit/Prescription Stimulants for Cognitive Enhancement 
PLoS ONE  2012;7(6):e40047.
Pharmacological cognitive enhancement (CE) is a topic of increasing public awareness. In the scientific literature on student use of CE as a study aid for academic performance enhancement, there are high prevalence rates regarding the use of caffeinated substances (coffee, caffeinated drinks, caffeine tablets) but remarkably lower prevalence rates regarding the use of illicit/prescription stimulants such as amphetamines or methylphenidate. While the literature considers the reasons and mechanisms for these different prevalence rates from a theoretical standpoint, it lacks empirical data to account for healthy students who use both, caffeine and illicit/prescription stimulants, exclusively for the purpose of CE. Therefore, we extensively interviewed a sample of 18 healthy university students reporting non-medical use of caffeine as well as illicit/prescription stimulants for the purpose of CE in a face-to-face setting about their opinions regarding differences in general and morally-relevant differences between caffeine and stimulant use for CE. 44% of all participants answered that there is a general difference between the use of caffeine and illicit/prescription stimulants for CE, 28% did not differentiate, 28% could not decide. Furthermore, 39% stated that there is a moral difference, 56% answered that there is no moral difference and one participant was not able to comment on moral aspects. Participants came to their judgements by applying three dimensions: medical, ethical and legal. Weighing the medical, ethical and legal aspects corresponded to the students' individual preferences of substances used for CE. However, their views only partly depicted evidence-based medical aspects and the ethical issues involved. This result shows the need for well-directed and differentiated information to prevent the potentially harmful use of illicit or prescription stimulants for CE.
doi:10.1371/journal.pone.0040047
PMCID: PMC3386931  PMID: 22768218
20.  Cannabis-Dependence Risk Relates to Synergism between Neuroticism and Proenkephalin SNPs Associated with Amygdala Gene Expression: Case-Control Study 
PLoS ONE  2012;7(6):e39243.
Background
Many young people experiment with cannabis, yet only a subgroup progress to dependence suggesting individual differences that could relate to factors such as genetics and behavioral traits. Dopamine receptor D2 (DRD2) and proenkephalin (PENK) genes have been implicated in animal studies with cannabis exposure. Whether polymorphisms of these genes are associated with cannabis dependence and related behavioral traits is unknown.
Methodology/Principal Findings
Healthy young adults (18–27 years) with cannabis dependence and without a dependence diagnosis were studied (N = 50/group) in relation to a priori-determined single nucleotide polymorphisms (SNPs) of the DRD2 and PENK genes. Negative affect, Impulsive Risk Taking and Neuroticism-Anxiety temperamental traits, positive and negative reward-learning performance and stop-signal reaction times were examined. The findings replicated the known association between the rs6277 DRD2 SNP and decisions associated with negative reinforcement outcomes. Moreover, PENK variants (rs2576573 and rs2609997) significantly related to Neuroticism and cannabis dependence. Cigarette smoking is common in cannabis users, but it was not associated to PENK SNPs as also validated in another cohort (N = 247 smokers, N = 312 non-smokers). Neuroticism mediated (15.3%–19.5%) the genetic risk to cannabis dependence and interacted with risk SNPs, resulting in a 9-fold increase risk for cannabis dependence. Molecular characterization of the postmortem human brain in a different population revealed an association between PENK SNPs and PENK mRNA expression in the central amygdala nucleus emphasizing the functional relevance of the SNPs in a brain region strongly linked to negative affect.
Conclusions/Significance
Overall, the findings suggest an important role for Neuroticism as an endophenotype linking PENK polymorphisms to cannabis-dependence vulnerability synergistically amplifying the apparent genetic risk.
doi:10.1371/journal.pone.0039243
PMCID: PMC3382183  PMID: 22745721
21.  Task-Selective Memory Effects for Successfully Implemented Encoding Strategies 
PLoS ONE  2012;7(5):e38160.
Previous behavioral evidence suggests that instructed strategy use benefits associative memory formation in paired associate tasks. Two such effective encoding strategies–visual imagery and sentence generation–facilitate memory through the production of different types of mediators (e.g., mental images and sentences). Neuroimaging evidence suggests that regions of the brain support memory reflecting the mental operations engaged at the time of study. That work, however, has not taken into account self-reported encoding task success (i.e., whether participants successfully generated a mediator). It is unknown, therefore, whether task-selective memory effects specific to each strategy might be found when encoding strategies are successfully implemented. In this experiment, participants studied pairs of abstract nouns under either visual imagery or sentence generation encoding instructions. At the time of study, participants reported their success at generating a mediator. Outside of the scanner, participants further reported the quality of the generated mediator (e.g., images, sentences) for each word pair. We observed task-selective memory effects for visual imagery in the left middle occipital gyrus, the left precuneus, and the lingual gyrus. No such task-selective effects were observed for sentence generation. Intriguingly, activity at the time of study in the left precuneus was modulated by the self-reported quality (vividness) of the generated mental images with greater activity for trials given higher ratings of quality. These data suggest that regions of the brain support memory in accord with the encoding operations engaged at the time of study.
doi:10.1371/journal.pone.0038160
PMCID: PMC3364974  PMID: 22693593
22.  Chronic Alcohol Consumption Impairs Visuo-Spatial Associative Memory in Periadolescent Rhesus Monkeys 
Drug and alcohol dependence  2010;114(1):31-40.
Alcohol abuse in the adult is often preceded by high alcohol consumption during adolescence. Profound changes in brain structure and function occur during this developmental period, therefore alcohol may impact essential cognitive skill development during the formal educational years. The objective of this study was to determine if chronic oral alcohol intake slows acquisition and performance of cognitive tasks in male adolescent rhesus monkeys. Treatment groups (Alcohol, N=4; Control, N=3) were evaluated on bimanual dexterity and tests of visuo-spatial memory and learning adapted from the Cambridge Neuropsychological Test Automated Battery. Animals were trained daily in 30 min sessions and had subsequent access to alcohol/Tang® solutions (Alcohol group) or Tang® only (Control group) Monday through Friday for 11 months. Recordings of brainstem auditory evoked potentials (BSAEP) were conducted periodically before and during the chronic drinking.
Results
Chronic alcohol drinking (ave of 1.78g/kg alcohol per session) impaired behavioral performance assessed ~22 hrs after the prior drinking session. The Alcohol group required more trials than the Control group to reach criterion on the visuo-spatial memory task and showed increased sensitivity to trial difficulty and retention interval. Alcohol animals also had slowed initial acquisition of the bimanual task. The latency of P4 and P5 BSAEP peaks were also delayed in the Alcohol group. Chronic alcohol consumption impaired the acquisition and performance of a spatial memory task and disrupted brainstem auditory processing, thus these results show that repeated alcohol exposure in adolescence interferes with a range of brain functions including complex visuo-spatial mnemonic processing.
doi:10.1016/j.drugalcdep.2010.09.002
PMCID: PMC3024459  PMID: 20951512
Cognition; brain functioning; CANTAB; adolescence; executive function; Rhesus Macaque
23.  Chronic alcohol consumption generates a vulnerable immune environment during early SIV infection in rhesus macaques 
Background
Alcohol consumption is a common problem in HIV-infected individuals, and the effects of alcohol may alter the efficiency of the immune response, potentially aggravating the disease as well as affecting end organs, such as the brain. However, the elements of the virus-host interaction that are modulated by ethanol are poorly dissected.
Methods
Ethanol intake was conditioned in rhesus macaques prior to SIV infection, in order to mimic this common human behavior, and allow the evaluation of aspects of the virus-immune system interactions during acute time-points, when important facets of the infection are set up and when virus reproducibly enters the brain.
