α-Conotoxin TxIB: A Uniquely Selective Ligand for α6/α3β2β3 Nicotinic Acetylcholine Receptor Attenuates Nicotine-Induced Conditioned Place Preference in Mice

Abstract

α-Conotoxin TxIB is a specific antagonist of α6/α3β2β3(α6β2*) nicotinic acetylcholine receptor (nAChR) with an IC50 of 28 nM. Previous studies have shown that α6β2* nAChRs are abundantly expressed in midbrain dopaminergic neurons and play an important role in mediating the mechanism of nicotine and other drugs reward effect. It provided important targets for the development of anti-addiction drugs. The present study evaluated the pharmacological activity of TxIB in vivo with conditioned place preference (CPP) model, which were induced by subcutaneous injection (s.c.) of nicotine (NIC, 0.5 mg/kg). α-Conotoxin TxIB inhibited the expression and reinstatement of CPP in mice dose-dependently, but had no significant effect on locomotor activity. The concentrations of dopamine (DA), γ-aminobutyric acid (GABA) and noradrenaline (NE) in different brain regions were measured by enzyme-linked immunosorbent assay (ELISA). We found that TxIB could inhibit the concentrations of DA, GABA and NE in different brain regions (such as nucleus accumbens (NAc), hippocampus (HIP) and prefrontal cortex (PFC)) in NIC-induced mice. The concentrations of DA and NE were decreased in ventral tegmental area (VTA), while GABA had little change. The current work described the inhibition activity of TxIB in NIC-induced CPP, suggesting that α6β2* nAChR-targeted compound may be a promising drug for nicotine addiction treatment.

α-Conotoxin TxID and [S9K]TxID, α3β4 nAChR Antagonists, Attenuate Expression and Reinstatement of Nicotine-Induced Conditioned Place Preference in Mice

“…The results showed that activation of α7 nAChRs can mediate the nicotine primary reinforcement and prevent smoking relapse triggered [ 36 , 37 ]. Previous studies had shown that the α6β2* nAChRs antagonists could inhibit nicotine addiction in the CPP model and self-administration of the nicotine [ 38 , 39 , 40 ]. Currently, increasing evidence suggests that the α3β4 nAChRs play an important role in nicotine addiction and withdrawal [ 9 , 27 , 41 , 42 ].…”

Selecting Potential Neuronal Drug Leads from Conotoxins of Various Venomous Marine Cone Snails in Bali, Indonesia

“…49 Furthermore, this group of cholinergic receptors has been recently known to be involved in the nicotine reward effect. 50 Because ACh is known as a dopamine release regulator, α-conotoxins may potentially exhibit a salutary effect in psychoses and Tourette’s syndrome treatment. 51 We assigned 27 peptides from six species to the α pharmacological class, which acts upon this receptor.…”

Characterization of an α 4/7-Conotoxin LvIF from Conus lividus That Selectively Blocks α3β2 Nicotinic Acetylcholine Receptor

“…The bacterial solution was centrifuged at 5000× g to obtain the cell precipitation, and the plasmid extraction kit was used to extract the plasmid. The plasmids containing various nAChRs subunits were digested with corresponding restriction endonucleases [ 48 , 49 , 50 , 51 , 52 , 53 ], and then the linearized DNA products were purified by Minibest DNA fragment recovery kit (TaKaRa, Beijing, China) and used as a template for in vitro transcription. The linearized DNA templates were transcribed by using mMESSAGE mMACHINE Kit (Thermo Fisher Scientific) at 37 °C for 4 h, and the 1 µL DNase was added and treated for 30 min to hydrolyze the DNA transcription template after the completion of transcription.…”