Forebrain D1 function and sensorimotor gating in rats: effects of D1 blockade, frontal lesions and dopamine denervation.
Prefrontal D1 hypoactivity is implicated in the pathophysiology of schizophrenia, and might contribute to sensorimotor gating deficits in schizophrenia patients, based on evidence that D1 blockade in the medial prefrontal cortex (MPFC) reduces prepulse inhibition of startle (PPI) in animal models. PPI is disrupted by systemic and intra-MPFC infusion of the D1 antagonist, SCH23390. We investigated the role of the MPFC in the PPI-disruptive effects of systemic SCH23390 administration, and more generally, in the dopaminergic regulation of PPI. PPI was measured in rats after forebrain manipulations, including systemic administration of SCH23390, ibotenic acid lesions of the MPFC, and 6OHDA-induced dopamine (DA) depletion from MPFC or nucleus accumbens. Systemic SCH23390 disrupted PPI; these effects were not opposed by ibotenic acid lesions of the MPFC. PPI remained intact after MPFC DA depletion, but--as predicted by Bubser and Koch [M. Bubser, M. Koch, Prepulse inhibition of the acoustic startle response of rats is reduced by 6 hydroxydopamine lesions of the medial prefrontal cortex, Psychopharmacology 113 (1994) 487-492]--a reduction in PPI from pre- to post-surgery correlated significantly with MPFC DA loss. The effects of systemic SCH23390 were not opposed by NAC DA depletion. D1 receptors regulate PPI in rats, but this effect does not appear to be mediated either by the MPFC or by increased mesolimbic DA activity.
Swerdlow
Neal R
NR
Department of Psychiatry, UCSD School of Medicine, La Jolla, CA 92093-0804, United States. nswerdlow@ucsd.edu
Shoemaker
Jody M
JM
Kuczenski
Ronald
R
Bongiovanni
Michele J
MJ
Neary
Alaina C
AC
Tochen
Laura S
LS
Saint Marie
Richard L
RL
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000161:Acoustic Stimulation / Q000379:methods; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001552:Benzazepines / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003714:Denervation / Q000379:methods; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology; D007794:Lameness, Animal / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D016627:Oxidopamine / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000293:injuries / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000502:physiology*; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology; D012701:Serotonin / Q000378:metabolism; D013565:Sympatholytics / Q000494:pharmacology; D013997:Time Factors
D001552:Benzazepines; D018492:Dopamine Antagonists; D017447:Receptors, Dopamine D1; D013565:Sympatholytics; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D016627:Oxidopamine; D004298:Dopamine; D009638:Norepinephrine