Do D1/D2 interactions regulate prepulse inhibition in rats?
Prepulse inhibition (PPI) of the startle reflex is an operational measure of sensorimotor gating that is reduced in schizophrenia patients and in dopamine (DA)-activated rats. We previously found that PPI is disrupted by systemic administration of the D2 agonist quinpirole, but not by the D1 agonist SKF 38393. In this report we further characterize the D1 and D2 substrates and their potential interactions in the regulation of PPI in rats. PPI is reduced by concomitant administration of the D1 agonist SKF 38393 (5 mg/kg; relative affinity D1:D2 = 50:1) and by a subthreshold dose (0.1 mg/kg) of the D2 agonist quinpirole, but not by either drug given alone at these doses. Pretreatment with the D2 antagonist raclopride (0.05 mg/kg), but not the D1 antagonist SCH 23390 (0.05 mg/kg), blocks the SKF 38393/quinpirole synergistic reduction of PPI. The relative D1 agonist SKF 82958 (5 mg/kg; relative affinity D1:D2 = 10:1) disrupts PPI, and this effect of SKF 82958 is reversed by the D2 antagonist raclopride but not by the D1 antagonist SCH 23390. Consistent with a recent report (Hoffman and Donovan 1994), the PPI-disruptive effects of the D1/D2 agonist apomorphine (0.5 mg/kg) could be blocked by pretreatment with the D1 antagonist SCH 23390. Surprisingly the PPI-disruptive effects of quinpirole are also opposed by pretreatment with SCH 23390. Our present findings confirm that D2 receptors are important for the regulation of PPI in rats, but they also suggest that there exists a synergistic interaction between D1 and D2 substrates in the regulation of PPI. D1 receptors might modulate PPI in a "rate-dependent" manner in which tonic D1 activity is essential for the full manifestation of the D2-mediated modulation of PPI. However, D1 receptors do not appear to participate in the modulatory mechanisms of sensorimotor gating as an independent substrate.
Wan
F J
FJ
Department of Neuroscience, UCSD School of Medicine, La Jolla, CA 92093-0804, USA.
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D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000818:Animals; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D008297:Male; D020891:Raclopride; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000187:drug effects*; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D012018:Reflex / Q000187:drug effects*; D012457:Salicylamides / Q000494:pharmacology
D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D012457:Salicylamides; D020891:Raclopride; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine