Abstract
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 GABAA 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 σ 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.
Footnotes
-
This study was supported by the National Institute of Mental Health (Grant R01MH049469), by the National Institute on Drug Abuse (Grant R01DA013724), and by the National Institute of General Medical Sciences (Grant T32GM008541).
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
doi:10.1124/jpet.108.143958.
-
ABBREVIATIONS: PS, pregnenolone sulfate; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid; NMDA, N-methyl-d-aspartate; NMDAR, NMDA receptor; DA, dopamine; DMSO, dimethyl sulfoxide; aCSF, artificial cerebrospinal fluid; d-AP5, d-(-)-2-amino-5-phosphonopentanoic acid; PHS, pregnenolone hemisuccinate; SKF 10,047, (+)-N-allylnormetazocine; BD 1063, 1(-)[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine; MK-801, dizocilpine maleate.
-
↵1 Current affiliation: Massachusetts General Hospital, MassGeneral Institute for Neurodegenerative Disease, Charlestown, Massachusetts.
-
↵2 Current affiliation: MEDTOX Scientific Inc., St. Paul, Minnesota.
-
↵3 Current affiliation: Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
- Received July 23, 2008.
- Accepted September 2, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|