Brian J. Piper

Apolipoprotein E4 and sex affect neurobehavioral performance in primary school children

Apolipoprotein E4 (apoE4) and female sex are risk factors for developing Alzheimers disease. It is unclear whether apoE4 contributes to behavioral function at younger ages. Standard neuropsychological assessments [intelligence quotient (IQ), attention, and executive function] and a test developed in this laboratory (Memory Island test of spatial learning and memory) were used to determine whether E4 and sex affect neuropsychological performance in healthy primary school children (age 7–10). A medical history was also obtained from the mother to determine whether negative birth outcomes were associated with apoE4. Mothers of apoE4+ children were more likely to report that their newborn was placed in an intensive care unit. A sex difference in birth weight was noted among apoE4− (males > females), but not apoE4+, offspring. Conversely, among apoE4+, but not apoE4− children, there was a sex difference in the Wechsler Abbreviated Scale of Intelligence (WASI) vocabulary score favoring boys. ApoE4− girls had better visual recall than apoE4+ girls or apoE4− boys on the Family Pictures test. Finally, apoE4+, unlike apoE4−, children did not show spatial memory retention during the Memory Island probe trial. Thus, apoE4 may affect neurobehavioral performance, particularly spatial memory, and antenatal health decades before any clinical expression of neurodegenerative processes.

Repeated Adolescent 3,4-Methylenedioxymethamphetamine (MDMA) Exposure in Rats Attenuates the Effects of a Subsequent Challenge with MDMA or a 5-Hydroxytryptamine 1A Receptor Agonist

Adolescent users of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) may escalate their dose because of the development of tolerance. We examined the influence of intermittent adolescent MDMA exposure on the behavioral, physiological, and neurochemical responses to a subsequent MDMA “binge” or to a 5-hydroxytryptamine1A (5-HT1A) receptor challenge. Male Sprague-Dawley rats were given MDMA (10 mg/kg b.i.d.) or saline every 5th day on postnatal days (PDs) 35 to 60. One week later on PD 67, animals were challenged with either multiple doses of MDMA (four 5 or 10 mg/kg doses) or a single dose of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (0.1 or 0.5 mg/kg). Adolescent MDMA exposure partially attenuated the hyperthermic effects of the PD 67 MDMA challenge, completely blocked the locomotor hypoactivity otherwise observed on the day after the challenge, and also prevented MDMA-induced serotonin neurotoxicity assessed on PD 74 by measuring regional [3H]citalopram binding to the serotonin transporter (SERT). Adolescent MDMA-treated animals also showed a partial attenuation of the serotonin syndrome but not the hypothermic response to the high dose of 8-OH-DPAT. However, there was no effect of MDMA administration on regional [3H]N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY-100635) binding to 5-HT1A receptors in the brain or spinal cord. These results suggest that chronic, intermittent MDMA exposure during adolescence induces neuroadaptive changes that can protect against the adverse consequences of a subsequent dose escalation. On the other hand, the same exposure pattern appears to produce a partial 5-HT1A receptor desensitization, which may negatively influence the therapeutic responses of chronic MDMA users treated with serotonergic agents for various affective or anxiety disorders.

Development and Characterization of a Novel Animal Model of Intermittent MDMA (“Ecstasy”) Exposure during Adolescence

Adult animals treated with high doses of MDMA (“ecstasy”) either on a single day or for several consecutive days show numerous behavioral changes as well as persistent reductions in brain serotonin (5‐HT) concentrations and 5‐HT transporter (SERT) protein expression. However, such dosing regimens do not adequately mimic the intermittent use patterns commonly seen in adolescent recreational ecstasy users. We have developed and characterized a rat model of intermittent adolescent MDMA exposure that simulates many of the features of human weekend use. Animals treated with our dosing regimen experience only small increases in core body temperature, and their plasma MDMA levels compare favorably with the levels reported for heavy ecstasy users under naturalistic conditions when species differences in drug clearance rates are taken into account. Intermittent adolescent MDMA exposure causes later deficits in object‐recognition memory, increased impulsivity in the elevated plus‐maze, and reduced sensitivity to a 5‐HT1A agonist challenge. SERT‐immunoreactive fiber density is significantly reduced in the hippocampus but not the neocortex, suggesting that the hippocampus may be particularly vulnerable to moderate MDMA exposure during adolescence. Finally, adolescent MDMA‐treated animals are protected (i.e., show tolerance) against the neurotoxic and depressant effects of a subsequent MDMA “binge” challenge. We believe that the present animal model has important clinical relevance based on the similarities between the model and the reported effects of regular ecstasy use.

