In vivo pharmacological characterization of (±)-4-[2-(1-methyl-2-pyrrolidinyl)ethyl]thiophenol hydrochloride (SIB-1553A), a novel cholinergic ligand: microdialysis studies

• Published in: Brain research 2003-10, Vol.986 (1), p.71-81
• Main Authors: Rao, Tadimeti S, Reid, Richard T, Correa, Lucia D, Santori, Emily M, Gardner, Michael F, Sacaan, Aida I, Lorrain, Daniel, Vernier, Jean-Michel
• Format: Article
• Language: English
• Subjects: Acetylcholine - metabolism; Animals; Biological and medical sciences; Cholinergic Fibers - drug effects; Cholinergic Fibers - metabolism; Cholinergic system; Cognition Disorders - drug therapy; Cognition Disorders - metabolism; Cognition Disorders - physiopathology; Dopamine - metabolism; Drug Administration Routes; Hippocampal ACh release; Hippocampus - drug effects; Hippocampus - metabolism; Ligands; Male; Medical sciences; Microdialysis; nAChR agonist; Neostriatum - drug effects; Neostriatum - metabolism; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Nicotinic Agonists - blood; Nicotinic Agonists - pharmacokinetics; Nicotinic Antagonists - pharmacology; Pharmacology. Drug treatments; Phenols - blood; Phenols - pharmacokinetics; Prefrontal Cortex - drug effects; Prefrontal Cortex - metabolism; Pyrrolidines - blood; Pyrrolidines - pharmacokinetics; Rats; Rats, Sprague-Dawley; Receptors, Dopamine - drug effects; Receptors, Dopamine - metabolism; Receptors, Nicotinic - drug effects; Receptors, Nicotinic - metabolism; SIB-1553A; Synaptic Transmission - drug effects; Synaptic Transmission - physiology
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/S0006-8993(03)03174-3

SIB-1553A ((±)-4-[2-(1-methyl-2-pyrrolidinyl)ethyl]thiophenol HCl) is a neuronal nicotinic acetylcholine receptor (nAChR) ligand which is active in rodent and primate models of cognition. In functional assays, SIB-1553A exhibits marked subtype selectivity for nAChRs as compared to nicotine. In addition SIB-1553A also exhibits affinities to histaminergic (H 3) and serotonergic (5-HT 1 and 5HT 2) receptors and sigma binding sites. In the present investigation, we characterized SIB-1553A-induced neurotransmitter release in vivo. Following subcutaneous injection (s.c., 10 mg/kg), SIB-1553A rapidly entered the brain achieving concentration of approximately 20 μM 15 min post-injection and was eliminated from plasma with a terminal half-life of approximately 32 min. In freely moving rats, SIB-1553A (1–40 mg/kg, s.c.), markedly increased ACh release in the hippocampus and prefrontal cortex. In both regions, the magnitude of SIB-1553A-induced ACh release was greater than that seen with the prototypical nAChR agonist, nicotine (0.4 mg/kg, s.c.). Both isomers of SIB-1553A induced similar levels of increase in hippocampal ACh release. Increased hippocampal ACh release was also observed following oral administration of SIB-1553A (40 mg/kg) or after local perfusion into the hippocampus (1 mM). SIB-1553A-induced hippocampal ACh release was significantly attenuated by two nAChR antagonists, mecamylamine (MEC) and dihydro-β-erythroidine (DHβE), and by the dopamine (DA) (D1) antagonist, SCH-23390, arguing that ACh release, in part, involves activation of nAChRs and a permissive DA synapse. In contrast to its robust effects on ACh release, SIB-1553A (40 mg/kg, s.c.) modestly increased striatal DA release (∼180% of baseline). Due to the proposed role of cholinergic pathways in learning and memory, the neurochemical profile of SIB-1553A suggests a potential for it to treat cognitive dysfunction.