title: Mapping brain activity following administration of a nicotinic acetylcholine receptor agonist, ABT-594, using functional magnetic resonance imaging in awake rats.
abstract: Administration of ABT-594, a potent agonist for nicotinic acetylcholine receptors with selectivity for the alpha4beta2 receptor subtype, is known to modulate a diverse array of behaviors including those associated with nociception, anxiety and motor function. In this study, we sought to gain insight into the neural actions of ABT-594, in vivo, by conducting functional magnetic resonance imaging in awake and anesthetized rats. Using T(2)*-weighted gradient echo imaging and an ultrasmall superparamagnetic iron oxide contrast agent, functional imaging was conducted on a 4.7 T magnet to measure changes in relative cerebral blood volume. In awake, restrained, male Sprague-Dawley rats that were acclimated to the imaging environment, injection of ABT-594 (0.03-0.3 micromol/kg, i.v.) evoked changes to relative cerebral blood volume in several neural regions including the cingulate, somatosensory, motor, auditory, and pre-frontal cortices as well as the thalamus and the periaqueductal gray/dorsal raphe. These effects were typically bimodal with significant decreases in relative cerebral blood volume at the 0.03 micromol/kg dose and increases at the higher doses (0.1 and 0.3 micromol/kg). The decreases and increases in relative cerebral blood volume were often observed within the same region, but triggered by different doses. Both increases and decreases in relative cerebral blood volume were blocked by pretreatment with the noncompetitive nicotinic acetylcholine receptor antagonist, mecamylamine (5 micromol/kg, i.p.) in awake rats. Administration of ABT-594 (0.1 micromol/kg, i.v.) to alpha-chloralose-anesthetized rats did not significantly alter relative cerebral blood volume in any brain region suggesting an anesthetic-related interference with the effects of ABT-594. The neural regions affected by administration of ABT-594 corresponded well to the known pre-clinical behavioral profile for this compound, and demonstrate the utility of using functional magnetic resonance imaging in awake animals to study pharmacological action.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, R4CL, AP9-1, 100 Abbott Park Road, Abbott Park, IL 60064-6118, USA.
authors.forename: P D
authors.initials: PD
authors.lastname: Skoubis
authors.forename: V
authors.initials: V
authors.lastname: Hradil
authors.forename: C-L
authors.initials: CL
authors.lastname: Chin
authors.forename: Y
authors.initials: Y
authors.lastname: Luo
authors.forename: G B
authors.initials: GB
authors.lastname: Fox
authors.forename: S
authors.initials: S
authors.lastname: McGaraughty
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D018686:Anesthetics, Intravenous / Q000494:pharmacology; D000818:Animals; D001384:Azetidines / Q000494:pharmacology*; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism*; D001931:Brain Mapping; D002560:Cerebrovascular Circulation / Q000187:drug effects* / Q000502:physiology; D002698:Chloralose / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004347:Drug Interactions / Q000502:physiology; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010146:Pain / Q000378:metabolism / Q000503:physiopathology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D014851:Wakefulness / Q000187:drug effects / Q000502:physiology
chemical_list: C109763:5-(2-azetidinylmethoxy)-2-chloropyridine; D018686:Anesthetics, Intravenous; D001384:Azetidines; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011725:Pyridines; D011978:Receptors, Nicotinic; D002698:Chloralose; D000109:Acetylcholine