Neural Effects of MDMA as Determined by Functional Magnetic Resonance Imaging and Magnetic Resonance Spectroscopy in Awake Marmoset Monkeys

Abstract:  We used functional magnetic resonance imaging (fMRI) to investigate the acute effects of a recreational dose (1 mg/kg p.o.) of 3,4‐methylenedioxymethamphetamine (MDMA) on regional brain activity in awake, restrained marmoset monkeys. In a second study, magnetic resonance spectroscopy (MRS) and postmortem measurements of serotonin transporter (SERT) binding and serotonin (5‐HT) concentrations were used to determine the neurotoxic effects of low (4 × 1 mg/kg p.o.) and high (4 × 10 mg/kg i.m.) doses of MDMA. Several brain areas were significantly activated by the low oral dose of MDMA, including the midbrain raphe nuclei, hippocampus, hypothalamus, amygdala, and the corticostriatal circuit composed of the dorsal thalamus, sensory motor cortex, and basal ganglia. MDMA activated the primary visual cortex under baseline conditions and also enhanced the visual cortical response to photic stimulation. The onset of brain activation correlated well with the rise in plasma MDMA concentrations measured in separate monkeys given the same drug treatment. In the second study, the ratio of N‐acetylaspartate (NAA; a putative neuronal marker) to creatine was significantly reduced in the hypothalamus following either MDMA treatment regimen, suggesting a particular vulnerability of this structure to MDMA‐induced damage. Monkeys given the high‐dose regimen also showed prolonged hyperthermia and reductions in 5‐HT and SERT in a number of brain areas. These results are the first to identify the pattern of MDMA‐induced brain activation in a nonhuman primate model, and they further suggest that even recreational doses of MDMA may have adverse consequences as indicated by the reduced hypothalamic NAA/creatine ratio.

Dissociation of the Neurochemical and Behavioral Toxicology of MDMA ('Ecstasy') by Citalopram

High or repeated doses of the recreational drug 3,4-methylenedioxymethamphetamine (MDMA, or ‘Ecstasy’) produce long-lasting deficits in several markers of serotonin (5-HT) system integrity and also alter behavioral function. However, it is not yet clear whether MDMA-induced serotonergic neurotoxicity is responsible for these behavioral changes or whether other mechanisms are involved. The present experiment tested the hypothesis that blocking serotonergic neurotoxicity by pretreatment with the selective 5-HT reuptake inhibitor citalopram will also prevent the behavioral and physiological consequences of an MDMA binge administration. Male, Sprague–Dawley rats (N=67) received MDMA (4 × 10 mg/kg) with or without citalopram (10 mg/kg) pretreatment. Core temperature, ejaculatory response, and body weight were monitored during and immediately following drug treatments. A battery of tests assessing motor, cognitive, exploratory, anxiety, and social behaviors was completed during a 10-week period following MDMA administration. Brain tissue was collected at 1 and 10 weeks after drug treatments for measurement of regional 5-HT transporter binding and (for the 1-week samples) 5-HT and 5-HIAA concentrations. Citalopram pretreatment blocked MDMA-related reductions in aggressive and exploratory behavior measured in the social interaction and hole-board tests respectively. Such pretreatment also had the expected protective effect against MDMA-induced 5-HT neurotoxicity at 1 week following the binge. In contrast, citalopram did not prevent most of the acute effects of MDMA (eg hyperthermia and weight loss), nor did it block the decreased motor activity seen in the binge-treated animals 1 day after dosing. These results suggest that some of the behavioral and physiological consequences of a high-dose MDMA regimen in rats are mediated by mechanisms other than the drugs effects on the serotonergic system. Elucidation of these mechanisms requires further study of the influence of MDMA on other neurotransmitter systems.

Executive function profile in the offspring of women that smoked during pregnancy.

INTRODUCTION Smoking tobacco during pregnancy results in exposure to the fetal neuroteratogen nicotine. The current study evaluated if the offspring of smokers show abnormalities in maternal ratings of executive function, prevalence of Attention Deficit Hyperactivity Disorder (ADHD), and academic performance. A secondary objective was to determine the utility of online data collection. METHODS Mothers (N = 357) completed the parent form of the Behavioral Rating Inventory of Executive Function (BRIEF) and provided information about smoking during pregnancy. RESULTS The internal consistency of the BRIEF when administered electronically was quite satisfactory (Cronbachs α = .98). As anticipated, ADHD was more frequently diagnosed in the offspring of women that smoked at least 10 cigarettes/day (odds ratio [OR] = 2.64, 95% CI = 1.22-5.71). Higher (i.e., more problematic) ratings relative to unexposed children (p < .01) were only identified on the total BRIEF score, the Metacognition Index, and on the Initiate, Plan/Organize, and Monitor scales among children exposed to ≥10 cigarettes/day. Nicotine-exposed children were also more likely to perform less well than their classmates in math (OR = 2.78, 95% CI = 1.59-4.87) and reading (OR = 2.00, 95% CI = 1.10-3.63), and these academic effects were independent of maternal education levels. CONCLUSIONS This report provides preliminary evidence that the BRIEF has adequate psychometric properties when administered electronically and that mothers who smoke have offspring with lower executive function proficiency. These findings contribute to a larger literature that indicates that smoking during pregnancy results in adverse reproductive outcomes and, possibly, subtle but enduring deficits in prefrontal function.

Age, sex, and handedness differentially contribute to neurospatial function on the Memory Island and Novel-Image Novel-Location tests.

