Serotonin-GABA interactions modulate MDMA-induced mesolimbic dopamine release.
3,4,-Methylenedioxymethamphetamine (MDMA; 'ecstasy') acts at monoamine nerve terminals to alter the release and re-uptake of dopamine and 5-HT. The present study used microdialysis in awake rats to measure MDMA-induced changes in extracellular GABA in the ventral tegmental area (VTA), simultaneous with measures of extracellular dopamine (DA) in the nucleus accumbens (NAC) shell. (+)-MDMA (0, 2.5, 5 and 10 mg/kg, i.p.) increased GABA efflux in the VTA with a bell-shaped dose-response. This increase was blocked by application of TTX through the VTA probe. MDMA (5 mg/kg) increased 5-HT efflux in VTA by 1037% (p < 0.05). The local perfusion of the 5-HT(2B/2C) antagonist SB 206553 into the VTA reduced VTA GABA efflux after MDMA from a maximum of 229% to a maximum of 126% of basal values (p < 0.05), while having no effect on basal extracellular GABA concentrations. DA concentrations measured simultaneously in the NAC shell were increased from a maximum of 486% to 1320% (p < 0.05). The selective DA releaser d-amphetamine (AMPH) (4 mg/kg) also increased VTA GABA efflux (180%), did not alter 5-HT and increased NAC DA (875%) (p < 0.05), but the perfusion of SB 206553 into the VTA failed to alter these effects. These results suggest that MDMA-mediated increases in DA within the NAC shell are dampened by increases in VTA GABA subsequent to activation of 5-HT(2B/2C) receptors in the VTA.
Bankson
Michael G
MG
Laboratory of Neurochemistry, Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Yamamoto
Bryan K
BK
D000818:Animals; D003913:Dextroamphetamine / Q000494:pharmacology; D004298:Dopamine / Q000032:analysis / Q000378:metabolism*; D004347:Drug Interactions; D045604:Extracellular Fluid / Q000737:chemistry / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D008032:Limbic System / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D013997:Time Factors; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism; D014851:Wakefulness / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000032:analysis / Q000378:metabolism*
D007211:Indoles; D011725:Pyridines; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D012701:Serotonin; D005680:gamma-Aminobutyric Acid; C094868:SB 206553; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D003913:Dextroamphetamine; D004298:Dopamine