Use of 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) has increased dramatically in recent years, yet little is known about its effects on the developing brain. Neonatal rats were administered MDMA on days 1-10 or 11-20 (analogous to early and late human third trimester brain development). MDMA exposure had no effect on survival but did affect body weight gain during treatment. After treatment, body weight largely recovered to 90-95% of controls. MDMA exposure on days 11-20 resulted in dose-related impairments of sequential learning and spatial learning and memory, whereas neonatal rats exposed on days 1-10 showed almost no effects. At neither stage of exposure did MDMA-treated offspring show effects on swimming ability or cued learning. Brain region-specific dopamine, serotonin, and norepinephrine changes were small and were not correlated to learning changes. These findings suggest that MDMA may pose a previously unrecognized risk to the developing brain by inducing long-term deleterious effects on learning and memory.

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In previous studies, we have shown that P11-20 treatment with D-methamphetamine (MA) (10 mg/kg x 4/day at 2-h intervals) induces impairments in spatial learning and memory in the Morris water maze after the offspring reach adulthood. Using a split-litter, multiple dose, design (0, 5, 10, and 15 mg/kg MA administered s.c. 4/day at 2-h intervals), the spatial learning effect was further explored with a multiple shifted platform (reversal), reference memory-based procedure and a working memory procedure. Prior to spatial learning, animals were first tested for swimming ability (in a straight swimming channel), sequential learning (in the Cincinnati multiple-T water maze), and proximal cue learning (in the Morris water maze). Rats were then assessed in the hidden platform, reference memory-based spatial version of the Morris maze for acquisition and on five subsequent phases in which the platform was moved to new locations. After the reference memory-based, fixed platform position learning phases, animals were tested in the trial-dependent, matching-to-sample, working memory version of the Morris maze. No group differences were found in straight channel, sequential maze, or cued Morris maze performance. By contrast, all MA groups were impaired in spatial learning during acquisition, multiple shift, and shifted with a reduced platform phases of reference memory-based learning. In addition, MA animals were impaired on memory (probe) trials during the acquisition and shifted with a reduced platform phases of learning. No effects on trial-dependent, matching-to-sample, working memory were found. The findings demonstrate that neonatal treatment with MA induces a selective impairment of reference memory-based spatial learning while sparing sequential, cued, and working memory-based learning.

The effects of neonatal d-methamphetamine (MA) treatment on cued and spatial learning and memory were investigated. MA was administered to neonatal rats on postnatal days 11-20. All groups received four subcutaneous injections per day. Group MA40-4 received 40 mg. kg(-1). d(-1) of MA in four divided doses (10 mg/kg per injection). Group MA40-2 received 40 mg. kg(-1). d(-1) of MA in two divided (20 mg/kg/injection) and saline for the other two injections per day. Controls received saline for four injections per day. As adults, both MA groups showed no differences in swimming ability in a straight swimming channel. The MA40-4 group showed no differences in cued learning, but was impaired in hidden platform learning in the Morris water maze on acquisition. They also showed reduced memory performance on probe trials. Similar trends were seen on reversal learning and reversal probe trials. Reduced platform-size learning trials caused spatial learning impairments to re-emerge in the MA40-4 group. The MA40-2 group showed no differences in straight channel swimming, but was slower at finding the visible platform during cued learning. They were also impaired during acquisition and memory trials in the Morris hidden platform maze. They showed a similar trend on reversal learning and memory trials, but were not different during reduced platform-size learning trials. When the MA40-2 group's performance on hidden platform learning and memory trials was adjusted for cued trial performance, the spatial learning deficits remained. Deficits of spatial learning and memory are a selective effect of neonatal methamphetamine treatment irrespective of other learning and performance variables.

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The effects of the dopamine D1 receptor antagonist R(+)-SCH-23390 and D2 receptor antagonist S(-)-eticlopride on d-methamphetamine-induced striatal monoamine reductions 72 h after treatment were investigated in relation to changes in body temperature. Rats were administered four 10-mg/kg doses of d-methamphetamine or saline with a 2-h interval between treatments; 0.5 mg/kg eticlopride or SCH-23390 was administered 15 min before each methamphetamine or saline injection. Two ambient temperature conditions were investigated: 24 and 33 degrees C. Methamphetamine administered at 24 degrees C induced hyperthermia and reduced striatal dopamine content by 73%; 0.5 mg/kg eticlopride or SCH-23390 administered in combination with methamphetamine at 24 degrees C attenuated methamphetamine-induced hyperthermia and prevented significant reductions in dopamine content. At 33 degrees C, eticlopride and SCH-23390 were ineffective in blocking methamphetamine-induced hyperthermia and dopamine content was reduced by 65% in the SCH-23390-methamphetamine group. By contrast, dopamine content was reduced by only 31% in the 33 degrees C eticlopride-methamphetamine group. Thus, although the eticlopride-methamphetamine treatment combination at 33 degrees C exhibited a hyperthermic response comparable to that seen with methamphetamine alone at 24 degrees C, reductions in dopamine content were attenuated in the combination group compared with methamphetamine alone at 24 degrees C. Serotonin changes showed similar attenuated reductions after SCH-23390 or eticlopride pretreatment at 24 degrees C in combination with methamphetamine, but this attenuation was absent at 33 degrees C. The dissociation of methamphetamine-induced striatal dopamine reduction and hyperthermia seen after eticlopride pretreatment suggests a dopamine D2 receptor mechanism in mediating methamphetamine-induced dopamine depletion. However this D2 mechanism does not apply to methamphetamine-induced striatal serotonin reductions.

Dopaminergic innervation to the nucleus accumbens was investigated following a neurotoxic regimen of methamphetamine (MA) treatment. Four 10 mg/kg doses of MA were administered s.c. to male Sprague-Dawley rats with a 2 h interval between doses. Rectal temperatures were monitored for the induction of MA-induced hyperthermia. Three days or 2 weeks after MA treatment the animals were sacrificed by transcardial perfusion and processed for tyrosine hydroxylase (TH-IR) and glial fibrillary acidic protein immunoreactivity (GFAP-IR). MA treatment produced a severe loss of TH-IR throughout the striatum, including the nucleus accumbens. However, within the nucleus accumbens, there was substantial sparing of TH-IR in the shell, while in the core immunoreactivity was almost entirely lost. Furthermore, astrogliosis, as demonstrated by GFAP-IR, was prevalent in the core but present only in sparse patches in the medial and lateral shell. Thus, dopaminergic innervation to the nucleus accumbens core undergoes degeneration following MA treatment, while innervation to the shell is resistant to the neurodegenerative effects of MA.