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ABSTRACT: RATIONALE: Whereas cannabinoid CB1 receptors have long been known to contribute to the rewarding effects and dependence liability of many drugs of abuse, recent studies have implicated the involvement of cannabinoid CB2 receptors. OBJECTIVE: Here, we evaluated the role of CB2 receptors in the rewarding properties of nicotine, as assessed in the conditioned place preference (CPP) paradigm and mecamylamine-precipitated withdrawal in nicotine dependent mice. METHODS: Using complementary pharmacological and genetic approaches, we investigated the involvement of CB2 receptors in nicotine- and cocaine-induced CPP in mice and mecamylamine-precipitated withdrawal in nicotine-dependent mice. We also determined whether deletion of CB2 receptors affects nicotine-induced hypothermia and hypoalgesia. RESULTS: Nicotine-induced (0.5 mg/kg) CPP was completely blocked by selective CB2 antagonist, SR144528 (3 mg/kg) in wild-type mice, and was absent in CB2 (-/-) mice. Conversely, the CB2 receptor agonist, O-1966 (1, 3, 5, 10, 20 mg/kg) given in combination with a subthreshold dose of nicotine (0.1 mg/kg) elicited a place preference. In contrast, O-1966 (20 mg/kg) blocked cocaine (10 mg/kg)-induced CPP in wild type mice, while CB2 (-/-) mice showed unaltered cocaine CPP. CB2 (+/+) and (-/-) nicotine-dependent mice showed almost identical precipitated withdrawal responses and deletion of CB2 receptor did not alter acute somatic effects of nicotine. CONCLUSIONS: Collectively, these results indicate that CB2 receptors are required for nicotine-induced CPP in the mouse, while it is not involved in nicotine withdrawal or acute effects of nicotine. Moreover, these results suggest that CB2 receptors play opposing roles in nicotine- and cocaine-induced CPP.
Psychopharmacologia 05/2013; · 4.08 Impact Factor
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ABSTRACT: The 15q25 gene cluster contains genes that code for the α5, α3, and β4 nicotinic acetylcholine receptor (nAChRs) subunits, and in human genetic studies, has shown the most robust association with smoking behavior and nicotine dependence to date. The limited available animal studies implicate a role for the α5 and β4 nAChR subunits in nicotine dependence and withdrawal; however studies focusing on the behavioral role of the α3β4* nAChR receptor subtype in nicotine dependence are lacking. Because of the apparent role of the α3β4* nAChR subtype in nicotine dependence, the goal of the current study was to better evaluate the involvement of this subtype in nicotine mediated behavioral responses. Using the selective α3β4* nAChR antagonist, α-conotoxin AuIB, we assessed the role of α3β4* nAChRs in acute nicotine, nicotine reward, and physical and affective nicotine withdrawal. Because α5 has also been implicated in nicotine dependence behaviors in mice and can form functional receptors with α3β4*, we also evaluated the role of the α3β4α5* nAChR subtype in nicotine reward and somatic nicotine withdrawal signs by blocking the α3β4* nAChR subtype in α5 nAChR knockout mice with AuIB. AuIB had no significant effect on acute nicotine behaviors, but dose-dependently attenuated nicotine reward and physical withdrawal signs, with no significant effect in affective withdrawal measures. Interestingly, AuIB also attenuated nicotine reward and somatic signs in α5 nAChR knockout mice. This study shows that α3β4* nAChRs mediate nicotine reward and physical nicotine withdrawal, but not acute nicotine behaviors or affective nicotine withdrawal signs in mice. The α5 subunit is not required in the receptor assembly to mediate these effects. Our findings suggest an important role for the α3β4* nAChR subtype in nicotine reward and physical aspects of the nicotine withdrawal syndrome.
