Method for screening drug and chemical effects in laboratory rats using computerized quantitative electroencephalography.
A minimally-invasive method of quantitative electroencephalography (qEEG) that requires no anesthetics and parallels techniques of naturalistic stimulation was developed and validated for regulatory testing of drugs and chemicals in rats. Male and female Fischer 344 rats were utilized in a randomized-block design to measure qEEG target parameters associated with a range of cholinesterase inhibition. For this study, physostigmine was administered ip at doses of 0.05, 0.2 or 1.0 mg/kg, resulting in average cholinesterase inhibition in plasma (28, 38 and 70%), erythrocytes (19, 24 and 36%), and brain (2, 10 and 31%) which correlated well with increased total power and amplitude changes. Additional treatment-related effects consisted of decreased relative alpha and beta, increased relative delta, and a left-shift in the spectral-edge frequency. In a second study, male and female Sprague-Dawley rats were utilized in a treatment-by-subjects design to determine qEEG target parameter changes due to the M2 autoreceptor agonist oxotremorine. Repeated incremental doses (0.05, 0.1, 0.2 mg/kg; ip) of oxotremorine resulted in increased beta contribution, a right-shift in the spectral-edge frequency and decreased alpha contribution. These qEEG results with physostigmine and oxotremorine correlate well with receptor-specific and general muscarinic effects, making it a reliable contribution to analysis of agonist and antagonist effects of cholinergic compounds.
Jones
R D
RD
Toxicology Department, Bayer Corporation, Stilwell, KS 66085-9104, USA.
Sheets
L P
LP
Mueller
R E
RE
D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D002802:Cholinesterases / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004569:Electroencephalography / Q000187:drug effects / Q000379:methods; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology; D005260:Female; D007274:Injections, Intraperitoneal; D008297:Male; D018721:Muscarinic Agonists / Q000008:administration & dosage / Q000633:toxicity*; D010095:Oxotremorine / Q000008:administration & dosage / Q000633:toxicity*; D010830:Physostigmine / Q000008:administration & dosage / Q000633:toxicity*; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley
D002800:Cholinesterase Inhibitors; D018721:Muscarinic Agonists; D010095:Oxotremorine; D010830:Physostigmine; D002802:Cholinesterases