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

Frau, Roberto

First

Writing - Original Draft Preparation

;Traccis, Francesco;Concas, Luca;Cadeddu, Roberto;Mosher, Laura J;Nordkild, Peter;Gaikwad, Nilesh W;Bortolato, Marco

2023-01-01

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Abstract

RationaleThe 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 D-1 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.ObjectivesWe tested whether AP is sufficient to increase the vulnerability of SD rats to PPI deficits in response to the D-1 receptor full agonist SKF82958.MethodsSD 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 mu g/mu l/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.ResultsSD rats exhibited marked PPI deficits in response to the combination of systemic and intra-mPFC AP with SKF82958 but not with the D-2 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).ConclusionThese results suggest that AP enables the detrimental effects of D-1 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.