Characterization of the Effects of Standard and Atypical Dopamine Uptake Inhibitors and Other Centrally Acting Drugs on the EEG of Freely Moving Rats

There is renewed interest in using electroencephalogram (EEG) as a tool to improve early diagnosis of neurological and behavioral disorders and to assist the preclinical development of related pharmacotherapies. Atypical dopamine uptake inhibitors (DUIs) bind with nano to micromolar affinities to the dopamine transporter and produce some of the effects of typical DUIs (i.e. cocaine) but have lower abuse potential, making them medication candidates for “stimulant” replacement pharmacotherapies. The aim of the current study is to establish an in‐vivo assay using EEG for the rapid classification of new chemical entities and the identification of DUIs with potential atypical profiles. EEG signals were collected from 6 stainless steel screws that served as electrodes implanted on the skull of male Sprague Dawley rats. These electrodes were connected through an electrode‐interface board to a connector on the animal's head. During 60 to 150 min experimental sessions, EEG signals, recorded through a digital headstage, were band passed between 0.1 to 250 Hz and digitized at 2 kHz. A pump delivered cumulative doses [mg/kg] of the standard DUI cocaine [0.1–3.2] and methylphenidate [0.1–5.6], the atypical DUI modafinil [1–32] and JHW 007 [1–10], the modafinil analog with improved solubility (−)‐JBG01049 [1–32], the mu‐opioid agonists morphine [0.32–17.8] and heroin [0.1–1] and the NMDA receptor antagonist ketamine [3.2–17.8], through an externalized jugular vein catheter. EEG power spectrum was estimated using the short‐time Fourier transform and grouped in 5 bands: Δ [0–4 Hz], θ [4–8 Hz], α [8–13], β [13–30], γ [30–50 Hz]. Power spectral values were normalized to the pre‐infusion interval [baseline] and expressed as % of baseline values. The standard DUIs dose‐dependently decreased power of the β and γ band to the same minimum [≈80%] with similar potency. Both modafinil and (−)‐JBG01049 decreased the power of β, but in contrast with cocaine, not of the γ frequency band. Administration of JHW007 did not significantly alter EEG power spectrum. Heroin and morphine dose‐dependently increased power of Δ, θ, α, β [≈ 140%] and decreased that of γ [≈ 70%] with different potencies (DR≈10). The effects of morphine on EEG power bands were antagonized by (−)‐naltrexone [0.032 mg/kg i.p.,]. Ketamine increased the power of all frequency bands. Therefore, standard and atypical DUIs and drugs of other classes differentially affected EEG spectra showing distinctive features in the magnitude and direction of the effect on different frequency bands. Comparative analysis of the effects of test drugs on EEG indicates a potential atypical profile of (−)‐JBG01049 with similar potency and effectiveness than its parent compound modafinil. These data suggest that EEG can be used to rapidly screen new chemical entities for potential activity at specific pharmacological targets and provide valuable information for guiding the early stages of drug development. Support or Funding Information Support provided by the Medication Development Program, NIDA‐IRP, NIH/DHHS; and by NIA‐IRP, NIH/DHHS This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .