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NEUROPHARMACOLOGY

Nanomolar Concentrations of Pregnenolone Sulfate Enhance Striatal Dopamine Overflow in Vivo

Laboratories of Molecular Neurobiology (G.S.-V, G.C.J, T.T.G, D.H.F.) and Neuropsychopharmacology (R.C.P.), Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts

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 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.

Address correspondence to: Dr. David H. Farb, Laboratory of Molecular Neurobiology, Department of Pharmacology, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118. E-mail: dfarb{at}acs.bu.edu