PDGFRα monoclonal antibody: Assessment of embryo-fetal toxicity and time-dependent placental transfer of a murine surrogate antibody of olaratumab in mice.

BACKGROUND: Olaratumab (Lartruvo™) is a recombinant human IgG1 monoclonal antibody that specifically binds PDGFRα. The maternal and in utero embryo-fetal toxicity and toxicokinetics of a human anti-mouse PDGFRα antibody (LSN3338786) were investigated in pregnant mice. METHODS: A pilot study was used to set doses for the definitive study. In the definitive study, mice were administered vehicle, 5, 50, or 150 mg/kg LSN3338786 by intravenous injection on gestation days (GD) 6, 9, 12, and 15. Fetal tissues and/or serum samples were collected on GD 10, 12, 15, and 18 to evaluate exposure of antibody. RESULTS: There were no adverse maternal effects at 50 and 150 mg/kg although maternal deaths and adverse clinical signs were observed at 5 mg/kg. LSN3338786 crossed the placenta as early as GD 10 during organogenesis. Elimination half-life of LSN3338786 in dams decreased between GD 6 and 15. On GD 18, fetal serum concentrations of antibody were substantially higher than maternal serum concentrations at all doses. Increased incidences of malformations consisting of open and partially open eye and increased incidences of skeletal variation frontal/parietal additional ossification site occurred in fetuses from mid- and high-dose groups. CONCLUSIONS: The majority of transplacental migration of antibody occurred in concert with rapid maternal serum clearance before parturition. The no-observed effect level for teratogenicity of 5 mg/kg was associated with GD 15 maternal serum concentrations 3-11 times lower than clinical exposure of olaratumab, suggesting that olaratumab may cause fetal harm when administered to pregnant women.

Developmental stress and lead (Pb): Effects of maternal separation and/or Pb on corticosterone, monoamines, and blood Pb in rats.

The level of lead (Pb) exposure in children has decreased dramatically since restrictions on its use were implemented. However, even with restrictions, children are exposed to Pb and still present with cognitive and behavioral deficits. One prominent aspect of the exposome of these children is that many come from low social economic status (SES) conditions, and low SES is associated with stress. In order to compare the combined effects of early stress and Pb, Sprague-Dawley rats were exposed to vehicle or Pb either alone or in combination with maternal separation stress during brain development (i.e., postnatal day (P)4-P11, P19, or P28). Maternally separated/isolated pups had lower body and thymus weights during exposure and had increased levels of blood Pb compared with vehicle controls. Isolation, but not Pb, affected the response to an acute stressor (standing in shallow water) when assessed on P19 and P29, but not earlier on P11. Interactions of Pb and isolation were found on monoamines in the neostriatum, hippocampus, and hypothalamus on turnover but not on levels, and most changes were on dopamine turnover. Isolation had greater short-term effects than Pb. Interactions were dependent on age, sex, and acute stress.

Elevated blood pressure in offspring of rats exposed to diverse chemicals during pregnancy.

Adverse intrauterine environments have been associated with increased risk of later cardiovascular disease and hypertension. In an animal model using diverse developmental toxicants, we measured blood pressure (BP), renal nephron endowment, renal glucocorticoid receptor (GR) gene expression, and serum aldosterone in offspring of pregnant Sprague Dawley rats exposed to dexamethasone (Dex), perfluorooctane sulfonate (PFOS), atrazine, perfluorononanoic acid (PFNA), arsenic, or nicotine. BP was assessed by tail cuff photoplethysmography, nephron endowment by confocal microscopy, and renal GR mRNA by qPCR. BP was also measured by telemetry, and corticosterone (CORT) was measured in resting or restrained Dex and atrazine offspring. Treated dams gained less weight during treatment in all groups except arsenic. There were chemical- and sex-specific effects on birth weight, but offspring body weights were similar by weaning. BP was higher in Dex, PFOS, atrazine, and PFNA male offspring by 7-10 weeks. Female offspring exhibited elevated BP at 10 weeks for PFNA and arsenic, and at 37 weeks for Dex, PFOS, and atrazine. Dex, PFOS, and atrazine offspring still exhibited elevated BP at 52-65 weeks of age; others did not. Elevated BP was associated with lower nephron counts. Dex, PFOS, and atrazine offspring had elevated renal GR gene expression. Elevations in BP were also observed in Dex and atrazine offspring by radiotelemetry. Atrazine offspring exhibited enhanced CORT response to restraint. Elevated offspring BP was induced by maternal exposure to toxicants. Because all treatments affected maternal gestational weight gain, maternal stress may be a common underlying factor in these observations.

