Heritable differences in the dopaminergic regulation of sensorimotor gating
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Rationale and objectives
The disruption of prepulse inhibition (PPI) of startle in rats by dopamine agonists has been used in a predictive model for antipsychotics, and more recently, to study the neural basis of strain differences in dopaminergic function. We have previously reported that Sprague-Dawley (SDH) and Long Evans (LEH) rats differed in their sensitivity to the PPI-disruptive effects of the D1/D2 agonist apomorphine (APO) in two distinct ways: 1) compared to LEH rats, SDH rats were more sensitive to the ability of APO to disrupt PPI with relatively long prepulse intervals (60–120 ms), and 2) APO enhanced PPI in LEH rats with 10–30 ms prepulse intervals, but this effect was limited to 10 ms prepulse intervals in SDH rats.
In the present study, we replicated this temporal profile in SDH versus LEH rats, assessed the role of D1 versus D2 substrates in the two components of this strain difference, and assessed the heritability of these temporally distinct processes.
Pharmacologic studies revealed that: 1) D2 blockade prevented the long interval PPI-disruptive effects of APO in both strains, and extended the temporal range of the PPI-enhancing effects of APO from 10 to 30 ms in SDH rats, and 2) D1 blockade increased PPI and blocked the PPI-enhancing effects of APO at short intervals in both strains. Generational studies in adult F0 (SDH and LEH), F1 (SDHxLEH) and N2 (SDHxF1) rats demonstrated that sensitivity to APO of both short and long interval PPI were inherited in a manner suggestive of relatively simple additive effects of multiple genes.
The present findings demonstrate that inherited differences in the dopaminergic regulation of sensorimotor gating are manifested not only in quantitative shifts (more versus less), but also in qualitative shifts in the temporal properties of sensorimotor gating that appear to be under separate control of D1 and D2 substrates.
KeywordsApomorphine Dopamine Genetics Prepulse inhibition Schizophrenia Startle
This study was supported by National Institute of Mental Health awards MH58384, MH01436 & MH42228. The authors are grateful for the assistance of Ms. Sarah Crain in the preparation of this manuscript.
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