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

The current study evaluated a new series of N,N′-alkane-diyl-bis-3-picolinium (bAPi) analogs with C6–C12 methylene linkers as nicotinic acetylcholine receptor (nAChR) antagonists, for nicotine-evoked [3H]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 α4β2* (* indicates putative nAChR subtype assignment) and α7* high-affinity ligand binding sites and exhibited no inhibition of DA transporter function. With the exception of C6, all analogs inhibited nicotine-evoked [3H]DA overflow (IC50 = 2 nM–6 μM; Imax = 54–64%), with N,N′-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB; C12) being most potent. bPiDDB did not inhibit electrically evoked [3H]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 [3H]DA overflow. To determine whether bPiDDB interacts with α-conotoxin MII-sensitive α6β2-containing nAChRs, slices were exposed concomitantly to maximally effective concentrations of bPiDDB (10 nM) and α-conotoxin MII (1 nM). Inhibition of nicotine-evoked [3H]DA overflow was not different with the combination compared with either antagonist alone, suggesting that bPiDDB interacts with α6β2-containing nAChRs. C7, C8, C10, and C12 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, C8, C9, C10, and C12 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.

[1]  L. Dwoskin,et al.  Nicotine increases dopamine clearance in medial prefrontal cortex in rats raised in an enriched environment , 2007, Journal of neurochemistry.

[2]  A. C. Collins,et al.  Pharmacology of α-Conotoxin MII-Sensitive Subtypes of Nicotinic Acetylcholine Receptors Isolated by Breeding of Null Mutant Mice , 2007, Molecular Pharmacology.

[3]  J. Changeux,et al.  Catecholamine outflow from mouse and rat brain slice preparations evoked by nicotinic acetylcholine receptor activation and electrical field stimulation , 2007, British journal of pharmacology.

[4]  R. Bevins,et al.  Behavioral and neuropharmacological characterization of nicotine as a conditional stimulus. , 2007, European journal of pharmacology.

[5]  R. Poland,et al.  Mecamylamine Attenuates Cue-Induced Reinstatement of Nicotine-Seeking Behavior in Rats , 2007, Neuropsychopharmacology.

[6]  L. Dwoskin,et al.  The effects of a novel nicotinic receptor antagonist N,N-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB) on acute and repeated nicotine-induced increases in extracellular dopamine in rat nucleus accumbens , 2007, Neuropharmacology.

[7]  Steven R. Goldberg,et al.  Nicotine as a typical drug of abuse in experimental animals and humans , 2006, Psychopharmacology.

[8]  L. Dwoskin,et al.  Effect of a novel nicotinic receptor antagonist, N,N′-dodecane-1,12-diyl-bis-3-picolinium dibromide, on nicotine self-administration and hyperactivity in rats , 2006, Psychopharmacology.

[9]  A. C. Collins,et al.  Expression of Nigrostriatal α6-Containing Nicotinic Acetylcholine Receptors Is Selectively Reduced, but Not Eliminated, by β3 Subunit Gene Deletion , 2005, Molecular Pharmacology.

[10]  P. Sokoloff,et al.  Dopamine D3 Receptor Ligands Block Nicotine-Induced Conditioned Place Preferences through a Mechanism that does not Involve Discriminative-Stimulus or Antidepressant-Like Effects , 2005, Neuropsychopharmacology.

[11]  C. Surowy,et al.  Different nicotinic acetylcholine receptor subtypes mediating striatal and prefrontal cortical [3H]dopamine release , 2005, Neuropharmacology.

[12]  W. Danysz,et al.  Drug discrimination analysis of NMDA receptor channel blockers as nicotinic receptor antagonists in rats , 2005, Psychopharmacology.

[13]  W. Geldenhuys,et al.  Cation Transport Specificity at the Blood–Brain Barrier , 2004, Neurochemical Research.

[14]  J. Zhang,et al.  Local Perfusion of Nicotine Differentially Modulates Somatodendritic Dopamine Release in the Rat Ventral Tegmental Area After Nicotine Preexposure , 2004, Neurochemical Research.

[15]  A. C. Collins,et al.  Subunit composition and pharmacology of two classes of striatal presynaptic nicotinic acetylcholine receptors mediating dopamine release in mice. , 2004, Molecular pharmacology.

[16]  L. Dwoskin,et al.  Subtype-selective nicotinic receptor antagonists: potential as tobacco use cessation agents. , 2004, Bioorganic & medicinal chemistry letters.

[17]  A. C. Collins,et al.  The β3 Nicotinic Receptor Subunit: A Component of α-Conotoxin MII-Binding Nicotinic Acetylcholine Receptors that Modulate Dopamine Release and Related Behaviors , 2003, The Journal of Neuroscience.

[18]  L. Dwoskin,et al.  N-n-Alkylpyridinium Analogs, a Novel Class of Nicotinic Receptor Antagonists: Selective Inhibition of Nicotine-Evoked [3H]Dopamine Overflow from Superfused Rat Striatal Slices , 2003, Journal of Pharmacology and Experimental Therapeutics.

