F. Ivy Carroll

Emory University, Atlanta, Georgia, United States

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Publications (465)1539.86 Total impact

  • Bioconjugate Chemistry 11/2014; · 4.82 Impact Factor
  • Journal of Medicinal Chemistry 08/2014; · 5.48 Impact Factor
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    ABSTRACT: A long-acting, thermostable bacterial cocaine esterase (CocE) has been identified that rapidly degrades cocaine with a KM of 1.33+0.085 μM. In vivo evaluation of CocE has shown protection against convulsant and lethal effects of cocaine in rodents, confirming the therapeutic potential of CocE against cocaine overdose. However, the current study is the first to evaluate the effects of CocE on cocaine brain levels. Positron emission tomogrpahy neuroimaging of [(11)C]cocaine was used to evaluate the time course of cocaine elimination from brain in the presence and absence of CocE in nonhuman primates. Systemic administration of CocE eliminated cocaine from the rhesus-monkey brain approximately three times faster than control conditions via peripheral actions through attenuating the input function from blood plasma. The efficiency of this process is sufficient to alleviate or prevent adverse central nervous system effects induced by cocaine. Although the present study used tracer doses of cocaine to access brain clearance, these findings further support the development of CocE for the treatment of acute cocaine toxicity.
    Translational psychiatry. 07/2014; 4:e407.
  • F. Ivy Carroll, Roland E. Dolle
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    ABSTRACT: N-Substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines are a class of pure opioid receptor antagonists with a novel pharmacophore. This opioid receptor antagonist pharmacophore was used as a lead structure to design and develop several interesting and useful opioid receptor antagonists. In this review we describe: 1) early SAR studies that led to the discovery of LY255582 and analogues that are nonselective opioid receptor antagonists developed for the treatment of obesity; 2) the discovery and commercialization of LY246736 (alvimopan; ENTEREG®), a peripherally selective opioid receptor antagonist that accelerates the time to upper and lower GI recovery following surgeries that include partial bowel resection with primary anastomosis; and 3) the discovery and development of the potent and selective κ opioid receptor antagonist JDTic and analogues as potential pharmacotherapies for treating depression, anxiety, and substance abuse (nicotine, alcohol, and cocaine). In addition, the use of JDTic for obtaining the X-ray structure of the human κ opioid receptor is discussed.
    ChemMedChem 06/2014; · 3.05 Impact Factor
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    ABSTRACT: The opioid receptor family is made up of four structurally homologous but functionally distinct receptors, the mu (MOP), delta (DOP), kappa (KOP), and nociceptin (NOP). Given that most opioid agonists are selective but not specific, a broad spectrum of behaviors due to activation of different opioid receptors is expected. In this study, we examine whether other opioid receptor systems influence KOP-mediated antinociception.
    British Journal of Pharmacology 06/2014; · 5.07 Impact Factor
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    ABSTRACT: Rationale: Receptor mechanisms underlying the in vivo effects of nicotinic acetylcholine receptor (nAChR) drugs need to be determined to better understand possible differences in therapeutic potential. Objective: This study compared the effects of agonists that are reported either to differ in intrinsic activity (i.e., efficacy) at α4β2 nAChR in vitro or to have in vivo effects consistent with differences in efficacy. The drugs included nicotine, varenicline, cytisine, epibatidine, and three novel epibatidine derivatives: 2′-fluoro-3′-(4-nitrophenyl)deschloroepibatidine (RTI-7527-102), 2′-fluorodeschloroepibatidine (RTI-7527-36), and 3′-(3″-dimethylaminophenyl)-epibatidine (RTI-7527-76). Methods: Mice discriminated nicotine base (1 mg/kg base) from saline; other mice were used to measure rectal temperature. Results: In the nicotine discrimination assay, the maximum percentage of nicotine-appropriate responding varied: 92 % for nicotine, 84 % for epibatidine, 77 % for RTI-7527-36, and 71 % for varenicline and significantly less for RTI-7527-76 (58 %), RTI-7527-102 (46 %), and cytisine (33 %). Each drug markedly decreased rectal temperature by as much as 12ºC. The rank-order potency in the discrimination and hypothermia assays was epibatidine>RTI-7527-36>nicotine>RTI-7527- 102>varenicline=cytisine=RTI-7527-76. The nAChR antagonist mecamylamine (3.2 mg/kg) antagonized the discriminative stimulus effects of epibatidine and RTI-7527-102, as well as the hypothermic effects of every drug except cytisine. The β2-subunit selective nAChR antagonist dihydro-β- erythroidine (DHβE; up to 10 mg/kg) antagonized hypothermic effects but less effectively so than mecamylamine. Conclusions: The marked hypothermic effects of all drugs except cytisine are due in part to agonism at nAChR containing β2- subunits. Differential substitution for the nicotine discriminative stimulus is consistent with differences in α4β2 nAChR efficacy; however, collectively the current results suggest that multiple nAChR receptor subtypes mediate the effects of the agonists.
