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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Severe and malignant hyperthermia is a frequently reported factor in Emergency Department (ED) visits and fatalities in which use of amphetamine drugs, such as (±)3,4-methylenedioxymethamphetamine (MDMA), (±)3,4-methylenedioxyamphetamine (MDA) and (+)methamphetamine (METH), is confirmed. Individuals who use “Ecstasy“ are also often exposed, intentionally or otherwise, to several of these structurally-related compounds alone or in combination. In animal studies the degree of (subcritical) hyperthermia is often related to the severity of amphetamine-induced neurotoxicity, suggesting health risks to the human user even when emergency medical services are not invoked. A clear distinction of thermoregulatory risks posed by different amphetamines is therefore critical to understand factors that may produce medical emergency related to hyperthermia. The objective of this study was therefore to determine the relative thermoregulatory disruption produced by recreational doses of MDMA, MDA and METH in nonhuman primates. Body temperature and spontaneous home cage activity were monitored continuously in six male rhesus monkeys via radiotelemetric devices. The subjects were challenged intramuscularly with 0.56–2.4 mg/kg MDMA, 0.56–2.4 mg/kg MDA and 0.1–1.0 mg/kg METH. All three amphetamines significantly elevated temperature; however the timecourse of effects differed. The acute effect of METH lasted hours longer than MDA or MDMA and a disruption of nighttime circadian cooling was observed as long as 18 hours after 1.0 mg/kg METH and 1.78–2.4 mg/kg MDA, but not after MDMA. Activity levels were only reliably increased by 0.32 mg/kg METH. It is concluded that while all three substituted amphetamines produce hyperthermia in rhesus monkeys, the effects do not depend on elevated locomotor activity and exhibit differences between compounds. The results highlight physiological risks posed both by recreational use of the amphetamines and by current trials for clinical MDMA use.

Background

Exposure to (±)3,4-methylenedioxymethamphetamine ((±)MDMA) results in lasting reductions of many markers for serotonin terminals in a range of species. In rodents, the severity of insult depends in large part on the generation of hyperthermia in the subject. (±)MDMA can produce either hyperthermia or hypothermia in rodents depending on the ambient temperature and these effects may be limited to the S(+) enantiomer. Limited prior evidence suggests (±)MDMA does not produce hyperthermia in chair-restrained monkeys [Bowyer et al., 2003, Neurotoxicology 24(3):379–390]. This study was therefore conducted to determine if racemic MDMA and its enantiomers induce hyperthermia and increase spontaneous locomotor activity in unrestrained rhesus monkeys.

Methods

Body temperature and spontaneous home cage activity were monitored continuously in four monkeys via radiotelemetric devices. The subjects were challenged with 1.7 mg/kg, i.m., (±)MDMA, S(+)MDMA and R(−)MDMA in pseudorandomized order.

Results

Maximum and average temperature in the four hour interval post-dosing was elevated 0.7–0.9°C by (±)MDMA and each enantiomer. Reductions in locomotor activity following dosing did not reliably differ from vehicle effects.

Conclusions

MDMA produces an acute hyperthermia in unrestrained rhesus monkeys, much as it does with rats, mice, pigs, rabbits and humans. Hyperthermia occurs despite no increase in locomotor activity thus the effect does not depend on motor activation. Each enantiomer appears to be equivalently active thus primates may differ from rodents in thermoregulatory sensitivity to the R(−) enantiomer. Significant differences in outcome between this and a prior study in monkeys indicate a need for additional study of the thermoregulatory impact of MDMA in nonhuman primates.

Rationale

Nicotine and other agonists of nicotinic cholinergic receptors (nAChR) have been shown to improve performance in specific memory domains in rodents and monkeys. Such beneficial effects are observed in preclinical models of age-related cognitive decline, stimulating interest in nAChR ligands as possible therapeutics. Prior work has typically focused on assays of spatial working memory in rodent studies and visual recognition memory in monkey studies.

Objective

The current study was conducted to determine the role nAChRs play in multiple types of memory in monkeys.

Methods

Rhesus monkeys (N = 6) were trained to perform a battery of 6 behavioral tasks and then serially challenged with acute doses of nicotine (3.2–56 μg/kg, i.m.) and the nAChR antagonist mecamylamine (0.32–1.78 mg/kg, i.m).

Results

Nicotine improved performance on tests designed to assay visual recognition memory, spatial working memory and visuo-spatial associative memory while mecamylamine impaired visuo-spatial associative memory. Ballistic and fine motor performance was not significantly improved by nicotine but fine motor performance was impaired by mecamylamine.

