Prefrontal allopregnanolone synergizes with D1 receptor activation to disrupt sensorimotor gating in male Sprague-Dawley rats

Abstract

Rationale: The prepulse inhibition (PPI) of the startle reflex is the best-established index of sensorimotor gating. We documented that the neurosteroid allopregnanolone (AP) is necessary to reduce PPI in response to D₁ dopamine receptor agonists. Since Sprague-Dawley (SD) rats are poorly sensitive to the PPI-disrupting effects of these drugs, we hypothesized that AP might increase this susceptibility.

Objectives: We tested whether AP is sufficient to increase the vulnerability of SD rats to PPI deficits in response to the D₁ receptor full agonist SKF82958.

Methods: SD rats were tested for PPI after treatment with SKF82958 (0.05-0.3 mg/kg, SC) in combination with either intraperitoneal (1-10 mg/kg) or intracerebral (0.5 μg/μl/side) AP administration into the medial prefrontal cortex (mPFC) or nucleus accumbens shell. To rule out potential confounds, we measured whether SKF82958 affected the endogenous mPFC levels of AP.

Results: SD rats exhibited marked PPI deficits in response to the combination of systemic and intra-mPFC AP with SKF82958 but not with the D₂ receptor agonist quinpirole (0.3-0.6 mg/kg, SC). SKF82958 did not elevate mPFC levels of AP but enhanced the content of its precursor progesterone. The PPI deficits caused by SKF82958 in combination with AP were opposed by the AP antagonist isoallopregnanolone (10 mg/kg, IP) and the glutamate NMDA receptor positive modulator CIQ (5 mg/kg, IP).

Conclusion: These results suggest that AP enables the detrimental effects of D₁ receptor activation on sensorimotor gating. AP antagonism or glutamatergic modulation counters these effects and may have therapeutic potential for neuropsychiatric disorders characterized by gating deficits.

Keywords: D1 receptors; allopregnanolone; dopamine; isoallopregnanolone; neuroactive steroids; prepulse inhibition of the startle; sensorimotor gating.