Neonatal (+)-methamphetamine increases brain derived neurotrophic factor, but not nerve growth factor, during treatment and results in long-term spatial learning deficits

Skelton, Matthew R.; Williams, Michael T.; Schaefer, Tori L.

doi:10.1016/j.psyneuen.2007.05.004

Cited by 40 publications

(29 citation statements)

References 52 publications

(71 reference statements)

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“…This is in line with data by Skelton et al [2007], who showed a regulation of NGF after neonatal methamphetamine exposure at P20 in the hippocampus. In adult rats, NGF expression was decreased only in the hippocampus, occipital cortex and hypothalamus after amphetamine injections, but no change in NGF levels was found in the frontal cortex [Angelucci et al, 2007].…”

Section: Discussionsupporting

confidence: 93%

Neurotoxic Effects of MDMA (Ecstasy) on the Developing Rodent Brain

Dzietko

Sifringer²,

Klaus³

et al. 2010

Dev Neurosci

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The incidence of methamphetamine abuse is particularly high in adolescents and is a common problem among women of childbearing age, leading to an increasing number of children with prenatal exposure. MDMA (3,4-methylenedioxymethamphetamine, ecstasy) is an amphetamine-like stimulant and is known to induce apoptotic damage to fine serotonergic fibers in the adult rat brain. Little is known about toxic effects of MDMA and potential underlying molecular mechanisms in the developing brain. Here, we investigated whether MDMA exposure during the period of rapid brain growth causes neurodegeneration in the developing rat brain. MDMA significantly enhanced neuronal death in the brains of 6-day-old rat pups at a dose of 60 mg/kg, but no significant toxicity was detected at the ages of 14 and 21 days. Brain regions mainly affected were the cortex, septum, thalamus, hypothalamus and the cornu ammonis 1 region. To explore possible molecular mechanisms involved in this neurodegenerative process, we investigated the impact of MDMA on the expression of the neurotrophins brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and nerve growth factor. Neonatal exposure of 6-day-old rats to MDMA triggered a considerable increase in cortical BDNF and NT-3 levels. Moreover, P7 CD1/BDNF knockout mice were noticeably more sensitive to MDMA exposure as compared to their wild-type age-matched littermates. These data suggest that a single injection of MDMA causes neurodegeneration in the neonatal rat brain. The upregulation of BDNF and NT-3 expression may indicate an important compensatory mechanism leading to the survival of neuronal cells in the developing brain.

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Section: Discussionsupporting

confidence: 93%

Neurotoxic Effects of MDMA (Ecstasy) on the Developing Rodent Brain

Dzietko

Sifringer²,

Klaus³

et al. 2010

Dev Neurosci

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“…This finding is consistent with previous studies in amphetamine-experienced animals, in which drug exposure (experimenter-delivered) significantly enhanced BDNF protein levels in the hippocampus (Skelton et al, 2007, Grace et al, 2008), but significantly extend the findings with methamphetamine self-administration, a paradigm that produces much lower levels of drug intake compared with high dose experimenter delivered paradigms. Upon release into the synaptic cleft, BDNF can bind to its receptor TrkB, localized at both pre- and postsynaptic sites of glutamatergic synapses in the hippocampus, and BDNF binding to TrkB induces receptor dimerization and phosphorylation at the autophosphorylation site Tyr-706 (Drake et al, 1999, Chao, 2003).…”

Section: Discussionsupporting

confidence: 91%

“…In the context of addiction, cocaine exposure produces a widespread, but transient, induction of BDNF protein in the nucleus accumbens, prefrontal cortex, ventral tegmental area, and the central and basolateral nuclei of the amygdala (Grimm et al, 2003, Le Foll et al, 2005, Graham et al, 2007), whereas fewer studies have been conducted to examine BDNF protein levels after exposure to amphetamines. For example, BDNF protein expression in the hippocampus in enhanced in juvenile animals after forced administration of neurotoxic doses of amphetamines and the findings demonstrate that these changes in the neurotrophin may relate to the cognitive deficits in methamphetamine experienced animals (Skelton et al, 2007, Grace et al, 2008). In contrast to these studies using noncontingent methamphetamine injections, there are no published studies on the effect of methamphetamine self-administration on hippocampal BDNF levels, and therefore, was the focus of the current study.…”

Section: Introductionmentioning

confidence: 90%

Methamphetamine differentially affects BDNF and cell death factors in anatomically defined regions of the hippocampus