Effects of developmental manganese, stress, and the combination of both on monoamines, growth, and corticosterone.

Developmental exposure to manganese (Mn) or stress can each be detrimental to brain development. Here, Sprague-Dawley rats were exposed to two housing conditions and Mn from postnatal day (P)4-28. Within each litter two males and 2 females were assigned to the following groups: 0 (vehicle), 50, or 100 mg/kg Mn by oral gavage every other day. Half the litters were reared in cages with standard bedding and half with no bedding. One pair/group in each litter had an acute shallow water stressor before tissue collection (i.e., standing in shallow water). Separate litters were assessed at P11, 19, or 29. Mn-treated rats raised in standard cages showed no change in baseline corticosterone but following acute stress increased more than controls on P19; no Mn effects were seen on P11 or P29. Mn increased neostriatal dopamine in females at P19 and norepinephrine at P11 and P29. Mn increased hippocampal dopamine at P11 and P29 and 5-HT at P29 regardless of housing or sex. Mn had no effect on hypothalamic dopamine, but increased norepinephrine in males at P29 and 5-HT in males at all ages irrespective of rearing condition. Barren reared rats showed no or opposite effects of Mn, i.e., barren rearing + Mn attenuated corticosterone increases to acute stress. Barren rearing also altered the Mn-induced changes in dopamine and norepinephrine in the neostriatum, but not in the hippocampus. Barren rearing caused a Mn-associated increase in hypothalamic dopamine at P19 and P29 not seen in standard reared Mn-treated groups. Developmental Mn alters monoamines and corticosterone as a function of age, stress (acute and chronic), and sex.

Thermoregulatory deficits in adult Long Evans rat exposed perinatally to the antithyroidal drug, propylthiouracil.

Developmental exposure to endocrine disrupting drugs and environmental toxicants has been shown to alter a variety of physiological processes in mature offspring. Body (core) temperature (T(c)) is a tightly regulated homeostatic system but is susceptible to disruptors of the hypothalamic pituitary thyroid (HPT) axis. We hypothesized that thermoregulation would be disrupted in adult offspring exposed perinatally to an HPT disruptor. Propylythiouracil (PTU) was used as a prototypical compound because of its well known antithyroidal properties. PTU was added to the drinking water of pregnant rats in concentrations of 0, 1, 2, 3, and 10 ppm from gestational day (GD) 6 through postnatal day (PND) 21. Adult male offspring were implanted with radiotransmitters to monitor Tc and motor activity (MA) and were observed undisturbed at an ambient temperature of 22 °C for 12 consecutive days. Data were averaged into a single 24 hour period to minimize impact of ultradian changes in T(c) and MA. All treatment groups showed a distinct circadian temperature rhythm. Rats exposed to 10 ppm PTU exhibited a marked deviation in their regulated T(c) with a reduction of approximately 0.4 °C below that of controls throughout the daytime period and a smaller reduction at night. Rats exposed to 1 or 2 ppm also had smaller but significant reductions in T(c). MA was unaffected by PTU. Overall, developmental exposure to moderate doses of an antithyroidal drug led to an apparent permanent reduction in T(c) of adult offspring that was independent of changes in MA.

Cognitive impairments from developmental exposure to serotonergic drugs: citalopram and MDMA.

We previously showed that developmental 3,4-methylenedioxymethamphetamine (MDMA) treatment induces long-term spatial and egocentric learning and memory deficits and serotonin (5-HT) reductions. During brain development, 5-HT is a neurotrophic factor influencing neurogenesis, synaptogenesis, migration, and target field organization. MDMA (10 mg/kg × 4/d at 2 h intervals) given on post-natal day (PD) 11-20 in rats (a period of limbic system development that approximates human third trimester brain development) induces 50% reductions in 5-HT during treatment and 20% reductions when assessed as adults. To determine whether the 5-HT reduction is responsible for the cognitive deficits, we used citalopram (Cit) pretreatment to inhibit the effects of MDMA on 5-HT reuptake in a companion study. Cit attenuated MDMA-induced 5-HT reductions by 50% (Schaefer et al., 2012). Here we tested whether Cit (5 or 7.5 mg/kg × 2/d) pretreatment attenuates the cognitive effects of MDMA. Within each litter, different offspring were treated on PD11-20 with saline (Sal) + MDMA, Cit + MDMA, Cit + Sal or Sal + Sal. Neither spatial nor egocentric learning/memory was improved by Cit pretreatment. Unexpectedly, Cit + Sal (at both doses) produced spatial and egocentric learning deficits as severe as those caused by Sal + MDMA. These are the first data showing cognitive deficits resulting from developmental exposure to a selective serotonin reuptake inhibitor. These data indicate the need for further research on the long-term safety of antidepressants during pregnancy.

