Effects of spiperone, raclopride, SCH 23390 and clozapine on apomorphine inhibition of sensorimotor gating of the startle response in the rat.
Previous work suggests that the dopamine agonist apomorphine decreases prepulse inhibition (PPI) of the acoustic startle response in rats. To better understand the dopamine substrates of this apomorphine response, we investigated the effects of four pharmacologically distinct dopamine antagonists on the apomorphine-induced loss of PPI. Apomorphine (0.5 mg/kg s.c.) markedly decreased PPI for all prepulse intervals tested. This effect of apomorphine on PPI was reversed by pretreatments with the D2 antagonists spiperone and raclopride but not by pretreatment with the D1 antagonist SCH 23390. The atypical antipsychotic clozapine exhibited an "inverted-U" shaped dose-response curve, reversing the apomorphine-induced loss of PPI at low doses but not at high doses. High doses of both SCH 23390 and clozapine decreased PPI independent of apomorphine treatment. The effects of apomorphine on baseline startle amplitude were also differentially modified by these drugs: apomorphine potentiated startle amplitude in spiperone- and raclopride-pretreated animals, but apomorphine decreased startle amplitude in animals pretreated with SCH 23390 or high doses of clozapine. Prepulse inhibition has been shown to be markedly impaired in humans with schizophrenia. Since our present findings suggest that the activation of D2 dopamine receptors is responsible for the loss of PPI in rats, overactivity of D2 dopamine receptors might also be a substrate for PPI deficits in schizophrenia.
Swerdlow
N R
NR
Department of Psychiatry, University of California, San Diego, La Jolla.
Keith
V A
VA
Braff
D L
DL
Geyer
M A
MA
D000704:Analysis of Variance; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology*; D001552:Benzazepines / Q000494:pharmacology*; D003024:Clozapine / Q000494:pharmacology*; D008297:Male; D020891:Raclopride; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects*; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D013216:Reflex, Startle / Q000187:drug effects*; D012457:Salicylamides / Q000494:pharmacology*; D012559:Schizophrenia / Q000503:physiopathology; D013134:Spiperone / Q000494:pharmacology*
D001552:Benzazepines; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D012457:Salicylamides; D020891:Raclopride; D013134:Spiperone; D003024:Clozapine; D001058:Apomorphine