2015

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Methamphetamine exposure reduces hippocampal long-term potentiation (LTP) and neurogenesis and these alterations partially contribute to hippocampal maladaptive plasticity. The potential mechanisms underlying methamphetamine-induced maladaptive plasticity were identified in the present study. Expression of brain-derived neurotrophic factor (BDNF; a regulator of LTP and neurogenesis), and its receptor tropomyosin-related kinase B (TrkB) were studied in the dorsal and ventral hippocampal tissue lysates in rats that intravenously self-administered methamphetamine in a limited access (1 h/day) or extended access (6 h/day) paradigm for 17 days post baseline sessions. Extended access methamphetamine enhanced expression of BDNF with significant effects observed in the dorsal and ventral hippocampus. Methamphetamine-induced enhancements in BDNF expression were not associated with TrkB receptor activation as indicated by phospho (p)-TrkB-706 levels. Conversely, methamphetamine produced hypophosphorylation of NMDA receptor subunit 2B (GluN2B) at Tyr-1472 in the ventral hippocampus, indicating reduced receptor activation. In addition, methamphetamine enhanced expression of anti-apoptotic protein Bcl-2 and reduced pro-apoptotic protein Bax levels in the ventral hippocampus, suggesting a mechanism for reducing cell death. Analysis of Akt, a pro-survival kinase that suppresses apoptotic pathways and pAkt at Ser-473 demonstrated that extended access methamphetamine reduces Akt expression in the ventral hippocampus. These data reveal that alterations in Bcl-2 and Bax levels by methamphetamine were not associated with enhanced Akt expression. Given that hippocampal function and neurogenesis vary in a subregion-specific fashion, where dorsal hippocampus regulates spatial processing and has higher levels of neurogenesis, whereas ventral hippocampus regulates anxiety-related behaviors, these data suggest that methamphetamine self-administration initiates distinct allostatic changes in hippocampal subregions that may contribute to the altered synaptic activity in the hippocampus, which may underlie enhanced negative affective symptoms and perpetuation of the addiction cycle.

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“…A relationship between CORT and BDNF was also observed, which could explain the BDNF effects discovered in the MDMA-treated animals (Roskoden et al, 2004). Increases in BDNF have also been shown in MA-treated animals on P15 and P20 (Skelton et al, 2007). MDMA (10 mg/kg) exposure from P1 to P4 increased the cleavage of caspase-3, an apoptotic marker, in the rostral forebrain on P5, suggesting that MDMA may be inducing apoptosis in developing neurons (Meyer et al, 2004).…”

Section: Biochemistrymentioning

confidence: 71%

Developmental effects of 3,4-methylenedioxymethamphetamine: a review

Skelton

Williams

Vorhees

2008

Behavioural Pharmacology

Self Cite

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Abstract± 3,4-Methylenedioxymethamphetamine (MDMA) is a chemical derivative of amphetamine that has become a popular drug of abuse and has been shown to deplete serotonin in the brains of users and animals exposed to it. To date, most studies have investigated the effects of MDMA on adult animals. With a majority of users of MDMA being young adults, the chances of the users becoming pregnant and exposing the fetuses to MDMA are also a concern. Evidence to date has shown that developmental exposure to MDMA results in learning and memory impairments in the Morris water maze, a task known to be sensitive to hippocampal disruption, when the animals are tested as adults. Developmental MDMA exposure leads to hypoactivity in the offspring as adults but does not affect outcome on tests of anxiety. MDMA administration decreases pup weight, increases corticosterone and brain-derived neurotrophic factor levels during treatment while decreasing brain levels of serotonin; a decrease that initially dissipates and then reappears in adulthood. Neonatal MDMA exposure increases the sensitivity of the serotonin 1A receptor, a possible mechanism underlying the learning and memory deficits seen. Taken together, the evidence shows that MDMA exposure has adverse effects on the developing brain and behavior. The animal and human data on developmental MDMA exposure are reviewed and their public health implications discussed.

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Neonatal (+)-methamphetamine increases brain derived neurotrophic factor, but not nerve growth factor, during treatment and results in long-term spatial learning deficits

Cited by 40 publications

References 52 publications

Neurotoxic Effects of MDMA (Ecstasy) on the Developing Rodent Brain

Neurotoxic Effects of MDMA (Ecstasy) on the Developing Rodent Brain

Methamphetamine differentially affects BDNF and cell death factors in anatomically defined regions of the hippocampus

Developmental effects of 3,4-methylenedioxymethamphetamine: a review

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