Neonatal +-methamphetamine exposure in rats alters adult locomotor responses to dopamine D1 and D2 agonists and to a glutamate NMDA receptor antagonist, but not to serotonin agonists.

Neonatal exposure to (+)-methamphetamine (Meth) results in long-term behavioural abnormalities but its developmental mechanisms are unknown. In a series of experiments, rats were treated from post-natal days (PD) 11-20 (stage that approximates human development from the second to third trimester) with Meth or saline and assessed using locomotor activity as the readout following pharmacological challenge doses with dopamine, serotonin and glutamate agonists or antagonists during adulthood. Exposure to Meth early in life resulted in an exaggerated adult locomotor hyperactivity response to the dopamine D1 agonist SKF-82958 at multiple doses, a high dose only under-response activating effect of the D2 agonist quinpirole, and an exaggerated under-response to the activating effect of the N-methyl-d-aspartic acid (NMDA) receptor antagonist, MK-801. No change in locomotor response was seen following challenge with the 5-HT releaser p-chloroamphetamine or the 5-HT2/3 receptor agonist, quipazine. These are the first data to show that PD 11-20 Meth exposure induces long-lasting alterations to dopamine D1, D2 and glutamate NMDA receptor function and may suggest how developmental Meth exposure leads to many of its long-term adverse effects.

Neonatal citalopram treatment inhibits the 5-HT depleting effects of MDMA exposure in rats.

Neonatal exposure to 3,4-methylenedioxymethamphetamine (MDMA) produces long-term learning and memory deficits and increased anxiety-like behavior. The mechanism underlying these behavioral changes is unknown but we hypothesized that it involves perturbations to the serotonergic system as this is the principle mode of action of MDMA in the adult brain. During development 5-HT is a neurotrophic factor involved in neurogenesis, synaptogenesis, migration, and target region specification. We have previously showed that MDMA exposure (4×10 mg/kg/day) from P11-20 (analogous to human third trimester exposure) induces ~50% decreases in hippocampal 5-HT throughout treatment. To determine whether MDMA-induced 5-HT changes are determinative, we tested if these changes could be prevented by treatment with a selective serotonin reuptake inhibitor (citalopram: CIT). In a series of experiments we evaluated the effects of different doses and dose regimens of CIT on MDMA-induced 5-HT depletions in three brain regions (hippocampus, entorhinal cortex, and neostriatum) at three time-points (P12, P16, P21) during the treatment interval (P11-20) known to induce behavioral alterations when animals are tested as adults. We found that 5 mg/kg CIT administered twice daily significantly attenuated MDMA-induced 5-HT depletions in all three regions at all three ages but that the protection was not complete at all ages. Striatal dopamine was unaffected. We also found increases in hippocampal NGF and plasma corticosterone following MDMA treatment on P16 and P21, respectively. No changes in BDNF were observed. CIT treatment may be a useful means of interfering with MDMA-induced 5-HT reductions and thus permit tests of the hypothesis that the drug's cognitive and/or anxiety effects are mediated through early disruptions to 5-HT dependent developmental processes.

Effects of neonatal methamphetamine treatment on adult stress-induced corticosterone release in rats.

In rats, neonatal (+)-methamphetamine (MA) exposure and maternal separation stress increase corticosterone during treatment and result in learning and memory impairments later in life. Early-life stress also changes later responses to acute stress. We tested the hypothesis that neonatal MA exposure would alter adult corticosterone after acute stress or MA challenge. Rats were treated with MA (10 mg/kg × 4/day), saline, or handling on postnatal (P) days 11-15 or 11-20 (days that lead to learning and memory impairments at this dose). As adults, corticosterone was measured before and after 15 min forced swim (FS) or 15 min forced confinement (FC), counterbalanced, and after an acute MA challenge (10 mg/kg) given last. FS increased corticosterone more than FC; order and stress type interacted but did not interact with treatment; treatment interacted with FS but not with FC. In the P11-15 regimen, MA-treated rats showed more rapid increases in corticosterone after FS than controls. In the P11-20 regimen, MA-treated rats showed a trend toward more rapid decrease in corticosterone after FS. No differences were found after MA challenge. The data do not support the hypothesis that neonatal MA causes changes in adult stress responsiveness to FS, FC, or an acute MA challenge.

