Nanomolar concentrations of pregnenolone sulfate enhance striatal dopamine overflow in vivo.
The balance between GABA-mediated inhibitory and glutamate-mediated excitatory synaptic transmission represents a fundamental mechanism for controlling nervous system function, and modulators that can alter this balance may participate in the pathophysiology of neuropsychiatric disorders. Pregnenolone sulfate (PS) is a neuroactive steroid that can modulate the activity of ionotropic glutamate and GABA(A) receptors either positively or negatively, depending upon the particular receptor subtype, and modulates synaptic transmission in a variety of experimental systems. To evaluate the modulatory effect of PS in vivo, we infused PS into rat striatum for 20 min via a microdialysis probe while monitoring local extracellular dopamine (DA) levels. The results demonstrate that PS at low nanomolar concentrations significantly increases extracellular DA levels. The PS-induced increase in extracellular DA is antagonized by the N-methyl-d-aspartate (NMDA) receptor antagonist, d-AP5 [d-(-)-2-amino-5-phosphonopentanoic acid], but not by the sigma receptor antagonist, BD 1063 [1(-)[2-(3,4-dichlorophenyl)-ethyl]-4-methylpiperazine]. The results demonstrate that exogenous PS, at nanomolar concentrations, is able to increase DA overflow in the striatum through an NMDA receptor-mediated pathway.
Sadri-Vakili
G
G
Laboratory of Molecular Neurobiology, Department of Pharmacology, Boston University School of Medicine, Boston, MA 02118, USA.
Janis
G C
GC
Pierce
R C
RC
Gibbs
T T
TT
Farb
D H
DH
D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D011284:Pregnenolone / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017480:Receptors, sigma / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction
D017480:Receptors, sigma; C018370:pregnenolone sulfate; D016202:N-Methylaspartate; D011284:Pregnenolone; D004298:Dopamine
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