    Psychopharmacology 05/2014; · 3.99 Impact Factor
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    ABSTRACT: N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines (2a-b) are opioid receptor antagonists where the antagonist properties are not due to the type of N-substituent. In order to gain a better understanding of the contribution that the 3- and 4-methyl groups make to the pure antagonist properties of 2a-b, we synthesized analogues of 2a-b which lacked the 4-methyl (5a-b), 3-methyl (6a-b) and both the 3- and 4-methyl group (7a-b) and compared their opioid receptor properties. We found that (1) all N-methyl and N-phenylpropyl substituted compounds were non-selective opioid antagonists (2) all N-phenylpropyl analogues were more potent than their N-methyl counterparts and (3) compounds 2a-b which have both a 3- and 4-methyl substituent, were more potent antagonists than analogs 5a-b, 6a-b and 7a-b. We also found that the removal of 3-methyl substituent of N-methyl and N-phenylpropyl 3-methyl-4-(3-hydroxyphenyl)piperazines (8a-b) gives (4a-b) which are opioid antagonists.
    Journal of Medicinal Chemistry 03/2014; · 5.48 Impact Factor
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    ABSTRACT: 2'-Fluoro-3-(substituted pyridine)epibatidine analogues 7a-e and 8a-e were synthesized and their in vitro and in vivo nAChR properties determined. 2'-Fluoro-3'-(4"-pyridinyl)deschloroepibatidine (7a) and 2'-fluoro-3'-(3"-pyridinyl)deschloroepibatidine (8a) were synthesized as bioisosteres of the 4'-nitrophenyl lead compounds 5a and 5g. Comparison of the in vitro nAChR properties of 7a and 8a to those of 5a and 5g showed that 7a and 8a had in vitro nAChR properties similar to those of 5a and 5g, but both were more selective for the α4β2-nAChR relative to the α3β4- and α7-nAChRs than 5a and 5g. The in vivo nAChR properties in mice of 7a were similar to those of 5a. In contrast, 8a was an agonist in all four mouse acute tests, whereas 5g was active only in a spontaneous activity test. In addition, 5g was a nicotine antagonist in both the tail-flick and hot-plate tests, whereas as 8a was only an antagonist in the tail-flick test.
    Journal of Medicinal Chemistry 01/2014; · 5.48 Impact Factor
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    ABSTRACT: Bupropion, introduced as an antidepressant in the 1980s, is also effective as a smoking cessation aid and is beneficial in the treatment of methamphetamine addiction, cocaine dependence, addictive behaviors such as pathological gambling, and attention deficit hyperactivity disorder. (2S,3S)-hydroxybupropion is an active metabolite of bupropion produced in humans that contributes to antidepressant and smoking cessation efficacy and perhaps benefits in other CNS disorders. Mechanisms underlying its antidepressant and smoking abstinence remain elusive. However, it seems likely that efficacy is due to a combination of the effects of bupropion and/or its active metabolite (2S,3S)-hydroxybupropion involving the inhibition of reuptake of dopamine (DA) and NE in reward centers of the brain and the noncompetitive antagonism of α4β2- and α3β4*-nAChRs. These combined effects of bupropion and its active metabolite may be responsible for its ability to decrease nicotine reward and withdrawal. Studies directed toward development of a bupropion analog for treatment of cocaine addiction led to compounds, typified by 2-(N-cyclopropylamino)-3'-chloropropiophenone (RTI-6037-39), thought to act as indirect DA agonists. In addition, (2S,3S)-hydroxybupropion analogs were developed, which had varying degrees of DA and NE uptake inhibition and antagonism of nAChRs. These compounds will be valuable tools for animal behavioral studies and as clinical candidates. Here, we review the (1) early studies leading to the development of bupropion, (2) bupropion metabolism and the identification of (2S,3R)-hydroxybupropion as an active metabolite, (3) mechanisms of bupropion and metabolite action, (4) effects in animal behavioral studies, (5) results of clinical studies, and (6) development of bupropion analogs as potential pharmacotherapies for treating nicotine and cocaine addiction.
