1.A novel choline-sensitive nicotinic receptor subtype that mediates enhanced GABA release in the chick ventral lateral geniculate nucleus.
Guo JZ;Chiappinelli VA Neuroscience. 2002;110(3):505-13.
Nicotinic acetylcholine receptors modulate the release of GABA, glutamate, acetylcholine and dopamine in the brain. Here we describe a novel choline-sensitive nicotinic acetylcholine receptor that mediates enhanced GABA release in the chick ventral lateral geniculate nucleus. Whole-cell recordings in slices demonstrated that choline (0.03-10 mM), generally considered an alpha7-selective agonist, and carbachol (3-300 microM), a non-selective cholinergic agonist, both increased the frequency of spontaneous GABAergic events in ventral lateral geniculate nucleus neurons. Tetrodotoxin (0.5 microM) partially reduced responses to carbachol, but eliminated responses to choline. During long-term (5 min) exposure to choline the GABA enhancement was maintained until choline was washed out. Choline (300 microM) enhanced the frequency of spontaneous GABAergic events by 4.28-fold in control artificial cerebrospinal fluid. This choline-mediated enhancement was significantly reduced by the following nicotinic acetylcholine receptor antagonists: 1 microM dihydro-beta-erythroidine (1.49-fold increase, P<0.001), 1 microM methyllycaconitine (1.53-fold, P<0.001) and 0.2 microM alpha-conotoxin ImI (1.84-fold, P<0.
2.The α3β4* nicotinic ACh receptor subtype mediates physical dependence to morphine: mouse and human studies.
Muldoon PP;Jackson KJ;Perez E;Harenza JL;Molas S;Rais B;Anwar H;Zaveri NT;Maldonado R;Maskos U;McIntosh JM;Dierssen M;Miles MF;Chen X;De Biasi M;Damaj MI Br J Pharmacol. 2014 Aug;171(16):3845-57. doi: 10.1111/bph.12741.
BACKGROUND AND PURPOSE: ;Recent data have indicated that α3β4* neuronal nicotinic (n) ACh receptors may play a role in morphine dependence. Here we investigated if nACh receptors modulate morphine physical withdrawal.;EXPERIMENTAL APPROACHES: ;To assess the role of α3β4* nACh receptors in morphine withdrawal, we used a genetic correlation approach using publically available datasets within the GeneNetwork web resource, genetic knockout and pharmacological tools. Male and female European-American (n = 2772) and African-American (n = 1309) subjects from the Study of Addiction: Genetics and Environment dataset were assessed for possible associations of polymorphisms in the 15q25 gene cluster and opioid dependence.;KEY RESULTS: ;BXD recombinant mouse lines demonstrated an increased expression of α3, β4 and α5 nACh receptor mRNA in the forebrain and midbrain, which significantly correlated with increased defecation in mice undergoing morphine withdrawal. Mice overexpressing the gene cluster CHRNA5/A3/B4 exhibited increased somatic signs of withdrawal. Furthermore, α5 and β4 nACh receptor knockout mice expressed decreased somatic withdrawal signs compared with their wild-type counterparts.
3.Relating neuronal nicotinic acetylcholine receptor subtypes defined by subunit composition and channel function.
Nai Q;McIntosh JM;Margiotta JF Mol Pharmacol. 2003 Feb;63(2):311-24.
Neuronal nicotinic acetylcholine receptors (nAChRs) are widespread, diverse ion channels involved in synaptic signaling, addiction, and disease. Despite their importance, the relationship between native nAChR subunit composition and function remains poorly defined. Chick ciliary ganglion neurons express two major nAChR types: those recognized by alpha-bungarotoxin (alphaBgt), nearly all of which contain only alpha7 subunits (alpha7-nAChRs) and those insensitive to alphaBgt, which contain alpha3, alpha5, beta4, and, in some cases, beta2 subunits (alpha3*-nAChRs). We explored the relationship between nAChR composition and channel function using toxins recognizing alpha7 subunits (alphaBgt), and alpha3/beta4 (alpha-conotoxin-AuIB), or alpha3/beta2 (alpha-conotoxin-MII) subunit interfaces to perturb responses induced by nicotine, alpha7-, or alpha3-selective agonists (GTS-21 or epibatidine, respectively). Using these reagents, fast-decaying whole-cell current components were attributed solely to alpha7-nAChRs, and slow-decaying components mostly to alpha3*-nAChRs. In outside-out patches, nicotine activated brief 60- and 80-pS single nAChR channel events, and mixed-duration 25- and 40-pS nAChR events.