Distinct periods of developmental sensitivity to the effects of 3,4-(±)-methylenedioxymethamphetamine (MDMA) on behaviour and monoamines in rats.

Previous findings showed allocentric and egocentric learning deficits in rats after MDMA treatment from postnatal days (PD) 11-20 but not after treatment from PD 1-10. Shorter treatment periods (PD 1-5, 6-10, 11-15, or 16-20) resulted in allocentric learning deficits averaged across intervals but not for any interval individually and no egocentric learning deficits individually or collectively. Whether this difference was attributable to treatment length or age at the start of treatment was unclear. In the present experiment rat litters were treated on PD 1-10, 6-15, or 11-20 with 0, 10, or 15 mg/kg MDMA q.i.d. at 2-h intervals. Two male/female pairs/litter received each treatment. One pair/litter received acoustic startle with prepulse inhibition, straight channel swimming, Cincinnati water maze (CWM), and conditioned fear in a latent inhibition paradigm. The other pair/litter received locomotor activity, straight channel swimming, Morris water maze (MWM), and locomotor activity retest with MK-801 challenge. MDMA impaired CWM learning following PD 6-15 or 11-20 exposure. In MWM acquisition, all MDMA-treated groups showed impairment. During reversal and shift, the PD 6-15 and PD 11-20 MDMA-treated groups were significantly impaired. Reductions in locomotor activity were most evident after PD 6-15 treatment while increases in acoustic startle were most evident after PD 1-10 treatment. After MK-801 challenge, MDMA-treated offspring showed less locomotion compared to controls. Region-specific changes in brain monoamines were also observed but were not significantly correlated with behavioural changes. The results show that PD 11-20 exposure to MDMA caused the largest long-term cognitive deficits followed by PD 6-15 exposure with PD 1-10 exposure least affected. Other effects, such as those upon MK-801-stimulated locomotion showed greatest effects after PD 1-10 MDMA exposure. Hence, each effect has a different window of developmental susceptibility.

Effect of physical restraint on the limits of thermoregulation in telemetered rats.

Physical restraint of rodents is needed for nose-only exposure to airborne toxicants and is also used as a means of psychological stress. Hyperthermia is often observed in restrained rats, presumably as a result of impairments in heat dissipation. However, such a hyperthermic response should be dependent on the prevailing ambient conditions. To understand how ambient temperature (T(a)) affects the thermoregulatory response to restraint, core temperature (T(c)) and heart rate (HR) were monitored by telemetry in rats subjected to 1 h of physical restraint while T(a) was maintained at 14-30 °C in 2 °C increments. The T(c) of unrestrained rats was unaffected by T(a). During restraint, T(c) was elevated at ambient temperatures with the exception of 14 °C, at which the rats became mildly hypothermic. There was an inverse relationship between T(a) and HR in both unrestrained and restrained rats; however, HR was significantly elevated in restrained rats at all ambient temperatures except 22 and 24 °C. Heat loss from the tail, estimated from T(c) and tail skin temperature, was markedly reduced at all but the highest ambient temperatures in restrained rats. The data suggest that the T(a) limits of normothermia are narrowed in the restrained rat. That is, between 16 and 20 °C, the rat maintains a relatively stable T(c) that is slightly elevated above that of the unrestrained rat. At ambient temperatures above or below this range, the rat shows signs of hyperthermia and hypothermia, respectively. In contrast, the limits of normothermia for unrestrained rats range from 14 (or lower) to 30 °C. Overall, the ideal T(a) for restrained rats appears to be 20 °C and no higher than 22 °C for the thermoregulatory system to maintain a regulated T(c) in rats well adapted to physical restraint.

Maternal influences on epigenetic programming of the developing hypothalamic-pituitary-adrenal axis.