    Advances in pharmacology (San Diego, Calif.) 01/2014; 69:177-216.
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    ABSTRACT: Nicotine dependence and cocaine abuse are major public health problems and most cocaine abusers also smoke cigarettes. An ideal treatment medication would reduce both cigarette smoking and cocaine abuse. Varenicline is a clinically available, partial agonist at α4β2* and α6β2* nicotinic acetylcholine receptors (nAChRs) and a full agonist at α7 nAChRs. Varenicline facilitates smoking cessation in clinical studies, and reduced nicotine self-administration and substituted for the nicotine discriminative stimulus in preclinical studies. The present study examined the effects of chronic varenicline treatment on self-administration of IV nicotine, IV cocaine, IV nicotine+cocaine combinations and concurrent food-maintained responding by five cocaine- and nicotine-experienced adult rhesus monkeys (Macaca mulatta). Varenicline (0.004 to 0.04 mg/kg/hr) was administered intravenously every 20 min for 23 h each day for 7-10 consecutive days. Each varenicline treatment was followed by saline-control treatment until food- and drug-maintained responding returned to baseline. During control treatment, nicotine+cocaine combinations maintained significantly higher levels of drug self-administration than nicotine or cocaine alone (P<0.05-0.001). Varenicline dose-dependently reduced responding maintained by nicotine alone (0.0032 mg/kg/inj) (P<0.05), and in combination with cocaine (0.0032 mg/kg/inj) (P<0.05) with no significant effects on food-maintained responding. However, varenicline did not significantly decrease self-administration of a low dose of nicotine (0.001 mg/kg), cocaine alone (0.0032 and 0.01 mg/kg/inj), or 0.01 mg/kg cocaine combined with the same doses of nicotine. We conclude that varenicline selectively attenuates the reinforcing effects of nicotine alone but not cocaine alone, and its effects on nicotine+cocaine combinations are dependent on the dose of cocaine.Neuropsychopharmacology accepted article preview online, 22 November 2013. doi:10.1038/npp.2013.325.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 11/2013; · 8.68 Impact Factor
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    ABSTRACT: In previous studies we reported that addition of 7α-acylamino groups to N-phenylpropyl-4β-methyl-5-(3-hydroxyphenyl)morphan (4) led to compounds that were pure opioid receptor antagonists. In contrast to these findings we report in this study that addition of a 7α-amino (5a), 7α-alkylamino (5b-e), or 7α-dialkylamino 5f-h) group to 4 leads to opioid receptor ligands with varying degrees of agonist/antagonist activity. The 7α-amino and 7α-methylamino analogues were full agonists at the μ and δ receptors and antagonists at the κ receptor. The 7α-cyclopropylmethylamino analogue 5h was a full agonist at the μ receptor with weaker agonist activity at the δ and κ receptors. Whereas the addition of a 7α-acylamino group to the pure non-selective opioid receptor antagonist N-phenylpropyl-4β-methyl-5-(3-hydroxyphenyl)morphan (4) led to κ selective pure opioid receptor antagonist, the addition of a 7α-amino, 7α-alkylamino or 7α-dialkylamino group to 4 leads to opioid ligands that are largely μ or δ agonist with mixed agonist/antagonist properties.
