D1 and D2 dopamine receptor antagonists reverse prepulse inhibition deficits in an animal model of schizophrenia.
The amplitude of the acoustic startle response is decreased if the startle stimulus is preceded by a nonstartle eliciting stimulus. This sensorimotor gating phenomenon, known as prepulse inhibition, is diminished in schizophrenic individuals. In rats, the dopamine agonist apomorphine disrupts prepulse inhibition and this disruption is reversed by classical and atypical antipsychotics. Furthermore, the ability of antipsychotics to reverse the apomorphine disruption is correlated with clinical potency and D2 receptor affinity. In the present study, the role of the D1 receptor in prepulse inhibition of the acoustic startle response was studied; the effects of the D1 receptor antagonist SCH 23390 were examined and compared to the effects of the D2 receptor antagonist eticlopride. Male Sprague-Dawley rats were placed into a startle chamber and presented with auditory stimuli consisting of either 95 or 105 dB noise bursts presented alone or preceded by a 75 dB noise burst. Trials consisting of no stimulus and the 75 dB prepulse stimulus alone were also included. These six trial types (ten each) were randomly presented within a 35-min session. Rats treated with 2.0 mg/kg apomorphine (SC) demonstrated a significant disruption of prepulse inhibition compared to vehicle controls. Pretreatment with the D1 antagonist SCH 23390 (0.01, 0.05, 0.1 mg/kg SC) or the D2 antagonist eticlopride (0.01, 0.05, 0.1 mg/kg SC) attenuated the disruptive effects of apomorphine. These results indicate that selective blockade of either the D1 or D2 receptor subtype is sufficient in reversing the sensorimotor gating deficits produced by apomorphine.(ABSTRACT TRUNCATED AT 250 WORDS)
Hoffman
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Neurogen Corporation, Branford, CT 06405.
Donovan
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D000161:Acoustic Stimulation; D000818:Animals; D001058:Apomorphine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001552:Benzazepines / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors*; D013216:Reflex, Startle / Q000187:drug effects*; D012457:Salicylamides / Q000494:pharmacology; D012565:Schizophrenic Psychology
D001552:Benzazepines; D065127:Dopamine D2 Receptor Antagonists; D017447:Receptors, Dopamine D1; D012457:Salicylamides; C045989:eticlopride; D001058:Apomorphine