Parental and environmental factors during the prenatal and postnatal periods permanently affect the physiology and metabolism of offspring, potentially increasing disease risk later in life. Underlying mechanisms are being elucidated, and effects on a number of organs and metabolic pathways are likely involved. In this review, we consider effects on the developing hypothalamic-pituitary-adrenal (HPA) axis, which may represent a common pathway for developmental programming. The focus is on prenatal and early postnatal development, during which the HPA axis may be programmed in a manner that affects health for a lifetime. Programming of the HPA axis involves, at least in part, epigenetic remodeling of chromatin, leading to alterations in the expression of genes in many organs and tissues involved in HPA activation and response, including the hippocampus and peripheral tissues. Examples of developmental epigenetic modifications affecting the HPA axis as well as target tissues are provided.

Effects of developmental stress and lead (Pb) on corticosterone after chronic and acute stress, brain monoamines, and blood Pb levels in rats.

Despite restrictions, exposure to lead (Pb) continues. Moreover, exposure varies and is often higher in lower socioeconomic status (SES) families and remains a significant risk to cognitive development. Stress is another risk factor. Lower SES may be a proxy for stress in humans. When stress and Pb co-occur, risk may be increased. A few previous experiments have combined Pb with intermittent or acute stress but not with chronic stress. To determine if chronic developmental stress affects outcome in combination with Pb, we tested such effects on growth, organ weight, brain monoamines, and response to an acute stressor. Sprague Dawley rats were gavaged with Pb acetate (1 or 10 mg/kg) or vehicle every other day from postnatal day (P)4-29 and reared in standard or barren cages. Subsets were analyzed at different ages (P11, 19, 29). Chronic stress did not alter blood Pb levels but altered HPA axis response during early development whereas Pb did not. Pb treatment and rearing each altered organ-to-body weight ratios, most notably of thymus weights. Both Pb and rearing resulted in age- and region-dependent changes in serotonin and norepinephrine levels and in dopamine and serotonin turnover. The model introduced here may be useful for investigating the interaction of Pb and chronic developmental stress.

Comparison of (+)-methamphetamine, ±-methylenedioxymethamphetamine, (+)-amphetamine and ±-fenfluramine in rats on egocentric learning in the Cincinnati water maze.

(+)-Methamphetamine (MA), (±)-3,4-methylenedioxymethamphetamine (MDMA), (+)-amphetamine (AMPH), and (±)-fenfluramine (FEN) are phenylethylamines with CNS effects. At higher doses, each induces protracted reductions in brain dopamine (DA) and/or serotonin. Chronic MA and MDMA users show persistent monoamine reductions and cognitive impairments. In rats, similar neurochemical effects can be induced, yet cognitive impairments have been difficult to demonstrate. We recently showed that rats treated on a single day with MA (10 mg/kg x 4 at 2 h intervals) exhibit impaired egocentric learning (Cincinnati water maze [CWM]) without affecting spatial learning (Morris water maze [MWM]) (Herring et al., [2008] Psychopharmacology (Berl) 199:637­650). Whether this effect is unique to MA or is a general characteristic of these drugs is unknown. Accordingly, this experiment compared these drugs on CWM performance. Drugs were given s.c. in four doses at 2 h intervals. MA doses were 10 or 12.5 mg/kg/dose, AMPH 25 mg/kg/dose (to match MA12.5-induced hyperthermia), MDMA 15 mg/kg/dose (previously established hyperthermia-inducing dose), and FEN 16.5 mg/kg/dose (equimolar to MA12.5). Two weeks later, rats were tested in the CWM (2 trials/day, 21 days). AMPH and MA (both doses) induced significant increases in CWM errors and latency to reach the goal with no differences in swim speed. MDMA and FEN did not significantly alter learning. Given that FEN selectively and MDMA preferentially affect serotonin whereas AMPH selectively and MA preferentially affect DA, the data suggest that egocentric learning may be predominantly dopaminergically mediated.

Effects of inhibiting neonatal methamphetamine-induced corticosterone release in rats by adrenal autotransplantation on later learning, memory, and plasma corticosterone levels.

