title: Drug-anaesthetic interaction in phMRI: the case of the psychotomimetic agent phencyclidine.
abstract: Pharmacological magnetic resonance imaging (phMRI) provides a powerful means to map the effects of drugs on brain activity, with important applications in pharmacological research. However, phMRI studies in preclinical species are often conducted under general anaesthesia as a means to avoid head motion and to minimise the stress induced by the procedure. Under these conditions, the phMRI response to the drug of interest may be affected by interactions with the anaesthetic agent, with consequences for the interpretation of the data. Here, we have investigated the phMRI response to phencyclidine (PCP), an NMDA receptor blocker, in the halothane-anaesthetised rat for varying levels of anaesthesia and different PCP challenge doses. PCP induces psychotic-like symptoms in humans and laboratory animals and is widely applied as a pharmacological model of schizophrenia. However, PCP possesses anaesthetic properties per se, and its interactions with halothane might result in significant effects on the phMRI activation patterns. We observed two qualitatively different patterns of phMRI response. At 0.5 mg/kg iv PCP and 0.8% halothane maintenance anaesthesia, the lowest doses explored, an activation of discrete cortico-limbo-thalamic structures was observed, consistent with neuroimaging studies in humans and 2-deoxyglucose functional mapping in conscious animal models. However, higher anaesthetic concentrations or higher PCP challenge doses resulted in complete abolition of the positive response and in a widespread cortical deactivation (negative response). In the intermediate regime, we observed a dichotomic behaviour, with individual subjects showing one pattern or the other. These findings indicate a dose-dependent drug-anaesthetic interaction, with a complete reversal of the effects of PCP at higher challenge doses or HT concentrations.
authors.affiliation: Department of Biology, Psychiatry CEDD, GlaxoSmithKline Medicines Research Centre, Verona, Italy. alessandro.gozzi@gsk.com
authors.forename: Alessandro
authors.initials: A
authors.lastname: Gozzi
authors.forename: Adam
authors.initials: A
authors.lastname: Schwarz
authors.forename: Valerio
authors.initials: V
authors.lastname: Crestan
authors.forename: Angelo
authors.initials: A
authors.lastname: Bifone
mesh_terms: D018685:Anesthetics, Inhalation / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects*; D001931:Brain Mapping / Q000379:methods; D004347:Drug Interactions; D006213:Hallucinogens / Q000008:administration & dosage / Q000494:pharmacology*; D006221:Halothane / Q000008:administration & dosage / Q000494:pharmacology*; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D010622:Phencyclidine / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D018685:Anesthetics, Inhalation; D006213:Hallucinogens; D010622:Phencyclidine; D006221:Halothane