N,N′-Alkane-diyl-bis-3-picoliniums as Nicotinic Receptor Antagonists: Inhibition of Nicotine-Evoked Dopamine Release and Hyperactivity

Abstract

The current study evaluated a new series of N, analogs with C 6 -C 12 methylene linkers as nicotinic acetylcholine receptor (nAChR) antagonists, for nicotine-evoked [ 3 H]dopamine (DA) overflow, for blood-brain barrier choline transporter affinity, and for attenuation of discriminative stimulus and locomotor stimulant effects of nicotine. bAPi analogs exhibited little affinity for ␣4␤2* (* indicates putative nAChR subtype assignment) and ␣7* high-affinity ligand binding sites and exhibited no inhibition of DA transporter function. With the exception of C 6 , all analogs inhibited nicotine-evoked [ 3 H]DA overflow (IC 50 ϭ 2 nM-6 M; I max ϭ 54 -64%), with N, C 12 ) being most potent. bPiDDB did not inhibit electrically evoked [ 3 H]DA overflow, suggesting specific nAChR inhibitory effects and a lack of toxicity to DA neurons. Schild analysis suggested that bPiDDB interacts in an orthosteric manner at nAChRs mediating nicotine-evoked [ 3 H]DA overflow.To determine whether bPiDDB interacts with ␣-conotoxin MIIsensitive ␣6␤2-containing nAChRs, slices were exposed concomitantly to maximally effective concentrations of bPiDDB (10 nM) and ␣-conotoxin MII (1 nM). Inhibition of nicotine-evoked [ 3 H]DA overflow was not different with the combination compared with either antagonist alone, suggesting that bPiDDB interacts with ␣6␤2-containing nAChRs. C 7 , C 8 , C 10 , and C 12 analogs exhibited high affinity for the blood-brain barrier choline transporter in vivo, suggesting brain bioavailability. Although none of the analogs altered the discriminative stimulus effect of nicotine, C 8 , C 9 , C 10 , and C 12 analogs decreased nicotine-induced hyperactivity in nicotine-sensitized rats, without reducing spontaneous activity. Further development of nAChR antagonists that inhibit nicotine-evoked DA release and penetrate brain to antagonize DA-mediated locomotor stimulant effects of nicotine as novel treatments for nicotine addiction is warranted.Nicotine, the principal tobacco alkaloid, is an agonist at neuronal nicotinic acetylcholine receptor (nAChR) subtypes modulating dopamine (DA) release. Habitual tobacco smoking is maintained via rapid nicotine delivery to brain (Le Foll and Goldberg, 2006) and results from the intrinsic rewarding properties of nicotine, believed to be due to increased DA release. Classical nAChR antagonists mecamylamine and dihydro-␤-erythroidine (DH␤E) inhibit nicotine-evoked DA release and decrease the locomotor stimulant and reinforcing effects of nicotine in rats Watkins et al., 1999;Rahman et al., 2004), suggesting a role for nAChRmediated DA release in these abuse-related behavioral efThis research was supported by National Institutes of Health Grants K02 DA00399, T32 DA007304, and U19 DA017548.Potential royalty payments to L.P.D., P.A.C., and J.T.A. may occur consistent with the University of Kentucky policy.Article, publication date, and citation information can be found at

The Novel Pyrrolidine Nor-Lobelane Analog UKCP-110 [cis-2,5-di-(2-phenethyl)-pyrrolidine hydrochloride] Inhibits VMAT2 Function, Methamphetamine-Evoked Dopamine Release, and Methamphetamine Self-Administration in Rats

“…Mechanisms that govern cue effects in drug discrimination are often similar to mechanisms that govern the reinforcing effects of a particular compound (Schuster et al, 1981), although dissociation between these two effects have been observed. For example, the nAChR antagonist N, picolinium dibromide, which has been reported to selectively inhibit ␣6␤2-containing nAChRs, effectively attenuates nicotine self-administration without blocking nicotine cue effects in drug discrimination assays (Neugebauer et al, 2006;Dwoskin et al, 2008). This dissociation suggests that nicotine drug discrimination and self-administration may be governed by separate underlying neurochemical mechanisms.…”

Nicotinic Receptor Antagonists as Treatments for Nicotine Abuse

“…In summary, bPiDDB is a selective, noncompetitive inhibitor of α6β2* nAChRs; bPiDDB inhibits [ 3 H]-nicotine and [ 3 H]-MLA binding (α4β2* and α7* nAChRs, respectively) only at high concentrations (>10 µM; Dwoskin et al, 2008) and decreases nicotine self-administration in rats. Furthermore, bPiDDB (1 µM) produced only 15% and 12% inhibition of acetylcholine (1 mM) -induced current at ganglionic-type α3β4 nAChRs and muscle-type α1β1εδ nAChRs, respectively, expressed in Xenopus oocytes (unpublished data).…”

“…It should be noted that when administered peripherally, several bis-quaternary ammonium antagonists, including bPiDDB, specifically decreased nicotine self-administration and reinstatement of nicotine seeking in rats, providing proof of concept of this representative class of drug as a new pharmacotherapy for nicotine addiction. Additional behavioral studies in the rat have been carried out on other structurally related N,N ′-alkane-diyl-bis-3-picoliniums (Dwoskin et al, 2008; Wooters et al, 2011). …”

Angiotensin AT1 and AT2 receptor antagonists modulate nicotine-evoked [3H]dopamine and [3H]norepinephrine release

“…The interaction of losartan and PD123319 with α4μ2* and α7* nAChRs was evaluated in [ 3 H]nicotine and [ 3 H]methyllycaconitine binding assays, respectively, using a previously described method [45]. Membrane suspensions (100-140 μg protein/100 μl) were prepared from whole brain (excluding cortex and cerebellum) and incubated for 60 min (250 μl final volume) at room temperature in tubes containing losartan (1 nM-1 mM) or PD123319 (1 nM-1 mM) with either 3 nM [ 3 H]nicotine or 3 nM [ 3 H]methyllycaconitine.…”