Stimulation of Glutamate Receptors Increases Expression of Brain‐Derived Neurotrophic Factor mRNA in Rat Hippocampus<sup>a</sup>

Lindefors, Nils; Ballarin, M.; Ernfors, Patrik; Falkenberg, Torkel; Persson, Håkan

doi:10.1111/j.1749-6632.1992.tb24561.x

Cited by 33 publications

(17 citation statements)

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“…In neurons, the expression of BDNF mRNA is enhanced when the AMPA-type glutamate receptor is activated [55,56], and requires an increase in intracellular calcium concentrations [57,58]. We found [59] that treatment with MDMA significantly disrupted calcium homeostasis, favoring glutamate release in the hippocampus.…”

Section: Discussionmentioning

confidence: 70%

Adaptive Plasticity in the Hippocampus of Young Mice Intermittently Exposed to MDMA Could Be the Origin of Memory Deficits

et al. 2015

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Concise title: Adaptive plasticity in the hippocampus of young mice exposed to MDMA 2 ABSTRACT (±)3,4-methylenedioxymethamphetamine (MDMA) is a relatively selective dopaminergic neurotoxin in mice. This study was designed to evaluate whether MDMA exposure affects their recognition memory and hippocampal expression of plasticity markers. Mice were administered with increasing doses of MDMA once per week for 8 weeks (three times in one day, every 3h) and sacrificed two weeks (2 w) or three months (3 m) later. The treatment did not modify hippocampal tryptophan hydroxylase 2, a serotonergic indicator, but induced an initial reduction in dopaminergic markers in substantia nigra, which remained stable for at least 3 months. In parallel, MDMA produced a decrease in dopamine (DA) levels in the striatum at 2 w, which were restored 3 months later, suggesting dopaminergic terminal regeneration (sprouting phenomenon). Moreover, recognition memory was assessed using the object recognition test. Young (2 w) and mature (3 m) adult mice exhibited impaired memory after 24 h but not after just 1 h retention interval. Two weeks after the treatment, animals showed constant levels of CREB but an increase in its phosphorylated form and in cFos expression. BDNF and especially Arc overexpression was sustained and long lasting.We cannot rule out the absence of MDMA injury in the hippocampus being due to the generation of BDNF. The levels of NMDAR2B, PSD-95 and synaptophysin were unaffected.In conclusion, the young mice exposed to MDMA showed increased expression of early key markers of plasticity, which sometimes remained for three months, and suggests hippocampal maladaptive plasticity that could explain memory deficits evidenced here.

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Section: Discussionmentioning

confidence: 70%

Adaptive Plasticity in the Hippocampus of Young Mice Intermittently Exposed to MDMA Could Be the Origin of Memory Deficits

et al. 2015

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“…Several studies have shown the upregulation of BDNF upon excitotoxicity (Isackson et al 1991;Lindefors et al 1992;Katoh-Semba et al 1999). In order to investigate whether α-MSH affects basal BDNF levels and/or whether the effects of α-MSH on KA-induced neurodegeneration may involve changes in BDNF, the levels were analysed in the hippocampus of KA-lesioned rats and control animals.…”

Section: Discussionmentioning

confidence: 99%

α-MSH Rescues Neurons from Excitotoxic Cell Death

et al. 2007

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This study investigates the effects of alpha-melanocyte-stimulating hormone (alpha-MSH), on neurodegeneration, gliosis and changes in the neurotrophic protein brain-derived neurotrophic factor (BDNF) and in pro-inflammatory cytokines, following kainic acid (KA)-induced excitotoxic damage in the rat. Male Sprague-Dawley rats were treated with alpha-MSH (intraperitoneally, i.p.) at 20 min, and 24 and 48 h following administration of 10 mg/kg KA (i.p.). The animals were sacrificed at 30 min, 4 h, 24 h and 72 h after KA-administration and the levels of interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) were analysed in samples of hippocampus and hypothalamus. Levels of BDNF were analysed in the hippocampus. Stereological quantification showed a markedly reduced number of viable neurons in the CA1 pyramidal cell layer upon KA-administration as compared to animals injected with vehicle (p < 0.05, 79,587 +/- 25,554 vs. 145,254 +/- 27,871). The number of viable neurons upon administration of alpha-MSH was significantly higher than upon KA alone (p < 0.05, 119,776 +/- 33,158, KA+alpha-MSH vs. 79,587 +/- 27,554, KA + Saline). Astrocyte activation due to the KA-induced excitotoxicity was reduced, and the KA-induced increase in IL-1beta levels was delayed by the treatment with alpha-MSH. In conclusion, the degree of reduction in cell viability in the hippocampus CA1 pyramidal cell layer upon KA-induced excitotoxicity was similar to that seen previously upon global cerebral ischaemia. Furthermore, the administration of alpha-MSH resulted in a similar increase in cell viability, supporting the hypothesis that administration of alpha-MSH has rescuing effects on neurons subjected to excitotoxic insults.