Neuropharmacology 02/2013; 70C:228-235. · 4.81 Impact Factor
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ABSTRACT: Nicotinic acetylcholine receptors are calcium-permeable and the initial targets for nicotine. Studies suggest that calcium-dependent mechanisms mediate some behavioral responses to nicotine; however, the post-receptor calcium-dependent mechanisms associated with chronic nicotine and nicotine withdrawal remain unclear. The proteins calcium/calmodulin-dependent protein kinase II (CaMKII) and synapsin I are essential for neurotransmitter release and were shown to be involved in drug dependence. In the current study, using pharmacological techniques, we sought to (a) complement previously published behavioral findings from our lab indicating a role for calcium-dependent signaling in nicotine dependence and (b) expand on previously published acute biochemical and pharmacological findings indicating the relevance of calcium-dependent mechanisms in acute nicotine responses by evaluating the function of CaMKII and synapsin I after chronic nicotine and withdrawal in the nucleus accumbens, a brain region implicated in drug dependence. Male mice were chronically infused with nicotine for 14 days, and treated with the β2 -selective antagonist dihydro-β-erythroidine (DHβE), or the α7 antagonist, methyllycaconitine citrate (MLA) 20minutes prior to dissection of the nucleus accumbens. Results show that phosphorylated and total CaMKII and synapsin I protein levels were significantly increased in the nucleus accumbens after chronic nicotine infusion, and reduced after treatment with DHβE, but not MLA. A spontaneous nicotine withdrawal assessment also revealed significant reductions in phosphorylated CaMKII and synapsin I levels 24h after cessation of nicotine treatment. Our findings suggest that post-receptor calcium-dependent mechanisms associated with nicotine withdrawal are mediated through β2-containing nicotinic receptors.
European journal of pharmacology 01/2013; · 2.59 Impact Factor
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ABSTRACT: The α7 nicotinic acetylcholine receptor (nAChR) subtype is abundantly expressed in the central nervous system (CNS) and in the periphery. Recent evidence suggests that α7 nAChR subtypes, which can be activated by an endogenous cholinergic tone, comprising acetylcholine (ACh) and the α7 nAChR agonist choline, play an important role in chronic pain and inflammation. This study's objective was to test whether α7 nAChR positive allosteric modulators (PAM) produce antinociception in mouse acute and persistent in vivo pain models. Testing type I (NS1738) and II (PNU-120596) α7 nAChR PAMs in acute and persistent pain, we found while neither reduced acute thermal pain, only PNU-120596 dose-dependently attenuated paw-licking behavior in the formalin test. The long-acting effect of PNU-120596 in this test was in discordance with its pharmacokinetic profile in mice, which suggest the involvement of post-receptors signaling mechanisms. Our results with selective (MEK) inhibitor U0126 argues for an impoartant role of extracellular signal-regulated kinase (ERK1/2) pathways activation in PNU-120596's antinociceptive effects. The α7 antagonist MLA, via intrathecal administration, reversed PNU-120596's effects, confirming PNU-120596's action in part through central α7 nAChRs. Importantly, tolerance to PNU-120596 was not developed after chronic treatment of the drug. Surprisingly, PNU-120596's antinociceptive effects were blocked by NS-1738. Our results indicate that type II α7 nAChR PAM PNU-120596, but not type I α7 nAChR PAM NS1738, shows significant antinociception effects in persistent pain models in mice.
Journal of Pharmacology and Experimental Therapeutics 10/2012; · 3.83 Impact Factor
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ABSTRACT: Agonists and positive allosteric modulators (PAMs) of α7 nicotinic acetylcholine receptors (nAChRs) are currently being considered as novel therapeutic approaches for managing cognitive deficits in schizophrenia and Alzheimer's disease. Though α7 agonists were recently found to possess antinociceptive and anti-inflammatory properties in rodent models of chronic neuropathic pain and inflammation, the effects of α7 nAChRs PAMs on chronic pain and inflammation remain largely unknown. The present study investigated whether PAMs, by increasing endogenous cholinergic tone, potentiate α7 nAChRs function to attenuate inflammatory and chronic neuropathic pain in mice. We tested two types of PAMS, type I (NS1738) and type II (PNU-120596) in carrageenan-induced inflammatory pain and chronic constriction injury (CCI) neuropathic pain models. We found that both NS1738 and PNU-120596 significantly reduced thermal hyperalgesia, while only PNU-120596 significantly reduced edema caused by a hind paw infusion of carrageenan. Importantly, PNU-120596 reversed established thermal hyperalgesia and edema induced by carrageenan. In the CCI model, PNU-120596 had long-lasting (up to 6 h), dose-dependent anti-hyperalgesic and anti-allodynic effects after a single injection, while NS1738 was inactive. Systemic administration of the α7 nAChR antagonist MLA reversed PNU-120596's effects, suggesting the involvement of central and peripheral α7 nAChRs. Furthermore, PNU-120596 enhanced an ineffective dose of selective agonist PHA-543613 to produce anti-allodynic effects in the CCI model. Our results indicate that the type II α7 nAChRs PAM PNU-120596, but not the type I α7 nAChRs PAM NS1738, shows significant anti-edematous and anti-allodynic effects in inflammatory and CCI pain models in mice.
