Curtis E. Grace

Effects of neonatal (+)-methamphetamine on path integration and spatial learning in rats: effects of dose and rearing conditions

Postnatal day (P)11–20 (+)‐methamphetamine (MA) treatment impairs spatial learning and reference memory in the Morris water maze, but has marginal effects on learning in a labyrinthine maze. A subsequent experiment showed that MA treatment on P11–15, but not P16–20, is sufficient to induce Morris maze deficits. Here we tested the effects of P11–15 MA treatment under two different rearing conditions on Morris maze performance and path integration learning in the Cincinnati water maze in which distal cues were unavailable by using infrared illumination. Littermates were treated with 0, 10, 15, 20, or 25 mg/kg MA × 4/day (2 h intervals). Half the litters were reared under standard housing conditions and half under partial enrichment by adding stainless steel enclosures. All MA groups showed impaired Cincinnati water maze performance with no significant effects of rearing condition. In the Morris maze, the MA‐25 group showed impaired spatial acquisition, reversal, and small platform learning. Enrichment significantly improved Morris maze acquisition in all groups but did not interact with treatment. The male MA‐25 group was also impaired on probe trial performance after acquisition and on small platform trials. A narrow window of MA treatment (P11–15) induces impaired path integration learning irrespective of dose within the range tested but impairments in spatial learning are dependent on dose. The results demonstrate that a narrower exposure window (5 days) changes the long‐term effects of MA treatment compared to longer exposures (10 days).

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 25 mg/kg MA/dose (four doses/day at 2 h 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.

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 ×4/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.

(±)-3,4-Methylenedioxymethamphetamine treatment in adult rats impairs path integration learning: A comparison of single vs once per week treatment for 5 weeks

3,4-Methlylenedioxymethamphetamine (MDMA) administration (4 x 15 mg/kg) on a single day has been shown to cause path integration deficits in rats. While most animal experiments focus on single binge-type models of MDMA use, many MDMA users take the drug on a recurring basis. The purpose of this study was to compare the effects of repeated single-day treatments with MDMA (4 x 15 mg/kg) once weekly for 5 weeks to animals that only received MDMA on week 5 and saline on weeks 1-4. In animals treated with MDMA for 5 weeks, there was an increase in time spent in the open area of the elevated zero maze suggesting a decrease in anxiety or increase in impulsivity compared to the animals given MDMA for 1 week and saline treated controls. Regardless of dosing regimen, MDMA treatment produced path integration deficits as evidenced by an increase in latency to find the goal in the Cincinnati water maze. Animals treated with MDMA also showed a transient hypoactivity that was not present when the animals were re-tested at the end of cognitive testing. In addition, both MDMA-treated groups showed comparable hyperactive responses to a later methamphetamine challenge. No differences were observed in spatial learning in the Morris water maze during acquisition or reversal but MDMA-related deficits were seen on reduced platform-size trials. Taken together, the data show that a single-day regimen of MDMA induces deficits similar to that of multiple weekly treatments.

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

RationaleWe 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.ObjectiveDue 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.MethodsWithin a litter, animals were treated from P11 to P20 with either MDMA, 5-MeO-DIPT, or saline.ResultsMDMA-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.ConclusionsThe 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.

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 × 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) 199:637–650). 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. Synapse, 2010.

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

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.

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 two females were assigned to the following groups: 0 (vehicle), 50, or 100 mg/kg Mn by 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.