Acute alcohol exposure produces cognitive deficits in adults but less is known about the acute cognitive effects of alcohol in adolescents. The cognitive impact of acute alcohol exposure includes deficits in discrimination and reversal learning, but traditional experimental approaches make it difficult to distinguish the effect of alcohol on discrimination learning from the effect of alcohol on reversal learning. Young rhesus macaques can be used to model some aspects of human adolescence because of their anatomical, neurophysiological and cognitive similarities with humans.
Adolescent male rhesus monkeys (N=10) were trained to respond to visual stimuli on touch-sensitive LCD panels controlled by the nonhuman primate version of CANTAB software. Discrimination and reversal learning tasks were subsequently assessed after monkeys were allowed to consume varying amounts of ethanol in a flavored vehicle (vehicle only, up to 0.5 g/kg ethanol, up to 1.0 g/kg ethanol and up to 1.5 g/kg ethanol).
Acute exposure to ethanol reduced perseverance, increased response accuracy, and reduced errors during reversal learning when the task was completed within 90 minutes of ethanol consumption. No reduction in reversal errors was observed when ethanol was consumed 3 or 24 hrs prior to reversal learning. Ethanol only impaired discrimination learning when monkeys had very little previous ethanol exposure.
The temporal relationship between ethanol consumption and reversal learning was consistent with selective ethanol-induced impairment of retrieval, but not storage, processes. This was evidenced by diminished perseverance on the previously correct stimulus leading to decreased errors to criterion.
ethanol; monkey; reversal learning; perseverance
BACKGROUND AND PURPOSE
Recent human studies suggest that recreational cannabis strains that are relatively high in cannabidiol (CBD) content produce less cognitive impairment than do strains with negligible CBD and similar Δ9tetrahydrocannabinol (THC) content. Self-selection in such studies means it is impossible to rule out additional variables which may determine both cannabis strain selection and basal cognitive performance level. Controlled laboratory studies can better determine a direct relationship.
In this study, adult male rhesus monkeys were assessed on visuospatial Paired Associates Learning and Self-Ordered Spatial Search memory tasks, as well as additional tests of motivation and manual dexterity. Subjects were challenged with THC (0.2, 0.5 mg·kg−1, i.m.) in randomized order and evaluated in the presence or absence of 0.5 mg·kg−1 CBD.
CBD attenuated the effects of THC on paired associates learning and a bimanual motor task without affecting the detrimental effects of THC on a Self-Ordered Spatial Search task of working memory. CBD did not significantly reverse THC-induced impairment of a progressive ratio or a rotating turntable task.
CONCLUSIONS AND IMPLICATIONS
This study provides direct evidence that CBD can oppose the cognitive-impairing effects of THC and that it does so in a task-selective manner when administered simultaneously in a 1:1 ratio with THC. The addition of CBD to THC-containing therapeutic products may therefore help to ameliorate unwanted cognitive side-effects.
This article is commented on by Mechoulam and Parker, pp 1363–1364 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12400
cannabis; marijuana; Macaca mulatta; working memory
Available evidence suggests that recreational use and abuse of the dissociative anaesthetic ketamine is increasing. Characterization of the cognitive risks of ketamine exposure contributes substantially to understanding this growing public health threat. Although prior human studies demonstrate that ketamine impairs a range of cognitive skills, investigation in nonhuman models permits more precise exploration of neurochemical mechanisms which may underlie detrimental behavioral effects. Adult male rhesus monkeys (7) were trained on a neuropsychological battery including tests of memory (delayed match-to-sample, DMS; self-ordered spatial search, SOSS), reaction time (RT), reinforcer efficacy and sustained attention (progressive ratio, PR) and fine motor coordination (bimanual motor skill, BMS). Battery performance was then serially challenged with acute doses of ketamine (0.3, 1.0, 1.78 mg/kg IM). Ketamine impaired DMS and SOSS in a dose × difficulty dependent manner with the most difficult task conditions disrupted at the 1.0 and 1.78 mg/kg doses. Thus, both visual recognition memory and working memory indices were affected. Ketamine also slowed RT and BMS performance and interfered with PR performance at the 1.78 mg/kg dose. Overall the present findings confirm that ketamine interferes with multiple aspects of cognition at subanesthetic doses in monkeys.
MEMORY; NMDA; CANTAB; CLUB DRUG
Analysis of the distribution of reaction times (RTs) in behavioral tasks can illustrate differences attributable to changes in attention, even when no change in mean RT is observed. Detrimental attentional effects of both acute and chronic exposure to alcohol may therefore be revealed by fitting RT data to an ex-Gaussian probability density function which identifies the proportion of long-RT responses.
