Comparison between intraperitoneal and subcutaneous phencyclidine administration in Sprague-Dawley rats: a locomotor activity and gene induction study.
In a putative model of acute phencyclidine (PCP)-induced psychosis we evaluated effects of the drug on locomotor activity (LMA) and immediate early gene (IEG) induction in the rat using two routes of drug administration, intraperitoneal (i.p.) and subcutaneous (s.c.). Adult male rats received saline or PCP (1.0-5.0 mg/kg) either i.p or s.c. and were assessed for LMA for 60 min. At the end of the LMA testing animals were culled and blood and brain samples were collected for PCP concentration analysis. Separate cohorts of animals received 5.0 mg/kg PCP (i.p. or s.c.) and were used to investigate (1) the pharmacokinetics of PCP or (2) induction of IEG (Arc, c-fos, BDNF, junB, Krox-20, sgk-1, NURR1, fra-2, Krox-24, and egr-3) mRNA expression in the prefrontal cortex (PFC). Administration of PCP resulted in locomotor hyperactivity which was more robust and longer-lasting in animals dosed s.c. compared to i.p.-treated-animals. Differences in hyperlocomotion were paralleled by higher concentrations of PCP in the blood and in the brain of s.c.-treated animals compared to i.p.-treated animals. The differences in the concentration of PCP between the two routes of administration were detected 30 min after dosing and persisted for up to 4 h. Administration of PCP via the s.c. route resulted in induction of more IEGs and consistently larger magnitudes of induction than that via the i.p. route. Therefore, we have outlined the dosing conditions to induce rapid and robust effect of acute PCP on behaviour, gene induction, and pharmacokinetic profile, to allow investigation of this as a potential animal model of acute psychosis.
Kalinichev
Mikhail
M
Biology Department, Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline plc, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, UK. mikhail.m.kalinichev@gsk.com
Robbins
Melanie J
MJ
Hartfield
Elizabeth M
EM
Maycox
Peter R
PR
Moore
Susan H
SH
Savage
Kevin M
KM
Austin
Nigel E
NE
Jones
Declan N C
DN
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects*; D017781:Genes, Immediate-Early / Q000187:drug effects / Q000235:genetics; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D008297:Male; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D010622:Phencyclidine / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011605:Psychoses, Substance-Induced / Q000209:etiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012559:Schizophrenia / Q000139:chemically induced*; D015533:Transcriptional Activation
D010622:Phencyclidine