Conclusions

Although nicotine may improve performance in multiple domains, effects on visuo-spatial associative memory is the most specifically attributable to nAChR signaling.

Rationale

Dopaminergic neurotransmission is critically involved in many aspects of complex behavior and cognition beyond reward/reinforcement and motor function. Mental and behavioral disorders associated with major disruptions of dopamine neurotransmission, including schizophrenia, Attention Deficit/Hyperactivity Disorder, Parkinson’s Disease, Huntington’s Disease and substance abuse, produce constellations of neuropsychological deficits in learning, memory and attention in addition to other defining symptoms.

Objective

To delineate the role dopaminergic D1-like and D2-like receptor subtypes play in complex brain functions.

Methods

Monkeys (N=6) were trained on cognitive tests adapted from a human neuropsychological assessment battery (CANTAB; CAmbridge Neuropsychological Test Automated Battery). The battery included tests of spatial working memory (self-ordered spatial search task, SOSS), visuo-spatial associative memory and learning (visuo-spatial paired associates learning task, vsPAL) and motivation (progressive ratio task, PR). Tests of motor function (bimanual motor skill task, BMS; rotating turntable task, RTT) were also included. Effects of the dopamine D2-like antagonist raclopride (10-56 μg/kg, i.m.) and the D1-like antagonist SCH23390 (SCH; 3.2-56 μg/kg, i.m.) on cognitive performance were then determined.

Results

Deficits on PR, RTT and BMS performance were observed after both raclopride and SCH23390. Spatial working memory accuracy was reduced to a greater extent by raclopride than by SCH which was unexpected, given prior reports on the involvement of D1 signaling for spatial working memory in monkeys. Deficits were observed on vsPAL performance after raclopride, but not after SCH23390.

Conclusions

The intriguing results suggest a greater contribution of D2-like over D1-like receptors to both spatial working memory and object-location associative memory.

The ambient temperature (TA) under which rodents are exposed to (±)3,4-methylenedioxymethamphetamine (MDMA) affects the direction and magnitude of the body temperature response, and the degree of hypo/hyperthermia generated in subjects can modify the severity of lasting brain changes in “neurotoxicity” models. The thermoregulatory effects of MDMA have not been well described in nonhuman primates and it is unknown if TA has the potential to affect acute hyperthermia and therefore other lasting consequences of MDMA. The objective of this study was to determine if the temperature alteration produced by MDMA in nonhuman primates depends on TA as it does in rats and mice. Body temperature and spontaneous home cage activity were monitored continuously in six male rhesus monkeys via radiotelemetry. The subjects were challenged intramuscularly with 0.56-2.4 mg/kg (±)MDMA under each of three TA conditions (18°C, 24°C, 30°C) in a randomized order. Temperature was significantly elevated following injection with all doses of MDMA under each ambient temperature. The magnitude of mean temperature change was ~1°C in most conditions suggesting a closely controlled thermoregulatory response in monkeys across a range of doses and ambient temperatures. Activity levels were generally suppressed by MDMA, however a 50% increase over vehicle was observed after 0.56 MDMA under the 30°C condition. It is concluded that MDMA produces very a similar degree of hyperthermia in rhesus monkeys across a range of TA conditions which result in hypothermia or exaggerated hyperthermia in rodents. Monkey temperature responses to MDMA appear to be more similar to humans than to rodents and therefore the monkey may offer an improved model of effects related to MDMA-induced hyperthermia.

The human immunodeficiency virus type 1-associated cognitive-motor disorder, including the AIDS dementia complex, is characterized by brain functional abnormalities that are associated with injury initiated by viral infection of the brain. Indoleamine 2,3-dioxygenase (IDO), the first and rate-limiting enzyme in tryptophan catabolism in extrahepatic tissues, can lead to neurotoxicity through the generation of quinolinic acid and immunosuppression and can alter brain chemistry via depletion of tryptophan. Using the simian immunodeficiency virus (SIV)-infected rhesus macaque model of AIDS, we demonstrate that cells of the macrophage lineage are the main source for expression of IDO in the SIV-infected monkey brain. Animals with SIV encephalitis have the highest levels of IDO mRNA, and the level of IDO correlates with gamma interferon (IFN-γ) and viral load levels. In vitro studies on mouse microglia reveal that IFN-γ is the primary inducer of IDO expression. These findings demonstrate the link between IDO expression, IFN-γ levels, and brain pathology signs observed in neuro-AIDS.