Mecamylamine, dihydro-β-erythroidine, and dextromethorphan block conditioned responding evoked by the conditional stimulus effects of nicotine

Abstract

Current smokers express the desire to quit. However, the majority find it difficult to remain abstinent. As such, research efforts continually seek to develop more effective treatment. One such area of research involves the interoceptive stimulus effects of nicotine as either a discriminative stimulus in an operant drug discrimination task, or more recently as a conditional stimulus (CS) in a discriminated goal-tracking task. The present work investigated the potential role nicotinic acetylcholine receptors in the CS effects of nicotine (0.4 mg/kg) using antagonists with differential selectivity for β2*, α7*, α6β2*, and α3β4* receptors. Methyllycaconitine (MLA) had no effect on nicotine-evoked conditioned responding. Mecamylamine and dihydro-β-erythroidine (DHβE) dose dependently blocked responding evoked by the nicotine CS. In a time-course assessment of mecamylamine and DHβE, each blocked conditioned responding when given 5 min before testing and still blocked conditioned responding when administered 200 min before testing. Two novel bis-picolinium analogs (N, N'-(3, 3′-(dodecan-1,12-diyl)-bis-picolinium dibromide [bPiDDB], and N, N'-(decan-1,10-diyl)-bis-picolinium diiodide [bPiDI]) did not block nicotine-evoked conditioned responding. Finally, pretreatment with low dose combinations of mecamylamine, dextromethorphan, and/or bupropion were used to target α3β4* receptors. No combination blocked conditioned responding evoked by the training dose of nicotine. However, a combination of mecamylamine and dextromethorphan partially blocked nicotine-evoked conditioned responding to a lower dose of nicotine (0.1 mg/kg). These results indicate that β2* and potentially α3β4* nicotinic acetylcholine receptors play a role in the CS effects of nicotine and are potential targets for the development of nicotine cessation aids.

Pharmacologic Characterization of a Nicotine-Discriminative Stimulus in Rhesus Monkeys

“…In addition to differences in selectivity for receptor subtypes, DH␤E is a competitive antagonist, whereas mecamylamine is a noncompetitive antagonist (Williams and Robinson, 1984;Varanda et al, 1985). DH␤E has been shown to antagonize the discriminative stimulus effects of nicotine in previous studies Gommans et al, 2000;Shoaib et al, 2000;Struthers et al, 2009). However, antagonism of nicotine by DH␤E is not unanimously reported when the training dose of nicotine is relatively large Jutkiewicz et al, 2011).…”

Selective nicotinic receptor antagonists: effects on attention and nicotine-induced attentional enhancement

“…We chose lower doses of the antagonists than previously tested. The largest test dose of DHβE was chosen to be the lowest dose to fully antagonize effects of nicotine in previous studies (Stolerman et al 1997;Blondel et al 2000;Grottick and Higgins 2000;Struthers et al 2009). The dose range of MLA was chosen such that the largest dose tested produced complete blockade of α7 nAChR responses in vitro (Alkondon et al 1992;Turek et al 1995) and approached doses previously tested in animal models of attention (Blondel et al 2000;Grottick and Higgins 2000;Shoaib and Bizarro 2005).…”

Improving the Stability of α-Conotoxin AuIB Through N-to-C Cyclization: The Effect of Linker Length on Stability and Activity at Nicotinic Acetylcholine Receptors

“…AuIB is a specific antagonist of the neuronal a 3 b 4 nAChR, making it a useful tool for probing the physiological functions maintained by this nAChR subtype (37). Antagonists of a 3 b 4 nAChRs have been shown to decrease nicotine self-administration in rats, suggesting that this receptor is also a potential target for treating nicotine dependence (23,43). As such, the discovery of new a 3 b 4 nAChR antagonists could have profound implications as in vivo research tools in the development of novel smoking cessation treatments.…”