Pharmacological MRI in awake rats reveals neural activity in area postrema and nucleus tractus solitarius: relevance as a potential biomarker for detecting drug-induced emesis.
Drug-induced vomiting (emesis) is a major concern in patient care and a significant hurdle in the development of novel therapeutics. With respect to the latter, rodents, such as the rat and mouse, are typically used in efficacy and safety studies; however, drug-induced emesis cannot be readily observed in these species due to the lack of an emetic reflex. It is known that emesis can be triggered by neural activity in brain regions including area postrema (AP) and nucleus tractus solitarius (NTS). In this study, using pharmacological magnetic resonance imaging (phMRI) and a blood-pool contrast agent, we imaged the hemodynamic consequences of brain activity in awake rats initiated by the administration of compounds (apomorphine 0.1, 0.3 micromol/kg i.v. and ABT-594 0.03, 0.1, 0.3 micromol/kg i.v.) that elicit emesis in other species. Regional drug-induced relative cerebral blood volume (rCBV) changes and percent activated area within the AP and NTS were calculated, in which a dose-dependent relationship was evident for both apomorphine and ABT-594. Additionally, to correlate with behavioral readouts, it was found that the activation of AP and NTS was observed at plasma concentrations consistent with those that induced emesis in ferrets for both drugs. Our data thus suggest that phMRI in awake rats may be a useful tool for predicting emetic liability of CNS-acting drugs and may provide insights into depicting the underlying emetic neural pathways in vivo.
Chin
Chih-Liang
CL
Global Pharmaceutical Research and Development, Abbott Laboratories, R46R Bldg. AP9-1, 100 Abbott Park Road, Abbott Park, IL 60064-6119, USA.
Fox
Gerard B
GB
Hradil
Vincent P
VP
Osinski
Mark A
MA
McGaraughty
Steve P
SP
Skoubis
Pamela D
PD
Cox
Bryan F
BF
Luo
Yanping
Y
D000818:Animals; D001058:Apomorphine / Q000009:adverse effects*; D031608:Area Postrema / Q000187:drug effects* / Q000503:physiopathology*; D001384:Azetidines / Q000009:adverse effects*; D018491:Dopamine Agonists / Q000009:adverse effects*; D008279:Magnetic Resonance Imaging; D008297:Male; D011725:Pyridines / Q000009:adverse effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017552:Solitary Nucleus / Q000187:drug effects* / Q000503:physiopathology*; D014839:Vomiting / Q000139:chemically induced* / Q000503:physiopathology*; D014851:Wakefulness / Q000502:physiology*
C109763:5-(2-azetidinylmethoxy)-2-chloropyridine; D001384:Azetidines; D018491:Dopamine Agonists; D011725:Pyridines; D001058:Apomorphine