Dose-response effect of acute phencyclidine on functional connectivity and dopamine levels, and their association with schizophrenia-like symptom classes in rat.
Current drug treatments for schizophrenia (SCZ) can alleviate positive symptoms, but have little effect on the negative symptoms and cognitive deficits that are difficult to translate into preclinical models for drug development. Therefore, we aimed to determine the dose-response effects of acute phencyclidine (PCP, 1.0-5.0 mg/kg) on rat brain connectivity and detect markers for different SCZ-like symptoms. Pharmacological functional magnetic resonance imaging (phMRI) and microdialysis were used to investigate PCP-induced effects on functional connectivity (FC) and dopamine levels, respectively. Next, we evaluated the association between PCP-induced changes in imaging parameters and behavior. PCP at doses of 3.0-5.0 mg/kg induced fMRI signal changes in several brain regions associated with SCZ. Additionally, the FC was globally disturbed, dopamine levels increased, and locomotor activity increased, reflecting the manifestation of SCZ-like positive symptoms. A distinct pattern in the measures was observed at lower PCP doses (1.0-2.0 mg/kg); PCP induced fMRI signal changes in the fronto-cortical regions, and increased dopamine levels in the medial prefrontal cortex. In addition to the dysconnectivity of these regions, the hippocampal FC was disrupted. These observations are consistent with the induction of SCZ-like cognitive deficits and negative symptoms, which were observed as impaired novel object recognition and decreased social interaction. No indicators for positive symptoms were observed at lower PCP doses. We conclude that acute PCP induces SCZ-like symptom classes in a dose-dependent manner; PCP doses of 1.0-2.0 mg/kg are more suitable for modeling SCZ-like negative symptoms and cognitive deficits, while SCZ-like positive symptoms dominate at doses of 3.0-5.0 mg/kg.
A.I.V. Institute for Molecular Sciences, Department of Neurobiology, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland.
Jaakko
J
Paasonen
A.I.V. Institute for Molecular Sciences, Department of Neurobiology, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland.
Raimo A
RA
Salo
School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland.
Jouni
J
Ihalainen
School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland.
Juuso V
JV
Leikas
School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland.
Katja
K
Savolainen
School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland.
Marko
M
Lehtonen
School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland. Electronic address: markus.forsberg@uef.fi.
Markus M
MM
Forsberg
A.I.V. Institute for Molecular Sciences, Department of Neurobiology, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland.
Olli
O
Gröhn
D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D001931:Brain Mapping; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006213:Hallucinogens / Q000633:toxicity*; D007091:Image Processing, Computer-Assisted; D007398:Interpersonal Relations; D008124:Locomotion / Q000187:drug effects; D008279:Magnetic Resonance Imaging; D008297:Male; D017551:Microdialysis; D010100:Oxygen / Q000097:blood; D010622:Phencyclidine / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D021641:Recognition, Psychology / Q000187:drug effects; D012559:Schizophrenia / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000473:pathology*; D012565:Schizophrenic Psychology
D006213:Hallucinogens; D010622:Phencyclidine; D010100:Oxygen; D004298:Dopamine
Behavioral tests; Functional; Magnetic resonance imaging; Microdialysis; Phencyclidine; Rats; Schizophrenia