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“…In one study , schizophrenic patients showed hypotrophic changes that included involvement of corticocortical projection neurons in layer IIIc. Glutamatergic or other calcium-dependent factors could be involved in the neurotrophic deficits or neurotoxicity described in cortical pyramidal neurons from schizophrenic patients in the period of more pronounced functional decline in late life (Ghosh et al 1994;Lindefors et al 1992;Marini et al 1998). …”

Section: Closing Observations: Glutamate and The Natural History Of Smentioning

confidence: 99%

Therapeutic Implications of the Hyperglutamatergic Effects of NMDA Antagonists

Krystal

1999

Neuropsychopharmacology

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Antagonists of the N-methyl-D-aspartate ( Lamotrigine; Serotonin; 5-HT2A; LY354740; M100907; MDL 100,907 The field of schizophrenia research is rapidly moving from a focus on the contributions of single neurotransmitters or brain regions toward an appreciation of the interactions of multiple neurotransmitter systems, neural networks, and intracellular mechanisms (Aghajanian and Marek 1999;Carlsson et al. 1997;Krystal et al. 1999b). Investigators are abandoning oversimplified dopaminergic models suggesting that all activation is detrimental to symptoms in schizophrenic patients. Instead, optimal levels of stimulation of particular dopamine-receptor subtypes are needed to sustain behavior and higher cognitive functions (Arnsten 1997;Goldman-Rakic and Selemon 1997 shortcomings of both typical and atypical neuroleptics (Meltzer 1997). As a result, it is now timely to consider the possibility that the next era in medications development for treating schizophrenia will involve mechanisms other than dopamine-2 (D 2 )-receptor antagonism. This review highlights a novel perspective on the neurobiology and treatment of schizophrenia growing from the study of the effects of the N-methyl-D-aspartate (NMDA) glutamate-receptor antagonists in animals and humans. It considers parallels between the transient symptomatic effects of single doses of NMDA antagonists in healthy human subjects and findings in schizophrenic patients. It then highlights similarities between disturbances in information processing produced by NMDA antagonists and deficits observed in schizophrenic patients. Next, this review attempts to provide some insights into mechanisms that link NMDA-receptor antagonism to glutamatergic activation and information-processing deficits. This review then summarizes evidence that dopaminergic systems have limited contributions to positive and negative symptoms produced by NMDA antagonists. Finally, it considers the utility of facilitation of the glycine-B site of the NMDA-receptor complex and drugs that attenuate glutamate release as pharmacotherapies for schizophrenia based on their capacity to attenuate the effects of NMDA antagonists in animals and humans. Because glutamate has both neurotrophic and neurotoxic effects in the brain, potential implications of glutamatergic pharmacotherapies for the course of schizophrenia is considered. PARALLELS BETWEEN NMDA-ANTAGONIST EFFECTS IN HEALTHY SUBJECTS AND SCHIZOPHRENIC PATIENTSLuby and his colleagues coined the term "schizophrenomimetic" to describe the striking similarities between the effects of phencyclidine (PCP), and the symptoms of schizophrenia (Luby et al. 1959). The identification of NMDA-receptor antagonism as the mechanism of action of PCP, the implication of NMDA receptors in many fundamental aspects of neural plasticity and neurotoxicity, and reports of altered glutamate-receptor binding in postmortem tissue from schizophrenic patients rekindled interest in the effects of PCP (Anis et al. 1983;Krystal et al. 1999b;Madison et al. 1991;Rothman and Olney 198...

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Stimulation of Glutamate Receptors Increases Expression of Brain‐Derived Neurotrophic Factor mRNA in Rat Hippocampus^a

Cited by 33 publications

References 3 publications

Adaptive Plasticity in the Hippocampus of Young Mice Intermittently Exposed to MDMA Could Be the Origin of Memory Deficits

Adaptive Plasticity in the Hippocampus of Young Mice Intermittently Exposed to MDMA Could Be the Origin of Memory Deficits

α-MSH Rescues Neurons from Excitotoxic Cell Death

Therapeutic Implications of the Hyperglutamatergic Effects of NMDA Antagonists

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Stimulation of Glutamate Receptors Increases Expression of Brain‐Derived Neurotrophic Factor mRNA in Rat Hippocampusa

Cited by 33 publications

References 3 publications

Adaptive Plasticity in the Hippocampus of Young Mice Intermittently Exposed to MDMA Could Be the Origin of Memory Deficits

Adaptive Plasticity in the Hippocampus of Young Mice Intermittently Exposed to MDMA Could Be the Origin of Memory Deficits

α-MSH Rescues Neurons from Excitotoxic Cell Death

Therapeutic Implications of the Hyperglutamatergic Effects of NMDA Antagonists

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Stimulation of Glutamate Receptors Increases Expression of Brain‐Derived Neurotrophic Factor mRNA in Rat Hippocampus^a