Allopregnanolone is required for prepulse inhibition deficits induced by D1 dopamine receptor activation

Abstract

Introduction: 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.

Methods: The effects of the selective D₁ dopamine receptor agonist SKF-82958 (SKF, 0.3 mg/kg, IP) and D₂ 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 D₁ 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.

Results: 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.

Conclusions: These results collectively suggest that 5αR1 enables the negative effects of D₁ dopamine receptor activation on information processing via production of AP. The contribution of AP to the PPI-disrupting mechanisms of D₁ receptor agonists, however, do not appear to be mediated by either GABA-A or PXR receptors.

Keywords: 5α-reductase; Allopregnanolone; Behavioral studies; D(1)receptors; Dopamine; Sensorimotor gating.