The mechanism of nicotinic acetylcholine receptor (nAChR)-induced hippocampal dopamine (DA) release was investigated using rat hippocampal slices. nAChRs involved in hippocampal DA and norepinephrine (NE) release were investigated using prototypical agonists and antagonists and several relatively novel compounds: ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine], (+/-)-UB-165 [(2-chloro-5-pyridyl)-9-azabicyclo [4.2.1]non2-ene], and MG 624 [N,N,N-triethyl-2-[4-(2 phenylethenyl)phenoxy]-ethanaminium iodine]. (+/-)-Epibatidine, (+/-)-UB-165, anatoxin-a, ABT-594, (-)-nicotine, 1,1-dimethyl-4-phenyl-piperazinium iodide, and (-)-cytisine (in decreasing order of potency) evoked [(3)H]DA release in a mecamylamine-sensitive manner. Aside from (+/-)-UB-165, all the agonists displayed full efficacy relative to 100 microM (-)-nicotine in [(3)H]DA release. In contrast, (+/-)-UB-165 was a partial agonist, evoking 58% of 100 microM (-)-nicotine response. Mecamylamine, MG 624, hexamethonium, d-tubocurare, and dihydro-beta-erythroidine (in decreasing order of potency), but not alpha-conotoxin-MII, methyllycaconitine, alpha-conotoxin-ImI, or alpha-bungarotoxin, attenuated 100 microM (-)-nicotine-evoked [(3)H]DA release in a concentration-dependent manner. (+/-)-UB-165, ABT-594, and MG 624 exhibited different pharmacologic profiles in the [(3)H]NE release assay when compared with their effect on [(3)H]DA release. ABT-594 was 4.5-fold more potent, and (+/-)-UB-165 was a full agonist in contrast to its partial agonism in [(3)H]DA release. MG 624 potently and completely blocked NE release evoked by 100 microM (-)-nicotine and 10 microM (+/-)-UB-165, whereas it only partially inhibited (-)-nicotine-evoked [(3)H]DA release. In conclusion, we provide evidence that [(3)H]DA can be evoked from the hippocampus and that the pharmacologic profile for nAChR-evoked hippocampal [(3)H]DA release suggests the involvement of alpha3beta4(*) and at least one other nAChR subtype, thus distinguishing it from that of nAChR-evoked hippocampal [(3)H]NE release.

2005-01-01·Neuropharmacology2区 · 医学

Different nicotinic acetylcholine receptor subtypes mediating striatal and prefrontal cortical [3H]dopamine release

2区 · 医学

Article

作者: Pamela S. Puttfarcken ; Ying-Jun Cao ; Carol S. Surowy

Different nicotinic acetylcholine receptor subtypes appear to modulate dopamine release from the striatum and prefrontal cortex. In this study a combination of subtype-selective antagonists and agonists were used to extensively characterize the nAChRs involved in dopamine release from slice preparations of these two brain regions. alpha-conotoxin-MII inhibited nicotine-evoked [3H]dopamine (DA) release from striatum by 45%, but did not affect cortical dopamine release. Neither methyllycaconitine, alpha-bungarotoxin, nor alpha-conotoxin-ImI affected nicotine-evoked [3H]DA release from either striatum or prefrontal cortex. MG 624, a novel selective nAChR antagonist, inhibited cortical [3H]DA by 53%, but had no effect on striatal release. Compared to nicotine, (+/-)-UB-165 showed less efficacy with respect to dopamine release from striatum, and had no effect on cortical dopamine release. (+/-)-UB-165-evoked striatal dopamine release was completely blocked by mecamylamine, partially blocked (up to 55%) by alpha-conotoxin-MII, and unaffected by methyllycaconitine or alpha-conotoxin-ImI. alpha4beta2* and alpha6beta2beta3* nAChRs appear to play a role in striatal dopamine release, whereas alpha4beta2* nAChRs modulate release from prefrontal cortex. alpha7* nAChRs do not appear to play a role in nAChR-mediated dopamine release from either brain region.

2003-11-01·Journal of neurophysiology3区 · 医学

β-Amyloid Peptide Activates Non-α7 Nicotinic Acetylcholine Receptors in Rat Basal Forebrain Neurons

3区 · 医学

Article

作者: Jhamandas, Jack H. ; Fu, Wen

Alzheimer's disease (AD) is a progressive neurodegenerative condition characterized by profound deficits in memory and cognitive function. Neuropathological hallmarks of the disease include a loss of basal forebrain cholinergic neurons and the deposition of β-amyloid peptide (Aβ) in neuritic plaques. At a cellular level, considerable attention has focused on a study of Aβ interactions with the neuronal nicotinic acetylcholine receptor (nAChR) subtypes. In this study, using cell-attached and outside-out single channel recordings from acutely dissociated rat basal forebrain neurons, we report that Aβ and nicotine activate nAChRs with two distinct levels of single-channel conductance. Whole cell recordings from these neurons reveal Aβ and nicotine, in a concentration-dependent and reversible manner, evoke brisk depolarizing responses and an inward current. The effects of Aβ on both single channel and whole cell are blocked by the noncompetitive nAChR antagonist mecamylamine and competitive nAChR antagonist dihydro-beta-erythroidine, but not the specific α7-selective nAChR antagonist methyllycaconitine, indicating that Aβ activated non-α7 nAChRs on basal forebrain neurons. In addition, the non-α7 nAChR agonists UB-165, epibatidine, and cytisine, but not the selective α7 agonist AR-R17779, induced similar responses as Aβ and nicotine. Thus non-α7 nAChRs may also represent a novel target in mediating the effects of Aβ in AD.

100 项与 UB-165 相关的药物交易

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