Nanomolar concentrations of pregnenolone sulfate enhance striatal dopamine overflow in vivo

J Pharmacol Exp Ther. 2008 Dec;327(3):840-5. doi: 10.1124/jpet.108.143958. Epub 2008 Sep 4.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Corpus Striatum / metabolism*
  • Dopamine / metabolism*
  • Dose-Response Relationship, Drug
  • N-Methylaspartate / antagonists & inhibitors
  • N-Methylaspartate / metabolism
  • Pregnenolone / administration & dosage
  • Pregnenolone / pharmacology*
  • Rats
  • Receptors, sigma / antagonists & inhibitors
  • Receptors, sigma / metabolism
  • Signal Transduction


  • Receptors, sigma
  • pregnenolone sulfate
  • N-Methylaspartate
  • Pregnenolone
  • Dopamine