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.
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Acknowledgments
The authors wish to thank all the personnel of CESAST (Centro Servizi di Ateneo per gli Stabulari) at the University of Cagliari for their expert assistance in animal care.
Funding
The work was funded by Regione Autonoma della Sardegna grant to RF (F72F16002850002, CRP29) and NIH grants R21 NS108722 and R21 NS125654 (to MB).
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PN is CEO and CMO for Asarina Pharma and has a 1.2% equity stake in Asarina Pharma. MB consults for Asarina Pharmaceuticals and receives research funding from Asarina and Lundbeck Pharmaceuticals. All the other authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest.
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Frau, R., Traccis, F., Concas, L. et al. Prefrontal allopregnanolone synergizes with D1 receptor activation to disrupt sensorimotor gating in male Sprague-Dawley rats. Psychopharmacology 240, 1359–1372 (2023). https://doi.org/10.1007/s00213-023-06375-x
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DOI: https://doi.org/10.1007/s00213-023-06375-x