Adolescent male rhesus macaques completed a 5-choice serial reaction time task (5CSRT) after acute alcohol consumption (up to 0.0, 1.0 and 1.5 g/kg). Monkeys were next divided into chronic alcohol (N=5) and control groups (N=5); the experimental group consumed 1.5–3.0 g/kg alcohol for 200 drinking sessions. Unintoxicated performance in the 5CSRT task was determined systematically across the study period and the effect of acute alcohol was redetermined after the 180th drinking session. The effect of extended abstinence from chronic alcohol was determined across 90 days.
Acute alcohol exposure dose-dependently reduced the probability of longer RT responses without changing the mean or the standard deviation of the RT distribution. The RT distribution of control monkeys tightened across 10 months whereas that of the chronic alcohol group was unchanged. Discontinuation from chronic alcohol increased the probability of long RT responses with a difference from control animals observed after 30 days of discontinuation.
Alcohol consumption selectively affected attention as reflected in the probability of long RT responses. Acute alcohol consumption focused attention, chronic alcohol consumption impaired the maturation of attention across the study period and alcohol discontinuation impaired attention.
Early, accurate detection of degenerative neurological disorders such as Alzheimer's Disease (AD) is essential for therapies designed to slow disease progression. Performance of a touch-screen mediated visuo-spatial paired-associates learning (vsPAL) task predicts neurocognitive decline in elderly populations presenting with mild cognitive impairment and distinguishes AD patients from elderly depressed individuals. Translation of this cognitive task to a nonhuman model may therefore provide an improved tool for study of the etiology and treatment of dementia.
The goal of the current study was to contrast cholinergic and glutamatergic contributions to performance of this AD-sensitive task by challenging rhesus monkeys performing vsPAL with muscarinic antagonist and non-competitive NMDA antagonist drugs.
Monkeys (7) were trained to perform vsPAL and then serially challenged with acute doses of scopolamine (3, 10, 17 µg/kg, i.m.) and ketamine (0.3, 1.0, 1.78 mg/kg, i.m.).
Scopolamine produced a dose × difficulty related impairment of both recognition memory and incremental acquisition aspects of task performance. In contrast, ketamine administration resulted in a dose-dependent impairment of recognition memory but not incremental acquisition.
Monkeys' performance of a task sensitive to AD in humans was impaired by two classic pharmacological models of cognitive impairment therefore supporting the use of this nonhuman model to explore mechanisms of AD-associated cognitive decline. The differential pattern of impairment observed is consistent with a hypothesis that muscarinic mechanisms are required for linking external events with an existing internal representation, whereas NMDA mechanisms are required for the formation/strengthening of such an internal representation.
Learning; Memory; Scopolamine; Ketamine; CANTAB; Alzheimer's Disease
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.
cannabis; marijuana; Macaca mulatta; extradimensional shift; reversal learning
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.
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).
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.
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.
cathinones; stimulants; activity wheel; Ecstasy; bath salts
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.
cannabis; marijuana; Macaca mulatta; memory
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.
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.
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.
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.
Ecstasy; hypothermia; endocannabinoid; thermoregulation; nonhuman primate; radiotelemetry
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.
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.
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.
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.
The study shows that data derived from the two major implantation locations used in existing literature are likely to be comparable.
Macaca mulatta; circadian; temperature; hyperthermia; hypothermia
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.
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.
Cognition; brain functioning; CANTAB; adolescence; executive function; Rhesus Macaque
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.
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.
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.
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.
alcohol; ethanol; nonhuman primate; rhesus macaque; self-administration
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.
To determine if MDMA and METH produce hyperthermia in monkeys following oral administration as they do when administered intramuscularly.
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.
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.
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.
Ecstasy; neurotoxicity; Macaca mulatta; circadian; thermoregulation; serotonin; amphetamine
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.
MDMA; drug abuse; neurotoxicity; Macaca mulatta; circadian; thermoregulation; serotonin; amphetamine
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.
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.
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.
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.
MDMA; Macaca mulatta; circadian; thermoregulation; serotonin
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.
The current study was conducted to determine the role nAChRs play in multiple types of memory in monkeys.
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).
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.
Although nicotine may improve performance in multiple domains, effects on visuo-spatial associative memory is the most specifically attributable to nAChR signaling.
Attention; Memory; Cholinergic; CANTAB; Alzheimer's Disease; Parkinson's Disease; Primate; Nicotinic
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.
To delineate the role dopaminergic D1-like and D2-like receptor subtypes play in complex brain functions.
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.
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.
The intriguing results suggest a greater contribution of D2-like over D1-like receptors to both spatial working memory and object-location associative memory.
Alzheimer’s Disease; Parkinson’s Disease; Substance Abuse; Working Memory; ADHD; Motor Function; Aging
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.
(±)MDMA; Macaca mulatta; circadian; thermoregulation; serotonin
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.