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

Tobacco dependence is the most preventable cause of death and is a chronic, relapsing disorder in which compulsive tobacco use persists despite known negative health consequences. All currently available cessation agents (nicotine, varenicline and bupropion) have limited efficacy and are associated with high relapse rates, revealing a need for more efficacious, alternative pharmacotherapies. The major alkaloid in tobacco, nicotine, activates nicotinic receptors (nAChRs) which increase brain extracellular dopamine producing nicotine reward leading to addiction. nAChRs are located primarily presynaptically and modulate synaptic activity by regulating neurotransmitter release. Subtype-selective nAChR antagonists that block reward-relevant mesocorticolimbic and nigrostriatal dopamine release induced by nicotine may offer advantages over current therapies. An innovative approach is to provide pharmacotherapies which are antagonists at nAChR subtypes mediating nicotine evoked dopamine release. In addition, providing multiple medications with a wider array of targets and mechanisms should provide more treatment options for individuals who are not responsive to the currently available pharmacotherapies. This review summarizes the currently available smoking cessation therapies and discusses emerging potential therapeutic approaches employing pharmacological agents which act as antagonists at nicotinic receptors.

BACKGROUND AND PURPOSENicotinic acetylcholine receptors (nAChRs) containing a6b2 subunits expressed by dopamine neurons regulate nicotine-evoked dopamine release. Previous results show that the a6b2* nAChR antagonist, N,NЈ-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB) inhibits nicotine-evoked dopamine release from dorsal striatum and decreases nicotine self-administration in rats. However, overt toxicity emerged with repeated bPiDDB treatment. The current study evaluated the preclinical pharmacology of a bPiDDB analogue. EXPERIMENTAL APPROACHThe C10 analogue of bPiDDB, N, , was evaluated preclinically for nAChR antagonist activity. KEY RESULTSbPiDI inhibits nicotine-evoked [ 3 H]dopamine overflow (IC50 = 150 nM, Imax = 58%) from rat striatal slices. Schild analysis revealed a rightward shift in the nicotine concentration-response curve and surmountability with increasing nicotine concentration; however, the Schild regression slope differed significantly from 1.0, indicating surmountable allosteric inhibition. Co-exposure of maximally inhibitory concentrations of bPiDI (1 mM) and the a6b2* nAChR antagonist a-conotoxin MII (1 nM) produced inhibition not different from either antagonist alone, indicating that bPiDI acts at a6b2* nAChRs. Nicotine treatment (0.4 mg·kg -1 ·day -1 , 10 days) increased more than 100-fold the potency of bPiDI (IC50 = 1.45 nM) to inhibit nicotine-evoked dopamine release. Acute treatment with bPiDI (1.94-5.83 mmol·kg -1 , s.c.) specifically reduced nicotine self-administration relative to responding for food. Across seven daily treatments, bPiDI decreased nicotine self-administration; however, tolerance developed to the acute decrease in food-maintained responding. No observable body weight loss or lethargy was observed with repeated bPiDI. CONCLUSIONS AND IMPLICATIONSThese results are consistent with the hypothesis that a6b2* nAChR antagonists have potential for development as pharmacotherapies for tobacco smoking cessation.Abbreviations bPIDDB, N, bPiDI, N,picolinium diiodide; DHbE, dihydro-b-erythroidine; FR5, fixed ratio 5; NAcc, nucleus accumbens; nAChR, nicotinic acetylcholine receptor; s.c., subcutaneous; TO180, 180 min timeout; TO20, 20 min timeout; VTA, ventral tegmental area; a-CtxMII, a-conotoxin MII BJP British Journal of Pharmacology DOI:10.1111DOI:10. /j.1476DOI:10. -5381.2011 346 British Journal of Pharmacology (2011) IntroductionDrugs of abuse activate the dopaminergic reward circuitry, leading to dopamine release in nucleus accumbens (NAcc) and striatum, which is associated with primary reward and habit formation respectively (Di Chiara et al., 2004;Koob and Volkow, 2010). The transition from reward seeking to compulsive behaviour associated with drug abuse appears to result from a shift from NAcc to striatal control (Koob and Volkow, 2010). Nicotine activates nicotinic acetylcholine receptors (nAChRs; receptor nomenclature follows Alexander et al., 2009) that modulate dopamine release. Identifying nAChRs regulating dopamine release is important because dopami...

Impulsivity is one of the core symptoms of attention-deficit/hyperactivity disorder (ADHD). The spontaneously hypertensive rat (SHR), a putative animal model of ADHD, has been used to investigate the neurobiology of impulsivity, although this model has been questioned over concerns that use of Wistar-Kyoto rats (WKY) as a comparison strain may exaggerate effects. The present study compared SHR, WKY and standard, outbred Sprague-Dawley (SD) rats on a delay discounting task where the primary measure was mean adjusted delay (MAD), or the indifference point (in sec) between choice of a immediate delivery of 1 grain-based pellet versus 3 pellets delivered after varying delays. The acute dose effects of the ADHD medications amphetamine (0.1–1.0 mg/kg) and methylphenidate (1.0–10 mg/kg) were then determined; in addition, the effect of the dopamine receptor antagonist fluphenazine (0.1–1.0 mg/kg) was also assessed for comparison with the indirect agonists. While there were no strain differences in the rate of task acquisition or stabilization of baseline MAD scores, SHR had significantly lower MAD scores than WKY but not SD due to the greater individual variability of MAD scores in SD. Although amphetamine did not alter MAD scores in any strain, methylphenidate selectively increased MAD scores in WKY and fluphenazine selectively increased MAD scores in SHR. WKY were also more sensitive than SHR and SD to the response-impairing effects of each drug. The finding that SHR showed a decrease in impulsivity following fluphenazine, but not following either amphetamine or methylphenidate, suggests that delay discounting in SHR may not represent a valid predictive model for screening effective ADHD medications in humans.