Dopamine modulation of excitatory currents in the striatum is dictated by the expression of D1 or D2 receptors and modified by endocannabinoids.
Striatal medium-sized spiny neurons (MSSNs) receive glutamatergic inputs modulated presynaptically and postsynaptically by dopamine. Mice expressing the gene for enhanced green fluorescent protein as a reporter gene to identify MSSNs containing D1 or D2 receptor subtypes were used to examine dopamine modulation of spontaneous excitatory postsynaptic currents (sEPSCs) in slices and postsynaptic N-methyl-d-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) currents in acutely isolated cells. The results demonstrated dopamine receptor-specific modulation of sEPSCs. Dopamine and D1 agonists increased sEPSC frequency in D1 receptor-expressing MSSNs (D1 cells), whereas dopamine and D2 agonists decreased sEPSC frequency in D2 receptor-expressing MSSNs (D2 cells). These effects were fully (D1 cells) or partially (D2 cells) mediated through retrograde signaling via endocannabinoids. A cannabinoid 1 receptor (CB1R) agonist and a blocker of anandamide transporter prevented the D1 receptor-mediated increase in sEPSC frequency in D1 cells, whereas a CB1R antagonist partially blocked the decrease in sEPSC frequency in D2 cells. At the postsynaptic level, low concentrations of a D1 receptor agonist consistently increased NMDA and AMPA currents in acutely isolated D1 cells, whereas a D2 receptor agonist decreased these currents in acutely isolated D2 cells. These results show that both glutamate release and postsynaptic excitatory currents are regulated in opposite directions by activation of D1 or D2 receptors. The direction of this regulation is also specific to D1 and D2 cells. We suggest that activation of postsynaptic dopamine receptors controls endocannabinoid mobilization, acting on presynaptic CB1Rs, thus modulating glutamate release differently in glutamate terminals projecting to D1 and D2 cells.
André
Véronique M
VM
Mental Retardation Research Center, David Geffen School of Medicine at UCLA, Semel Institute for Neuroscience and Human Behavior, 760 Westwood Plaza, NPI 58-258, Los Angeles, CA 90095, USA. vandre@mednet.ucla.edu
Cepeda
Carlos
C
Cummings
Damian M
DM
Jocoy
Emily L
EL
Fisher
Yvette E
YE
William Yang
X
X
Levine
Michael S
MS
D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism*; D063388:Endocannabinoids; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D016202:N-Methylaspartate / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism
D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D043884:Receptor, Cannabinoid, CB1; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D018698:Glutamic Acid; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D004298:Dopamine