Memory Island and the Novel-Image Novel-Location are recently developed measures of spatial learning and recognition-memory modeled after the Morris water maze and the novel object-recognition tests. The goal of this study was to characterize how sex, age, and handedness contribute to Memory Island and Novel-Image Novel-Location performance. Volunteers (N=287, ages 6 to 67) from a local science museum completed four Memory Island trials containing a visible target and four trials containing a hidden target. A pronounced sex difference favoring males was noted in all measures of hidden trial performance. The total latency during the hidden trials among older-adults was longer than younger-adults or adolescents. Faster and more efficient performance by males was also identified during the visible trials, particularly among children. Adolescents and younger-adults outperformed children and older ages. Sinistrals had a lower cumulative distance to the target. Novel-Image Novel-Location behavior was examined in a separate sample (N=128, ages 6 to 86). Females had higher Novel-Image and Novel-Location scores than males. Novel-Image performance was independent of age while sinistrals had elevated Novel-Image scores relative to dextrals. Together, these findings identify how sex, age, and handedness uniquely contribute to performance on these tasks.

Age, handedness, and sex contribute to fine motor behavior in children

The original rotor pursuit test requires that the subject attempts to keep a metal stylus in contact with a small metal disk that was placed in the surface of a turntable that rotated at a constant speed. The present study evaluated the Psychology Experiment Building Language (PEBL) pursuit rotor task. Children (N=427, ages 9-13, 44.4% females) completed a handedness inventory followed by four pursuit rotor trials with each hand. The total time on target increased with age with the dominant as well as non-dominant hands. A small, but significant, sex difference favoring males was also observed. Dextrals spent more time on target than sinistrals with their dominant hand but the reverse pattern was observed for the non-dominant hand. These group differences were independent of prior computer experience. These findings indicate that the freely downloadable PEBL pursuit rotor task is a useful measure of psychomotor function (http://pebl.sf.net) in children and adolescents.

Substitution of medical cannabis for pharmaceutical agents for pain, anxiety, and sleep:

A prior epidemiological study identified a reduction in opioid overdose deaths in US states that legalized medical cannabis (MC). One theory to explain this phenomenon is a potential substitution effect of MC for opioids. This study evaluated whether this substitution effect of MC for opioids also applies to other psychoactive medications. New England dispensary members (n = 1,513) completed an online survey about their medical history and MC experiences. Among respondents that regularly used opioids, over three-quarters (76.7%) indicated that they reduced their use since they started MC. This was significantly (p < 0.0001) greater than the patients that reduced their use of antidepressants (37.6%) or alcohol (42.0%). Approximately two-thirds of patients decreased their use of anti-anxiety (71.8%), migraine (66.7%), and sleep (65.2%) medications following MC which significantly (p < 0.0001) exceeded the reduction in antidepressants or alcohol use. The patient’s spouse, family, and other friends were more likely to know about their MC use than was their primary care provider. In conclusion, a majority of patients reported using less opioids as well as fewer medications to treat anxiety, migraines, and sleep after initiating MC. A smaller portion used less antidepressants or alcohol. Additional research is needed to corroborate these self-reported, retrospective, cross-sectional findings using other data sources.

Repeated intermittent methylenedioxymethamphetamine exposure protects against the behavioral and neurotoxic, but not hyperthermic, effects of an MDMA binge in adult rats

We have recently shown that chronic intermittent exposure of adolescent rats to 3,4‐methylenedioxymethamphetamine (MDMA or Ecstasy) completely blocks the reduction in serotonin transporter (SERT) binding and the hypoactivity seen following a subsequent MDMA binge treatment. The present study determined whether a similar neuroprotective effect also occurs in rats given the same intermittent MDMA exposure in adulthood. Adult male Sprague–Dawley rats were given either MDMA (10 mg/kg × 2) or saline, every fifth day, from postnatal day (PD) 60 to PD 85. The MDMA‐induced latency until seminal plug production was reduced over the course of intermittent treatments. After a 1‐week wash‐out period, animals received either a low‐ or high‐dose MDMA binge (2.5 or 5.0 mg/kg × 4). Core body temperature was measured during and after the binge to determine the effects of MDMA pretreatment on MDMA‐induced hyperthermia. Spontaneous motor activity was determined the next day, and cortical and hippocampal samples were collected at 1 week postbinge to measure serotonin (5‐HT) and 5‐hydroxyindoleacetic acid (5‐HIAA) concentrations as well as [3H]citalopram binding to SERT. Hyperthermia occurred more rapidly and seminal discharge was more common in the MDMA‐pretreated group compared to the MDMA‐naïve group in animals given the low‐dose binge. MDMA preexposure protected animals from the reductions in cortical 5‐HT levels and SERT binding produced by the high‐dose binge and blocked the postbinge hypoactivity. These findings indicate that chronic, intermittent MDMA exposure in adulthood induces neuroprotective effects similar to those seen with adolescent treatment. However, there was also evidence for drug‐induced sensitization in adults that was not observed in adolescents. Thus, altered drug sensitivity in chronic Ecstasy users may depend not only on the frequency and pattern of use but also on the age of the user. Synapse 64:421–431, 2010.