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Allopregnanolone is required for prepulse inhibition deficits induced by D 1 dopamine receptor activation
Ist Teil von
Psychoneuroendocrinology, 2019-10, Vol.108, p.53
Ort / Verlag
England
Erscheinungsjahr
2019
Quelle
ScienceDirect
Beschreibungen/Notizen
The extraction of salient information from the environment is modulated by the activation of dopamine receptors. Using rodent models, we previously reported that gating deficits caused by dopamine receptor activation - as measured by the prepulse inhibition (PPI) of startle - are effectively opposed by inhibitors of the steroidogenic enzyme 5α-reductase (5αR). The specific 5αR isoenzyme and steroids implicated in these effects, however, remain unknown.
The effects of the selective D
dopamine receptor agonist SKF-82958 (SKF, 0.3 mg/kg, IP) and D
receptor agonist quinpirole (QUIN, 0.5 mg/kg, IP) were tested in the startle reflex and PPI of knockout (KO) mice for either 5αR type 1 (5αR1) or type 2 (5αR2). Furthermore, we established whether these effects may be modified by the 5α-reduced steroids dihydroprogesterone (DHP), allopregnanolone (AP), dihydrotestosterone (DHT), 5α-androstane-3α,17β-diol (3α-diol), or androsterone. To test the mechanisms whereby 5αR products may alter the PPI-disrupting properties of D
agonists, we studied the involvement of GABA-A and PXR, two receptors targeted by neuroactive steroids. Specifically, we tested the effects of SKF in combination with the GABA-A antagonist bicuculline, as well as in KO mice for the GABA-A δ subunit and PXR.
5αR1, but not 5αR2, knockout (KO) mice were insensitive to the PPI-disrupting effects of SKF. This sensitivity was reinstated by AP (3 mg/kg, IP), but not other 5α-reduced steroids. The PPI deficits induced by SKF were not modified by bicuculline, δ-subunit KO mice and PXR KO mice.
These results collectively suggest that 5αR1 enables the negative effects of D
dopamine receptor activation on information processing via production of AP. The contribution of AP to the PPI-disrupting mechanisms of D
receptor agonists, however, do not appear to be mediated by either GABA-A or PXR receptors.
Sprache
Englisch
Identifikatoren
eISSN: 1873-3360
DOI: 10.1016/j.psyneuen.2019.06.009
Titel-ID: cdi_pubmed_primary_31228750
Format
–
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