Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
4329084 | Brain Research | 2008 | 9 Pages |
Abstract
(S)-(2)-5-ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine HCl (SIB-1508Y, Altinicline), is a subtype-selective neuronal nicotinic acetylcholine receptor (nAChR) agonist. In rodents, SIB-1508Y exhibited antidepressant activity, reversed age-related decrements in vigilance, and improved motor and cognitive function in primate models of Parkinson's disease. The goal of the study was to explore neurochemical effects of SIB-1508Y and its isomer, SIB-1680WD. In vitro, SIB-1508Y increased dopamine (DA) release from slices of rat striatum, nucleus accumbens (NAc), olfactory tubercles (OT) and prefrontal cortices (PFC) in a concentration-dependent manner. Relative to its robust effects on DA release from various brain regions, SIB-1508Y was minimally effective at increasing NE release from hippocampus or PFC, and 5-HT release from PFC. SIB-1680WD was less potent and efficacious than SIB-1508Y, but did not act as a partial agonist. Subcutaneous injection of SIB-1508Y (10 mg/kg) increased striatal DA release and this release was sensitive to blockade by the non-competitive nAChR antagonist, mecamylamine (Mec). SIB-1508Y also increased hippocampal ACh release selectively without affecting striatal ACh release. Hippocampal ACh release evoked by SIB-1508Y was attenuated by nAChR antagonists Mec and Dihydro-β-erythroidine (DHβE), and also by the DA D1 receptor antagonist, SCH-23390. These results are consistent with previously established pharmacology of nAChR regulation of hippocampal ACh release. Repeated administration of SIB-1508Y did not result in an enhanced striatal DA release or hippocampal ACh release. In summary, the abilities of SIB-1508Y to release multiple neurotransmitters in distinct brain regions may contribute to its behavioral profile.
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Authors
Tadimeti S. Rao, Pamala B. Adams, Lucia D. Correa, Emily M. Santori, Aida I. Sacaan, Richard T. Reid, Nicholas D.P. Cosford,