RATIONALE: Neonatal rat methamphetamine (MA) exposure has been shown to cause long-term behavioral impairments similar to some of those observed following neonatal stress. The mechanism by which MA induces impairments is unknown but may be related to early increases in corticosterone release. We previously developed a method to attenuate MA-induced corticosterone release using adrenal autotransplantation (ADXA) in neonatal rats. This exposure period corresponds to the second-half of human pregnancy. OBJECTIVE: To determine whether inhibition of neonatal MA-induced increases in corticosterone attenuates the long-term behavioral deficits associated with early MA treatment. RESULTS: ADXA successfully attenuated MA-induced plasma corticosterone increases by approximately 50% during treatment (P11-20) but did not attenuate the long-term behavioral effects of MA treatment. MA-treated rats, regardless of surgery, showed increased errors and latencies in the Cincinnati water maze test of egocentric learning and increased latency, path length, and cumulative distance in three phases of Morris water maze spatial learning and reference memory. MA-treated offspring were hypoactive, had subtle reductions in anxiety in the elevated zero maze but not in the light-dark test. ADXA had no effect on MA-induced long-term 5-HT reductions in the neostriatum or entorhinal cortex or on 5-HIAA reductions in the hippocampus. CONCLUSIONS: Fifty percent attenuation of neonatal MA-induced elevations in corticosterone does not alter the long-term egocentric or allocentric learning deficits or other behavioral effects of neonatal MA exposure. Because the ADXA effect was partial, the data cannot rule out the possibility that a more complete block of MA-induced corticosterone release might not prevent later cognitive deficits.

Neonatal methamphetamine-induced corticosterone release in rats is inhibited by adrenal autotransplantation without altering the effect of the drug on hippocampal serotonin.

Rat neonatal methamphetamine exposure results in corticosterone release and learning and memory impairments in later life; effects also observed after neonatal stress. Previous attempts to test the role of corticosterone release after methamphetamine using corticosterone inhibitors were unsuccessful and adrenalectomy caused reductions in hippocampal serotonin greater than those caused by methamphetamine alone. Here we tested whether adrenal autotransplantation could be used to attenuate methamphetamine-induced corticosterone release without also altering the effects of the drug on serotonin. Adrenal autotransplantation surgery occurred on postnatal day 9 followed by methamphetamine or saline treatment from postnatal day 11-20 (10mg/kg/dosex4/day). Plasma corticosterone and hippocampal serotonin and 5-hydroxyindoleacetic acid were determined 30min following the first treatment on each day between postnatal days 11-20. Adrenal autotransplantation attenuated neonatal methamphetamine-induced corticosterone release by approximately 70% initially, approximately 55% midway through treatment, and approximately 25% by the end of treatment. Methamphetamine reduced serotonin and 5-hydroxyindoleacetic acid in the hippocampus in the ADXA rats to the same degree as in SHAM rats. The data show that neonatal adrenal autotransplantation is an effective method for partially reducing treatment-induced corticosterone release while providing sufficient corticosterone to sustain normal growth and development. The method should be applicable to other models of developmental stress/corticosterone release.

Effect of a neurotoxic dose regimen of (+)-methamphetamine on behavior, plasma corticosterone, and brain monoamines in adult C57BL/6 mice.

RATIONALE: In rats, neurotoxic doses of methamphetamine (MA) induce astrogliosis, long lasting monoamine reductions, reuptake transporter down-regulation, and learning impairments. OBJECTIVE: We tested whether comparable effects occur in C57BL/6 mice. METHOD: C57BL/6 mice were treated with 10mg/kgs.c.x4 MA on a single day and evaluated at various intervals thereafter. RESULTS: The neurotoxic dose regimen of MA caused the predicted acute hyperthermia and increased striatal glial fibrillary acidic protein and reduced neostriatal dopamine. The MA-treated mice were hypoactive 24h later but not 48h later. MA-treated mice also showed exaggerated initial hyperactivity after a pharmacological dose of MA used to stimulate locomotion followed by a later phase of hypoactivity compared to saline-treated mice. No differences were observed on learning or memory tests (novel object recognition, egocentric, or spatial learning/memory). MA-treated mice showed a trend toward increased prepulse inhibition but not baseline acoustic startle reactivity. After testing, MA-treated mice showed reduced neostriatal dopamine and increased basal plasma corticosterone. CONCLUSIONS: A neurotoxic/binge regimen of MA in mice that produces the typical pattern of neurotoxic changes to those seen in rats, results in few behavioral changes. This may limit the utility of C57BL/6 mice for modeling the cognitive and behavioral effects described in human MA users who show such changes even after prolonged abstinence.