Neuropharmacology 10/2012; · 4.81 Impact Factor
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ABSTRACT: Herein, we report the synthesis and nicotinic acetylcholine receptor (nAChR) in vitro and in vivo pharmacological properties of 2'-fluoro-3'-(substituted phenyl)deschloroepibatidines 5b-g, analogues of 3'-(4-nitrophenyl) compound 5a. All compounds had high affinity for α4β2-nAChR and low affinity for α7-nAChR. Initial electrophysiological studies showed that all analogues were antagonists at α4β2-, α3β4-, and α7-nAChRs. The 4-carbamoylphenyl analogue 5g was highly selective for α4β2-nAChR over α3β4- and α7-nAChRs. All the analogues were antagonists of nicotine-induced antinociception in the tail-flick test. Molecular modeling docking studies using the agonist-bound form of the X-ray crystal structure of the acetylcholine binding protein suggested several different binding modes for epibatidine, varenicline, and 5a-g. In particular, a unique binding mode for 5g was suggested by these docking simulations. The high binding affinity, in vitro efficacy, and selectivity of 5g for α4β2-nAChR combined with its nAChR functional antagonist properties suggest that 5g will be a valuable pharmacological tool for studying the nAChR and may have potential as a pharmacotherapy for addiction and other central nervous system disorders.
Journal of Medicinal Chemistry 06/2012; 55(14):6512-22. · 4.80 Impact Factor
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ABSTRACT: The endogenous cannabinoid anandamide (AEA) exerts the majority of its effects at CB(1) and CB(2) receptors and is degraded by fatty acid amide hydrolase (FAAH). FAAH KO mice and animals treated with FAAH inhibitors are impaired in their ability to hydrolyze AEA and other non-cannabinoid lipid signaling molecules, such as oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). AEA and these other substrates activate non-cannabinoid receptor systems, including TRPV1 and PPAR-α receptors. In this mini review, we describe the functional consequences of FAAH inhibition on nicotine reward and dependence as well as the underlying endocannabinoid and non-cannabinoid receptor systems mediating these effects. Interestingly, FAAH inhibition seems to mediate nicotine dependence differently in mice and rats. Indeed, pharmacological and genetic FAAH disruption in mice enhances nicotine reward and withdrawal. However, in rats, pharmacological blockade of FAAH significantly inhibits nicotine reward and has no effect in nicotine withdrawal. Studies suggest that non-cannabinoid mechanisms may play a role in these species differences.
Life sciences 06/2012; · 2.56 Impact Factor
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ABSTRACT: Nicotinic agonists display a wide-range profile of antinociceptive activity in acute, tonic, and chronic pain models. However, their effectiveness is limited by their unacceptable side effects. We investigated the antinociceptive effects of two new α4β2* nicotinic partial agonists, varenicline and sazetidine-A, in acute thermal and tonic pain mouse models. Both drugs failed to induce significant effects in the tail-flick and hot-plate tests after subcutaneous administration. However, they blocked nicotine's effects in these tests at very low doses. In contrast to acute pain tests, varenicline and sazetidine-A dose-dependently induced an analgesic effect in the mouse formalin test after systemic administration. Their antinociceptive effects were mediated, however, by different nicotinic acetylcholine receptor (nAChR) subtypes. Sazetidine-A effects were mediated by β2* nAChR subtypes, whereas varenicline actions were attributed to α3β4 nAChRs. Moreover, low inactive doses of varenicline blocked nicotine's actions in phase II of the formalin test. Overall, our results suggest that the antagonistic actions of varenicline at low doses are mediated by β2*-nAChRs and at higher doses as an agonist by α3β4*-nAChRs. In contrast, both actions of sazetidine-A are mediated by β2*-nAChR subtypes. These results suggest that nicotinic partial agonists possess analgesic effects in a rodent tonic pain model and may provide a potential treatment for the treatment of chronic pain disorders.
