6 research outputs found
Gene expression analysis indicates CB1 receptor upregulation in the hippocampus and neurotoxic effects in the frontal cortex 3 weeks after single-dose MDMA administration in Dark Agouti rats.
BACKGROUND: 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") is a widely used recreational drug known to impair cognitive functions on the long-run. Both hippocampal and frontal cortical regions have well established roles in behavior, memory formation and other cognitive tasks and damage of these regions is associated with altered behavior and cognitive functions, impairments frequently described in heavy MDMA users. The aim of this study was to examine the hippocampus, frontal cortex and dorsal raphe of Dark Agouti rats with gene expression arrays (Illumina RatRef bead arrays) looking for possible mechanisms and new candidates contributing to the effects of a single dose of MDMA (15 mg/kg) 3 weeks earlier. RESULTS: The number of differentially expressed genes in the hippocampus, frontal cortex and the dorsal raphe were 481, 155, and 15, respectively. Gene set enrichment analysis of the microarray data revealed reduced expression of 'memory' and 'cognition', 'dendrite development' and 'regulation of synaptic plasticity' gene sets in the hippocampus, parallel to the upregulation of the CB1 cannabinoid- and Epha4, Epha5, Epha6 ephrin receptors. Downregulated gene sets in the frontal cortex were related to protein synthesis, chromatin organization, transmembrane transport processes, while 'dendrite development', 'regulation of synaptic plasticity' and 'positive regulation of synapse assembly' gene sets were upregulated. Changes in the dorsal raphe region were mild and in most cases not significant. CONCLUSION: The present data raise the possibility of new synapse formation/synaptic reorganization in the frontal cortex three weeks after a single neurotoxic dose of MDMA. In contrast, a prolonged depression of new neurite formation in the hippocampus is suggested by the data, which underlines the particular vulnerability of this brain region after the drug treatment. Finally, our results also suggest the substantial contribution of CB1 receptor and endocannabinoid mediated pathways in the hippocampal impairments. Taken together the present study provides evidence for the participation of new molecular candidates in the long-term effects of MDMA
Unraveling the Functions of Endogenous Receptor Oligomers in the Brain Using Interfering Peptide: The Example of D1R/NMDAR Heteromers
Decoding signaling pathways in different brain structures is crucial to develop pharmacological strategies for neurological diseases. In this perspective, the targeting of receptors by selective ligands is one of the classical therapeutic strategies. Nonetheless, this approach often results in a decrease of efficiency over time and deleterious side effects because physiological functions can be affected. An emerging concept has been to target mechanisms that fine-tune receptor signaling, such as heteromerization, the process by which physical receptor-receptor interaction at the membrane allows the reciprocal modulation of receptors' signaling. Because of the central role of the synergistic transmission mediated by dopamine (DA) and glutamate (Glu) in brain physiology and pathophysiology, heteromerization between DA and Glu receptors has received a lot of attention. However, the study of endogenous heteromers has been challenging because of the lack of appropriate tools. Over the last years, progress has been made in the development of techniques to study their expression in the brain, regulation and function. In this chapter, we provide a methodological framework for the design and use of interfering peptides to study endogenous receptor oligomers through the example of the dopamine type 1 receptor (D1R) and the GluN1 subunit of NMDA receptor heteromers