[19]  J. Changeux,et al.  Effects of nicotine in the dopaminergic system of mice lacking the alpha4 subunit of neuronal nicotinic acetylcholine receptors , 2003, The European journal of neuroscience.

[20]  L. Dwoskin,et al.  Active Transport of High-Affinity Choline and Nicotine Analogs into the Central Nervous System by the Blood-Brain Barrier Choline Transporter , 2003, Journal of Pharmacology and Experimental Therapeutics.

[21]  L. Dwoskin,et al.  N-n-Alkylnicotinium Analogs, a Novel Class of Nicotinic Receptor Antagonists: Interaction with α4β2* and α7* Neuronal Nicotinic Receptors , 2003, Journal of Pharmacology and Experimental Therapeutics.

[22]  M. Zoli,et al.  Identification of the Nicotinic Receptor Subtypes Expressed on Dopaminergic Terminals in the Rat Striatum , 2002, The Journal of Neuroscience.

[23]  L. Dwoskin,et al.  N-n-alkylpyridinium analogs, a novel class of nicotinic receptor antagonists: selective inhibition of nicotine-evoked [3H] dopamine overflow from superfused rat striatal slices. , 2002 .

[24]  F. Leslie,et al.  Expression of neuronal nicotinic acetylcholine receptor subunit mRNAs within midbrain dopamine neurons , 2002, The Journal of comparative neurology.

[25]  P. Clarke,et al.  Disruption of dopaminergic neurotransmission in nucleus accumbens core inhibits the locomotor stimulant effects of nicotine and d-amphetamine in rats , 2001, Neuropharmacology.

[26]  Michele Zoli,et al.  Molecular and Physiological Diversity of Nicotinic Acetylcholine Receptors in the Midbrain Dopaminergic Nuclei , 2001, The Journal of Neuroscience.

[27]  S. Wonnacott,et al.  alpha-bungarotoxin-sensitive nicotinic receptors indirectly modulate [(3)H]dopamine release in rat striatal slices via glutamate release. , 2000, Molecular pharmacology.

[28]  G. Koob,et al.  Blockade of Nicotine Self-Administration with Nicotinic Antagonists in Rats , 1999, Pharmacology Biochemistry and Behavior.

[29]  P. Clarke,et al.  Effect of ventral tegmental 6-hydroxydopamine lesions on the locomotor stimulant action of nicotine in rats , 1998, Neuropharmacology.

[30]  J. Changeux,et al.  Acetylcholine receptors containing the β2 subunit are involved in the reinforcing properties of nicotine , 1998, Nature.

[31]  L. Teng,et al.  Nicotinic-receptor mediation of S(-)nornicotine-evoked -3H-overflow from rat striatal slices preloaded with -3H-dopamine. , 1997, The Journal of pharmacology and experimental therapeutics.

[32]  J. McIntosh,et al.  α-Conotoxin MII Blocks Nicotine-Stimulated Dopamine Release in Rat Striatal Synaptosomes , 1997, The Journal of Neuroscience.

[33]  D. Yoshikami,et al.  A New -Conotoxin Which Targets 32 Nicotinic Acetylcholine Receptors (*) , 1996, The Journal of Biological Chemistry.

[34]  Andrew N. Rowan.  Guide for the Care and Use of Laboratory Animals , 1996 .

[35]  W. Corrigall,et al.  Self-administered nicotine activates the mesolimbic dopamine system through the ventral tegmental area , 1994, Brain Research.

[36]  E. Levin,et al.  Mecamylamine combined with nicotine skin patch facilitates smoking cessation beyond nicotine patch treatment alone , 1994, Clinical pharmacology and therapeutics.

[37]  W. Corrigall,et al.  Dopamine mechanisms play at best a small role in the nicotine discriminative stimulus , 1994, Pharmacology Biochemistry and Behavior.

[38]  A. C. Collins,et al.  Characterization of Nicotinic Receptor‐Mediated [3H]Dopamine Release from Synaptosomes Prepared from Mouse Striatum , 1992, Journal of neurochemistry.

[39]  M. Benwell,et al.  The effects of acute and repeated nicotine treatment on nucleus accumbens dopamine and locomotor activity , 1992, British journal of pharmacology.

[40]  L. Dwoskin,et al.  Robust modulation of [3H]dopamine release from rat striatal slices by D-2 dopamine receptors. , 1986, The Journal of pharmacology and experimental therapeutics.

[41]  L. Goodman,et al.  The Pharmacological Basis of Therapeutics , 1976 .

[42]  J. H. Burn,et al.  Effects of Nicotine , 1968, British medical journal.

[43]  J. Stenlake,et al.  NEUROMUSCULAR BLOCKING AGENTS , 1961 .

[44]  A. C. Collins,et al.  The beta3 nicotinic receptor subunit: a component of alpha-conotoxin MII-binding nicotinic acetylcholine receptors that modulate dopamine release and related behaviors. , 2003, The Journal of neuroscience : the official journal of the Society for Neuroscience.