Journal of Pharmacology and Experimental Therapeutics 06/2012; 342(3):742-9. · 3.83 Impact Factor
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ABSTRACT: Genome-wide studies have strongly associated a non-synonymous polymorphism (rs16969968) that changes the 398th amino acid in the nAChR α5 subunit from aspartic acid to asparagine (D398N), with greater risk for increased nicotine consumption. We have used a pentameric concatemer approach to express defined and consistent populations of α3β4α5 nAChR in Xenopus oocytes. α5(Asn-398; risk) variant incorporation reduces ACh-evoked function compared with inclusion of the common α5(Asp-398) variant without altering agonist or antagonist potencies. Unlinked α3, β4, and α5 subunits assemble to form a uniform nAChR population with pharmacological properties matching those of concatemeric α3β4* nAChRs. α5 subunit incorporation reduces α3β4* nAChR function after coinjection with unlinked α3 and β4 subunits but increases that of α3β4α5 versus α3β4-only concatemers. α5 subunit incorporation into α3β4* nAChR also alters the relative efficacies of competitive agonists and changes the potency of the non-competitive antagonist mecamylamine. Additional observations indicated that in the absence of α5 subunits, free α3 and β4 subunits form at least two further subtypes. The pharmacological profiles of these free subunit α3β4-only subtypes are dissimilar both to each other and to those of α3β4α5 nAChR. The α5 variant-induced change in α3β4α5 nAChR function may underlie some of the phenotypic changes associated with this polymorphism.
Journal of Biological Chemistry 06/2012; 287(30):25151-62. · 4.77 Impact Factor
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ABSTRACT: Recently, we reported that nicotine in vitro at a low 1-μM concentration suppresses hyperexcitability of colonic dorsal root ganglia (DRG; L(1)-L(2)) neurons in the dextran sodium sulfate (DSS)-induced mouse model of acute colonic inflammation (1). Here we show that multiple action potential firing in colonic DRG neurons persisted at least for 3 wk post-DSS administration while the inflammatory signs were diminished. Similar to that in DSS-induced acute colitis, bath-applied nicotine (1 μM) gradually reduced regenerative multiple-spike action potentials in colonic DRG neurons to a single action potential in 3 wk post-DSS neurons. Nicotine (1 μM) shifted the activation curve for tetrodotoxin (TTX)-resistant sodium currents in inflamed colonic DRG neurons (voltage of half-activation changed from -37 to -32 mV) but did not affect TTX-sensitive currents in control colonic DRG neurons. Further, subcutaneous nicotine administration (2 mg/kg b.i.d.) in DSS-treated C57Bl/J6 male mice resulted in suppression of hyperexcitability of colonic DRG (L(1)-L(2)) neurons and the number of abdominal constrictions in response to intraperitoneal injection of 0.6% acetic acid. Collectively, the data suggest that neuronal nicotinic acetylcholine receptor-mediated suppression of hyperexcitability of colonic DRG neurons attenuates reduction of visceral hypersensitivity in DSS mouse model of colonic inflammation.
AJP Gastrointestinal and Liver Physiology 01/2012; 302(7):G740-7. · 3.43 Impact Factor
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ABSTRACT: The influx of Ca(2+) through calcium-permeable nicotinic acetylcholine receptors (nAChRs) leads to activation of various downstream processes that may be relevant to nicotine-mediated behaviors. The calcium activated protein, calcium/calmodulin-dependent protein kinase IV (CaMKIV) phosphorylates the downstream transcription factor cyclic AMP response element binding protein (CREB), which mediates nicotine responses; however the role of CaMKIV in nicotine dependence is unknown. Given the proposed role of CaMKIV in CREB activation, we hypothesized that CaMKIV might be a crucial molecular component in the development of nicotine dependence. Using male CaMKIV genetically modified mice, we found that nicotine reward is attenuated in CaMKIV knockout (-/-) mice, but cocaine reward is enhanced in these mice. CaMKIV protein levels were also increased in the nucleus accumbens of C57Bl/6 mice after nicotine reward. In a nicotine withdrawal assessment, anxiety-related behavior, but not somatic signs or the hyperalgesia response are attenuated in CaMKIV -/- mice. To complement our animal studies, we also conducted a human genetic association analysis and found that variants in the CaMKIV gene are associated with a protective effect against nicotine dependence. Taken together, our results support an important role for CaMKIV in nicotine reward, and suggest that CaMKIV has opposing roles in nicotine and cocaine reward. Further, CaMKIV mediates affective, but not physical nicotine withdrawal signs, and has a protective effect against nicotine dependence in human genetic association studies. These findings further indicate the importance of calcium-dependent mechanisms in mediating behaviors associated with drugs of abuse.
