Heritable differences in the dopaminergic regulation of sensorimotor gating. II. Temporal, pharmacologic and generational analyses of apomorphine effects on prepulse inhibition.
OBJECTIVE
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 D(1)/D(2) 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.


METHODS
In the present study, we replicated this temporal profile in SDH versus LEH rats, assessed the role of D(1) versus D(2) substrates in the two components of this strain difference, and assessed the heritability of these temporally distinct processes.


RESULTS
Pharmacologic studies revealed that: 1) D(2) 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) D(1) 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.


CONCLUSIONS
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 D(1) and D(2) substrates.
Department of Psychiatry, UCSD School of Medicine, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0804, USA. nswerdlow@ucsd.edu
Neal R
NR
Swerdlow
Jody M
JM
Shoemaker
Pamela P
PP
Auerbach
Leia
L
Pitcher
Jana
J
Goins
Amanda
A
Platten
D000704:Analysis of Variance; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology*; D001552:Benzazepines / Q000494:pharmacology; D004298:Dopamine / Q000502:physiology*; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D005684:Gait / Q000187:drug effects* / Q000235:genetics; D008297:Male; D008954:Models, Biological; D009433:Neural Inhibition / Q000187:drug effects*; D011247:Pregnancy; D051381:Rats; D020318:Rats, Long-Evans; D013216:Reflex, Startle / Q000187:drug effects* / Q000235:genetics; D013045:Species Specificity
D001552:Benzazepines; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D001058:Apomorphine; D004298:Dopamine