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

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 5 alpha-reductase (5 alpha R). The specific 5 alpha R isoenzyme and steroids implicated in these effects, however, remain unknown. Methods: The effects of the selective D-1 dopamine receptor agonist SKF-82958 (SKF, 0.3 mg/kg, IP) and D-2 receptor agonist quinpirole (QUIN, 0.5 mg/kg, IP) were tested in the startle reflex and PPI of knockout (KO) mice for either 5 alpha R type 1 (5 alpha R1) or type 2 (5 alpha R2). Furthermore, we established whether these effects may be modified by the 5 alpha-reduced steroids dihydroprogesterone (DHP), allopregnanolone (AP), dihydrotestosterone (DHT), 5 alpha-androstane-3 alpha,17 beta-diol (3 alpha-diol), or androsterone. To test the mechanisms whereby 5 alpha R products may alter the PPI-disrupting properties of D-1 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 delta subunit and PXR. Results: 5 alpha R1, but not 5 alpha R2, 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 5 alpha-reduced steroids. The PPI deficits induced by SKF were not modified by bicuculline, delta-subunit KO mice and PXR KO mice. Conclusions: These results collectively suggest that 5 alpha R1 enables the negative effects of D-1 dopamine receptor activation on information processing via production of AP. The contribution of AP to the PPI-disrupting mechanisms of D-1 receptor agonists, however, do not appear to be mediated by either GABA-A or PXR receptors.