Results
Although ethanol had a limited effect on the acute plasma viral load, it resulted in reduced circulating memory CD4+ T cells and increased levels of monocytes expressing the viral coreceptor CCR5. In organs, ethanol consumption impacted immune cells in the liver as well as lymphoid and other nonlymphoid tissues, where CD4+ T cells were predominantly affected.
Conclusion
Overall, the consumption of alcohol causes immune cell alterations that can contribute to the generation of a disease susceptible environment upon SIV infection.
doi:10.1111/j.1530-0277.2008.00730.x
PMCID: PMC2579901  PMID: 18616669
24.  Robust and Stable Drinking Behavior Following Long-Term Oral Alcohol Intake In Rhesus Macaques 
Drug and alcohol dependence  2007;91(2-3):236-243.
Face validity in animal models of alcohol abuse and dependence is often at odds with robust demonstrations of ethanol-seeking. This study determined the relative influence of ethanol and a flavorant in maintaining ethanol intake in a nonhuman primate model of “cocktail” drinking. Four year old male monkeys were maintained on a 6% ethanol/6% Tang® solution made available in daily (M-F) 1-hr sessions. Experiments determined the effect of: 1) a second daily access session, 2) concurrent presentation of the Tang® vehicle, 3) sequential presentation of the vehicle in the first daily session and the ethanol solution in the second session, 4) altering the Tang® concentration, 5) altering the ethanol concentration, and 6) removal of the flavorant. Mean daily intake (2.7 ± 0.2 g/kg/day) was stable over 7 months. Simultaneous availability of a large, but not a low-moderate, volume of the vehicle reduced ethanol intake by about 50%. Decreasing the concentration of Tang® in the first daily session reduced ethanol intake whereas intake of the standard solution was increased in the second session. Ethanol consumption was decreased by only 27% when the flavorant was removed. In summary, alterations that reduced intake in the first daily session resulted in compensatory increases in ethanol intake in the second session suggesting that animals sought a specific level of ethanol intake per day. It is concluded that models with excellent face validity (flavored beverages) can produce reliable ethanol intake in patterns that are highly consistent with ethanol-seeking behavior.
doi:10.1016/j.drugalcdep.2007.06.002
PMCID: PMC2231844  PMID: 17628350
alcohol; ethanol; nonhuman primate; rhesus macaque; self-administration
25.  Oral Administration of (±)3,4-Methylenedioxymethamphetamine and (+)Methamphetamine Alters Temperature and Activity in Rhesus Macaques 
Rationale
Emergency Department visits and fatalities in which (±)3,4-methylenedioxymethamphetamine (MDMA) or (+)methamphetamine (METH) are involved frequently feature unregulated hyperthermia. MDMA and METH significantly elevate body temperature in multiple laboratory species and, most importantly, can also produce unregulated and threatening hyperthermia in nonhuman primates. A majority of prior animal studies have administered drugs by injection whereas human consumption of “Ecstasy“ is typically oral, an important difference in route of administration which may complicate the translation of animal data to the human condition.
Objective
To determine if MDMA and METH produce hyperthermia in monkeys following oral administration as they do when administered intramuscularly.
Methods
Adult male rhesus monkeys were challenged intramuscularly (i.m.) and per os (p.o.) with 1.78 or 5 mg/kg (±)MDMA and with 0.1 or 0.32 mg/kg (+)METH. Temperature and activity were monitored with a radiotelemetry system.
Results
Oral administration of either MDMA or METH produced significant increases in body temperature. Locomotor activity was suppressed by MDMA and increased by METH following either route or administration.
Conclusions
The data show that the oral route of administration is not likely to qualitatively reduce the temperature increase associated with MDMA or METH although oral administration did slow the rate of temperature increase. It is further established that MDMA reduces activity in monkeys even after relatively high doses and oral administration.
doi:10.1016/j.pbb.2007.03.015
PMCID: PMC1975960  PMID: 17475314
Ecstasy; neurotoxicity; Macaca mulatta; circadian; thermoregulation; serotonin; amphetamine

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