(+/-)3,4-Methylenedioxymethamphetamine (MDMA) dose-dependently impairs spatial learning in the morris water maze after exposure of rats to different five-day intervals from birth to postnatal day twenty.

During postnatal days (PD) 11-20, (+/-)3,4-methylenedioxymethamphetamine (MDMA) treatment impairs egocentric and allocentric learning, and reduces spontaneous locomotor activity; however, it does not have these effects during PD 1-10. How the learning impairments relate to the stress hyporesponsive period (SHRP) is unknown. To test this association, the preweaning period was subdivided into 5-day periods from PD 1-20. Separate pups within each litter were injected subcutaneously with 0, 10, 15, 20, or 25 mg/kg MDMA x4/day on PD 1-5, 6-10, 11-15, or 16-20, and tested as adults. The 3 highest MDMA dose groups showed reduced locomotor activity during the first 10 min (of 60 min), especially in the PD 1-5 and 6-10 dosing regimens. MDMA groups in all dosing regimens showed impaired allocentric learning in the Morris water maze (on acquisition and reversal, all MDMA groups were affected; on the small platform phase, the 2 high-dose groups were affected). No effects of MDMA were found on anxiety (elevated zero maze), novel object recognition, or egocentric learning (although a nonsignificant trend was observed). The Morris maze results did not support the idea that the SHRP is critical to the effects of MDMA on allocentric learning. However, since no effects on egocentric learning were found, but were apparent after PD 11-20 treatment, the results show that these 2 forms of learning have different exposure-duration sensitivities.

Comparison of the developmental effects of 5-methoxy-N,N-diisopropyltryptamine (Foxy) to (+/-)-3,4-methylenedioxymethamphetamine (ecstasy) in rats.

RATIONALE: We have previously shown that (+/-)-3,4-methylenedioxymethamphetamine (MDMA) treatment from postnatal days (P)11 to P20 leads to learning and memory deficits when the animals are tested as adults. Recently, the club drug 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) has gained popularity. OBJECTIVE: Due to the similarities between MDMA and 5-MeO-DIPT and the substitution of 5-MeO-DIPT for MDMA, the purpose of this study was to compare the developmental effects of these drugs. METHODS: Within a litter, animals were treated from P11 to P20 with either MDMA, 5-MeO-DIPT, or saline. RESULTS: MDMA-treated animals showed increased anxiety in a measure of defensive marble burying, as well as deficits in spatial and path integration learning. 5-MeO-DIPT-treated animals showed spatial learning deficits; however, there were no deficits observed in spatial memory or path integration learning. 5-MeO-DIPT-treated animals also showed hyperactivity in response to a challenge dose of methamphetamine. CONCLUSIONS: The results show that treatment with either 5-MeO-DIPT or MDMA during development results in cognitive deficits and other behavioral changes but the pattern of effects is distinct for each drug.

Effects of (+)-methamphetamine on path integration and spatial learning, but not locomotor activity or acoustic startle, align with the stress hyporesponsive period in rats.

Rats treated with (+)-methamphetamine (MA) on postnatal days (P) 11-20 exhibit long-term spatial and path integration (Morris water maze (MWM) and Cincinnati water maze (CWM)) learning deficits whereas those treated on P1-10 do not. MA treatment increases corticosterone release in an age-dependent U-shaped pattern that corresponds to the stress hyporesponsive period (SHRP; P4-15). Here we tested the hypothesis that the cognitive effects induced by MA are associated with treatment that begins within the SHRP. Three treatment regimens were compared, P1-10, P6-15, and P11-20. One male/female pair/litter received 0, 10, or 25mg/kg MA/dose (four doses/day at 2h intervals given s.c. with 19-21 litters/regimen). Locomotor activity and acoustic startle were tested as behaviors not predicted to be associated with the SHRP. Cincinnati and Morris water maze findings were consistent with the hypothesis in that MA-treated animals exposed from P6-15 or P11-20 showed impaired learning compared to those exposed from P1-10; however, on probe trials in the Morris water maze, MA-induced memory impairments were not regimen-specific and were contributed to by all treatment regimens. All MA treatment regimens induced reductions in locomotor activity and acoustic startle facilitation as expected. No differential effect on prepulse trials was seen suggesting no impairment in sensory gating. Cognitive deficits from neonatal MA treatment are associated with the SHRP and may be the product of hypothalamic-pituitary-adrenal (HPA) axis dysregulation during critical periods of brain development.