PLoS ONE 01/2012; 7(11):e51154. · 4.09 Impact Factor
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ABSTRACT: The neuropeptide galanin and its receptors are expressed in brain regions implicated in drug dependence. Indeed, several lines of evidence support a role for galanin in modulating the effects of drugs of abuse, including morphine, cocaine, amphetamine, and alcohol. Despite these findings, the role of galanin and its receptors in the effects of nicotine is largely underexplored. Here, using mouse models of nicotine reward and withdrawal, we show that there is a significant correlation between mecamylamine-precipitated nicotine withdrawal somatic signs and basal galanin or galanin receptor 1 (GALR1) expression in mesolimbocortical dopamine regions across the BXD battery of recombinant inbred mouse lines. The non-peptide galanin receptor agonist, galnon, also blocks nicotine rewarding effects and reverses mecamylamine-precipitated nicotine withdrawal signs in ICR mice. Additionally, we conducted a meta-analysis using smoking information from six European-American and African-American data sets. In support of our animal data, results from the association study show that variants in the GALR1 gene are associated with a protective effect in nicotine dependence (ND). Taken together, our data suggest that galanin has a protective role against progression to ND, and these effects may be mediated through GALR1.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2011; 36(11):2339-48. · 6.99 Impact Factor
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ABSTRACT: Tobacco smoking during adolescence has become a prominent preventable health problem faced in the United States. Addictive properties of smoking are thought to have a pronounced effect at a young age, thereby increasing vulnerability to a life-long addiction and decreasing the likelihood of smoking cessation during adulthood. Learning and memory involvement in nicotine reward was assessed in early adolescent (PND 28-34) and adult (PND 70+) male ICR mice by conducting conditioning sessions of nicotine (0.5mg/kg) acquisition at varying time-spans, and evaluating extinction and reinstatement of nicotine preference using Conditioned Place Preference. Acquisition studies resulted in a significant preference for nicotine after 3 days of conditioning for both age groups, but not after only 1 or 2 conditioning days. In the extinction study, adolescent mice exhibited preference for nicotine 72 h after the last conditioning session, whereas preference for nicotine was extinct in adult mice by 72 h. Reinstatement studies showed adolescent mice, but not adult mice, recovering nicotine preference after a priming injection of 0.1mg/kg nicotine on day 9 after the mice underwent extinction. No significant differences were found when nAChRs were quantified in both early adolescent and adult mice using binding techniques including cytisine sensitive, α-conotoxin-MII sensitive, and α-bungarotoxin sensitive nAChRs. Levels of striatal dopamine release were measured in both age groups using a dopamine release assay over a range of nicotine doses, which also resulted in no significant differences. More sensitive assays may facilitate in understanding the mechanisms of nicotine reward in adolescent mice.
Biochemical pharmacology 06/2011; 82(8):1008-14. · 4.25 Impact Factor
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ABSTRACT: Toward development of smoking cessation aids superior to bupropion (2), we describe synthesis of 2-(substituted phenyl)-3,5,5-trimethylmorpholine analogues 5a-5h and their effects on inhibition of dopamine, norepinephrine, and serotonin uptake, nicotinic acetylcholine receptor (nAChR) function, acute actions of nicotine, and nicotine-conditioned place preference (CPP). Several analogues encompassing aryl substitutions, N-alkylation, and alkyl extensions of the morpholine ring 3-methyl group provided analogues more potent in vitro than (S,S)-hydroxybupropion (4a) as inhibitors of dopamine or norepinephrine uptake and antagonists of nAChR function. All of the new (S,S)-5 analogues had better potency than (S,S)-4a as blockers of acute nicotine analgesia in the tail-flick test. Two analogues with highest potency at α3β4*-nAChR and among the most potent transporter inhibitors have better potency than (S,S)-4a in blocking nicotine-CPP. Collectively, these findings illuminate mechanisms of action of 2 analogues and identify deshydroxybupropion analogues 5a-5h as possibly superior candidates as aids to smoking cessation.
