Extensive neuroadaptive changes in cortical gene-transcript expressions of the glutamate system in response to repeated intermittent MDMA administration in adolescent rats.
BACKGROUND
Many studies have focused on the implication of the serotonin and dopamine systems in neuroadaptive responses to the recreational drug 3,4-methylenedioxy-metamphetamine (MDMA). Less attention has been given to the major excitatory neurotransmitter glutamate known to be implicated in schizophrenia and drug addiction. The aim of the present study was to investigate the effect of repeated intermittent MDMA administration upon gene-transcript expression of the glutamate transporters (EAAT1, EAAT2-1, EAAT2-2), the glutamate receptor subunits of AMPA (GluR1, GluR2, GluR3), the glutamate receptor subunits of NMDA (NR1, NR2A and NR2B), as well as metabotropic glutamate receptors (mGluR1, mGluR2, mGluR3, mGluR5) in six different brain regions. Adolescent male Sprague Dawley rats received MDMA at the doses of 3 x 1 and 3 x 5 mg/kg/day, or 3x vehicle 3 hours apart, every 7th day for 4 weeks. The gene-transcript levels were assessed using real-time PCR validated with a range of housekeeping genes.


RESULTS
The findings showed pronounced enhancements in gene-transcript expression of GluR2, mGluR1, mGluR5, NR1, NR2A, NR2B, EAAT1, and EAAT2-2 in the cortex at bregma +1.6. In the caudate putamen, mRNA levels of GluR3, NR2A, and NR2B receptor subunits were significantly increased. In contrast, the gene-transcript expression of GluR1 was reduced in the hippocampus. In the hypothalamus, there was a significant increase of GluR1, GluR3, mGluR1, and mGluR3 gene-transcript expressions.


CONCLUSIONS
Repeated intermittent MDMA administration induces neuroadaptive changes in gene-transcript expressions of glutamatergic NMDA and AMPA receptor subunits, metabotropic receptors and transporters in regions of the brain regulating reward-related associative learning, cognition, and memory and neuro-endocrine functions.
Kindlundh-Högberg
Anna M S
AM
Department of Neuroscience, Division of Functional Pharmacology, Uppsala University, 751 24 Uppsala, Sweden. Anna.Kindlundh@neuro.uu.se
Blomqvist
Anna
A
Malki
Rana
R
Schiöth
Helgi B
HB
D000222:Adaptation, Physiological / Q000187:drug effects* / Q000235:genetics; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000367:Age Factors; D000375:Aging / Q000378:metabolism; D019969:Amphetamine-Related Disorders / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects / Q000235:genetics; D002540:Cerebral Cortex / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D004334:Drug Administration Schedule; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000235:genetics; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics; D050496:Vesicular Glutamate Transport Proteins / Q000235:genetics
D018759:Adrenergic Uptake Inhibitors; D012333:RNA, Messenger; D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D050496:Vesicular Glutamate Transport Proteins; D018698:Glutamic Acid; D018817:N-Methyl-3,4-methylenedioxyamphetamine