MDMA is a widely abused psychostimulant which causes release of serotonin in various forebrain regions. Recently, we reported that MDMA increases extracellular glutamate concentrations in the dentate gyrus, via activation of 5HT2A receptors. We examined the role of prostaglandin signaling in mediating the effects of 5HT2A receptor activation on the increases in extracellular glutamate and the subsequent long-term loss of parvalbumin interneurons in the dentate gyrus caused by MDMA. Administration of MDMA into the dentate gyrus of rats increased PGE2 concentrations which was prevented by coadministration of MDL100907, a 5HT2A receptor antagonist. MDMA-induced increases in extracellular glutamate were inhibited by local administration of SC-51089, an inhibitor of the EP1 prostaglandin receptor. Systemic administration of SC-51089 during injections of MDMA prevented the decreases in parvalbumin interneurons observed 10 days later. The loss of parvalbumin immunoreactivity after MDMA exposure coincided with a decrease in paired-pulse inhibition and afterdischarge threshold in the dentate gyrus. These changes were prevented by inhibition of EP1 and 5HT2A receptors during MDMA. Additional experiments revealed an increased susceptibility to kainic acid-induced seizures in MDMA treated rats which could be prevented with SC51089 treatments during MDMA exposure. Overall, these findings suggest that 5HT2A receptors mediate MDMA-induced PGE2 signaling and subsequent increases in glutamate. This signaling mediates parvalbumin cell losses as well as physiologic changes in the dentate gyrus, suggesting that the lack of the inhibition provided by these neurons increases the excitability within the dentate gyrus of MDMA treated rats.
Recent studies have demonstrated that a preconditioning regimen (i.e., repeated low doses) of MDMA provides protection against the reductions in tissue concentrations of 5-HT and 5-HT transporter (SERT) density and/or expression produced by a subsequent binge regimen of MDMA. In the present study, the effects of preconditioning and binge treatment regimens of MDMA on SERT function were assessed by synaptosomal 5-HT uptake. Synaptosomal 5-HT uptake was reduced by 72% 7 days following the binge regimen (10 mg/kg, ip every 2 hr for a total of 4 injections). In rats exposed to the preconditioning regimen of MDMA (daily treatment with 10 mg/kg for 4 days), the reduction in synaptosomal 5-HT uptake induced by a subsequent binge regimen was significantly less. Treatment with the preconditioning regimen alone resulted in a transient 46% reduction in 5-HT uptake that was evident 1 day, but not 7 days, following the last injection of MDMA. Furthermore, the preconditioning regimen of MDMA did not alter tissue concentrations of 5-HT, whereas the binge regimen of MDMA resulted in a long-term reduction of 40% of tissue 5-HT concentrations. The distribution of SERT immunoreactivity (ir) in membrane and endosomal fractions of the hippocampus also was evaluated following the preconditioning regimen of MDMA. There was no significant difference in the relative distribution of SERTir between these two compartments in control and preconditioned rats. The results demonstrate that SERT function is transiently reduced in response to a preconditioning regimen of MDMA, while long-term reductions in SERT function occur in response to a binge regimen of MDMA. Moreover, a preconditioning regimen of MDMA provides protection against the long-term reductions in SERT function evoked by a subsequent binge regimen of the drug. It is tempting to speculate that the neuroprotective effect of MDMA preconditioning results from a transient down-regulation in SERT function.
3,4-Methylenedioxy-methamphetamine (MDMA) is a unique psychostimulant that continues to be a popular drug of abuse. It has been well documented that MDMA reduces markers of 5-HT axon terminals in rodents, as well as humans. A loss of parvalbumin-immunoreactive (IR) interneurons in the hippocampus following MDMA treatment has only been documented recently. In the present study, we tested the hypothesis that MDMA reduces glutamic acid decarboxylase (GAD) 67-IR, another biochemical marker of GABA neurons, in the hippocampus and that this reduction in GAD67-IR neurons and an accompanying increase in seizure susceptibility involve glutamate receptor activation. Repeated exposure to MDMA (3×10mg/kg, ip) resulted in a reduction of 37–58% of GAD67-IR cells in the dentate gyrus (DG), CA1, and CA3 regions, as well as an increased susceptibility to kainic acid-induced seizures, both of which persisted for at least 30 days following MDMA treatment. Administration of the NMDA antagonist MK-801 or the glutamate transporter type 1 (GLT-1) inducer ceftriaxone prevented both the MDMA-induced loss of GAD67-IR neurons and the increased vulnerability to kainic acid-induced seizures. The MDMA-induced increase in the extracellular concentration of glutamate in the hippocampus was significantly diminished in rats treated with ceftriaxone, thereby implicating a glutamatergic mechanism in the neuroprotective effects of ceftriaxone. In summary, the present findings support a role for increased extracellular glutamate and NMDA receptor activation in the MDMA-induced loss of hippocampal GAD67-IR neurons and the subsequent increased susceptibility to evoked seizures.
A new hemoglobin mutant was detected as a fast-moving variant on cellulose acetate electrophoresis at pH 8.4. The mutation is in the alpha-chain at position 127, where lysine is substituted by asparagine. This is an external residue, and mutation at this site does not lead to any altered physiologic function of the hemoglobin.
Within the brain, the basal ganglia (basal nuclei) regulates wanted movement and inhibits unwanted movement. This area of the brain is intertwined with capillary beds that bring nutrients to the brain and form the blood brain barrier. During disease state, antibodies are increased in circulation, and movement of these antibodies into the basal ganglia can occur. Streptococcal infection can lead to the generation of antibodies that have autoimmune activity within the brain. These antibodies have been implicated in neurological disorders. In our laboratory, an in vitro study of a monoclonal mouse antibody generated against the class 1 epitope of the M6 protein has demonstrated binding within the basal ganglia of Lewis rat brains. Here we present an in vivo study using Lewis rats injected with either the streptococcal antibody or an anti-myosin positive control. The interaction and movement of the antibody from blood vessels into the tissues of the basal ganglia was determined through the use of immunofluorescence and fluorescent microscopy and is contrasted with IgG injected and uninjected controls. Our data demonstrates that the streptococcal antibody penetrates the blood brain barrier within 24 hours (as determined by the presence of immunofluorescence outside of blood vessels) and remains significantly elevated above control values even 72 hours after injection (p < 0.05). In contrast, the anti-myosin positive control was not visualized in the interstitial fluid until 48 hours post injection and was no longer significantly above control levels by 72 hours. IgG injected controls did not display movement of antibody into the brain. Therefore, the streptococcal antibody is capable of crossing the blood brain barrier and interacting with tissues of the basal ganglia.
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