Journal of Medicinal Chemistry 02/2011; 54(5):1441-8. · 4.80 Impact Factor
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ABSTRACT: In this study, we compared the in vitro and in vivo neuronal nicotinic acetylcholine receptor (nAChR) properties of 1,2,3,3a,4,8b-hexahydro-2-benzyl-6-N,N-dimethylamino-1-methylindeno[1,2,-b]pyrrole (HDMP, 4) to that of negative allosteric modulator (NAM), PCP. Patch-clamp experiments showed that HDMP exhibited an inhibitory functional activity at α7 nAChRs with an IC(50) of 0.07 μM, and was 357- and 414-fold less potent at α4β2 and α3β4 nAChRs, with IC(50)s of 25.1 and 29.0 μM, respectively. Control patch-clamp experiments showed that PCP inhibited α7, α4β2 and α3β4 nAChRs with IC(50)s of to 1.3, 29.0 and 6.4 μM, respectively. Further, HDMP did not exhibit any appreciable binding affinity to either α7 or α4β2 nAChRs, suggesting its action via a non-competitive mechanism at these neuronal nAChR subtypes. The in vivo study showed that HDMP was a potent antagonist of nicotine-induced analgesia in the tail-flick (AD(50)=0.008 mg/kg), but not in the hot-plate test. All together, our in vitro and in vivo data suggest that HDMP is a novel NAM of neuronal nAChRs with potent inhibitory activity at α7 nAChR subtype at concentrations ≤ 1μM that are not effective for α4β2 and α3β4 nAChRs.
Neuropharmacology 11/2010; 59(6):511-7. · 4.81 Impact Factor
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ABSTRACT: There is a need for different and better aids to tobacco product use cessation. Useful smoking cessation aids, bupropion (2) and varenicline (3), share some chemical features with 3-phenyltropanes (4), which have promise in cocaine dependence therapy. Here we report studies to generate and characterize pharmacodynamic features of 3-phenyltropane analogues. These studies extend our work on the multiple molecular target model for aids to smoking cessation. We identified several new 3-phenyltropane analogues that are superior to 2 in inhibition of dopamine, norepinephrine, and sometimes serotonin reuptake. All of these ligands also act as inhibitors of nicotinic acetylcholine receptor (nAChR) function with a selectivity profile that favors, like 2, inhibition of α3β4*-nAChR. Many of these ligands also block acute effects of nicotine-induced antinociception, locomotor activity, and hypothermia. Importantly, all except one of the analogues tested have better potencies in inhibition of nicotine conditioned place preference than 2. We have identified new compounds that have utility as research tools and possible promise for treatment of nicotine dependence.
Journal of Medicinal Chemistry 11/2010; · 4.80 Impact Factor
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ABSTRACT: Bupropion is an atypical antidepressant that also has utility as a smoking cessation aid. Hydroxybupropions are major metabolites of bupropion and are believed to contribute to antidepressant and perhaps smoking cessation activities. Because bupropion metabolism is more similar in humans and mice than in humans and rats, the present study investigated effects of hydroxybupropion enantiomers in mouse behavioral models measuring various aspects of nicotine dependence. Bupropion and (2S,3S)-hydroxybupropion, but not (2R,3R)-hydroxybupropion, significantly decreased the development of nicotine reward as measured in the conditioned place preference and withdrawal paradigm in mice. Bupropion and both of its metabolites reversed affective and somatic withdrawal signs in nicotine-dependent mice, but the (2S,3S)-hydroxymetabolite had higher potency. Bupropion and (2S,3S)-, but not (2R,3R)-hydroxybupropion, produced partial substitution for nicotine in drug discrimination tests. Our findings support the hypothesis that the effects of bupropion on measures of nicotine dependence reflect actions of bupropion itself, its hydroxymetabolites, or a combination and suggest that the (2S,3S)-hydroxy isomer is the most active principle, making it a potentially better drug candidate for smoking cessation than bupropion.
Journal of Pharmacology and Experimental Therapeutics 09/2010; 334(3):1087-95. · 3.83 Impact Factor
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ABSTRACT: Controlled clinical trials of nicotine transdermal patch for treatment of ulcerative colitis have been shown to improve histological and global clinical scores of colitis. Here we report that nicotine (1 microM) suppresses in vitro hyperexcitability of colonic dorsal root ganglia (DRG) (L(1)-L(2)) neurons in the dextran sodium sulfate (DSS)-induced mouse model of acute colonic inflammation. Nicotine gradually reduced regenerative multiple-spike action potentials in colitis mice to a single action potential. Nicotine's effect on hyperexcitability of inflamed neurons was blocked in the presence of an alpha(7)-nicotinic acetylcholine receptor (nAChR) antagonist, methyllicaconitine, while choline, the alpha(7)-nAChR agonist, induced a similar effect to that of nicotine. Consistent with these findings, nicotine failed to suppress hyperexcitability in colonic DRG neurons from DSS-treated alpha(7) knockout mice. Furthermore, colonic DRG neurons from DSS-treated alpha(7) knockout mice were characterized by lower rheobase (10 +/- 5 vs. 77 +/- 13 pA, respectively) and current threshold (28 +/- 4 vs. 103 +/- 8 pA, respectively) levels than DSS-treated C57BL/J6 mice. An interesting observation of this study is that 8 of 12 colonic DRG (L(1)-L(2)) neurons from control alpha(7) knockout mice exhibited multiple-spike action potential firing while no wild-type neurons did. Overall, our findings suggest that nicotine at low 1 microM concentration suppresses in vitro hyperexcitability of inflamed colonic DRG neurons in a mouse model of acute colonic inflammation via activation of alpha(7)-nAChRs.
AJP Gastrointestinal and Liver Physiology 09/2010; 299(3):G761-8. · 3.43 Impact Factor
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ABSTRACT: To create potentially superior aids to smoking cessation and/or antidepressants and to elucidate bupropion's possible mechanisms of action(s), 23 analogues based on its active hydroxymetabolite (2S,3S)-4a were synthesized and tested for their abilities to inhibit monoamine uptake and nAChR subtype activities in vitro and acute effects of nicotine in vivo. The 3',4'-dichlorophenyl [(+/-)-4n], naphthyl (4r), and 3-chlorophenyl or 3-propyl analogues 4s and 4t, respectively, had higher inhibitory potency and/or absolute selectivity than (2S,3S)-4a for inhibition of DA, NE, or 5HT uptake. The 3'-fluorophenyl, 3'-bromophenyl, and 4-biphenyl analogues 4c, 4d, and 4l, respectively, had higher potency for antagonism of alpha4beta2-nAChR than (2S,3S)-4a. Several analogues also had higher potency than (2S,3S)-4a as antagonists of nicotine-mediated antinociception in the tail-flick assay. The results suggest that compounds acting via some combination of DA, NE, or 5HT inhibition and/or antagonism of alpha4beta2-nAChR can potentially be new pharmacotherapeutics for treatment of nicotine dependence.
Journal of Medicinal Chemistry 06/2010; 53(12):4731-48. · 4.80 Impact Factor
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ABSTRACT: In 1992, John Daly et al. reported the isolation and structure determination of epibatidine. Epibatidine's unique structure and its potent nicotinic agonist activity have had a tremendous impact on nicotine receptor research. This research has led to a better understanding of the nicotinic acetylcholine receptor (nAChR) pharmacophore and to epibatidine analogues with potential as pharmacotherapies for treating various CNS disorders. In this study, we report the synthesis, receptor binding ([(3)H]epibatidine and [(125)I]iodoMLA), and in vivo pharmacological properties (mouse tail flick, hot plate, hypothermia, and spontaneous activity) of a series of 3'-(substituted phenyl)epibatidine analogues (5a-m). Results from these studies have added to the understanding of the nAChR pharmacophore and led to nicotinic partial agonists that may have potential for smoking cessation. All the analogues had affinities for the alpha4beta2 nAChR similar to epibatidine (1). 3'-(3-Dimethylaminophenyl)epibatidine (5m) has a nicotinic partial agonist pharmacological profile similar to the smoking cessation drug varenicline. Other analogues are partial agonists with varying degrees of nicotinic functional agonist and antagonist activity. 3'-(3-Aminophenyl)epibatidine (5j) is a more potent functional agonist and antagonist in all tests than varenicline. 3'-(3-Fluorophenyl)epibatidine and 3'-(3-chlorophenyl)epibatidine (5c and 5e) are more potent than varenicline when tested as agonists in four pharmacological tests and antagonists when evaluated against nicotine in the analgesia hot-plate test.
Journal of Natural Products 03/2010; 73(3):306-12. · 3.13 Impact Factor