    Journal of Medicinal Chemistry 10/2013; · 5.48 Impact Factor
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    ABSTRACT: Over the past five years the number of internet sites advertising "legal highs" has literally exploded, as have user reports of experiences (both pleasurable and frightening) with these substances and the number of emergency room visits by users. Although the majority of these "legal highs" have been described as bath salts and herbal extracts, most contain neither plant derived compounds nor components of personal hygiene products. So-called "Bath Salts" largely contain synthetic analogs of the natural compound khat; Spice-related materials, claimed to be "legal marijuana," are mostly synthetic analogs of cannabinoid receptor ligands that were developed as research tools. This review describes the emergence and properties of these two groups of "legal highs" from medicinal chemist's perspective.
    Life sciences 10/2013; · 2.56 Impact Factor
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    ABSTRACT: Nor-BNI, GNTI and JDTic induce selective κ opioid antagonism that is delayed and extremely prolonged, but some other effects are of rapid onset and brief duration. The transient effects of these compounds differ, suggesting that some of them may be mediated by other targets. In binding assays, the three antagonists showed no detectable affinity (K i≥10 µM) for most non-opioid receptors and transporters (26 of 43 tested). There was no non-opioid target for which all three compounds shared detectable affinity, or for which any two shared sub-micromolar affinity. All three compounds showed low nanomolar affinity for κ opioid receptors, with moderate selectivity over μ and δ (3 to 44-fold). Nor-BNI bound weakly to the α2C-adrenoceptor (K i = 630 nM). GNTI enhanced calcium mobilization by noradrenaline at the α1A-adrenoceptor (EC50 = 41 nM), but did not activate the receptor, displace radioligands, or enhance PI hydrolysis. This suggests that it is a functionally-selective allosteric enhancer. GNTI was also a weak M1 receptor antagonist (K B = 3.7 µM). JDTic bound to the noradrenaline transporter (K i = 54 nM), but only weakly inhibited transport (IC50 = 1.1 µM). JDTic also bound to the opioid-like receptor NOP (K i = 12 nM), but gave little antagonism even at 30 µM. All three compounds exhibited rapid permeation and active efflux across Caco-2 cell monolayers. Across 43 non-opioid CNS targets, only GNTI exhibited a potent functional effect (allosteric enhancement of α1A-adrenoceptors). This may contribute to GNTI's severe transient effects. Plasma concentrations of nor-BNI and GNTI may be high enough to affect some peripheral non-opioid targets. Nonetheless, κ opioid antagonism persists for weeks or months after these transient effects dissipate. With an adequate pre-administration interval, our results therefore strengthen the evidence that nor-BNI, GNTI and JDTic are highly selective κ opioid antagonists.
    PLoS ONE 08/2013; 8(8):e70701. · 3.53 Impact Factor
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    ABSTRACT: Abnormal involuntary movements or dyskinesias are a serious complication of long-term L-dopa treatment for Parkinson's disease, for which there are few treatment options. Accumulating pre-clinical data show that nicotine decreases L-dopa-induced dyskinesias (LIDs), suggesting it may be a useful antidyskinetic therapy for Parkinson's disease. Here, we investigated whether nicotinic acetylcholine receptor (nAChR) agonists reduced LIDs in nonhuman primates. We first tested the nonselective nAChR agonist varenicline, which offers the advantage that it is FDA approved for use in humans. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys (n=23) were first administered L-dopa/carbidopa (10/2.5 mg/kg) twice daily 5 days/wk until stably dyskinetic. Oral varenicline (0.03-0.10 mg/kg) decreased LIDs ~50% compared to vehicle-treated monkeys, while nicotine treatment (300 µg/ml in drinking water) reduced LIDs by 70% in a parallel group of animals. We next tested the selective α4β2*/α6β2* nAChR agonist TC-8831 on LIDs in the same set of monkeys after a 10 wk washout. We also tested TC-8831 in another set of MPTP-lesioned monkeys (n=16) that were nAChR drug naive. Oral TC-8831 (0.03-0.3 mg/kg) reduced LIDs in both sets by 30-50%. After a washout period, repeat TC-8831 dosing led to a greater decline in LIDs (60%) in both sets of monkeys that was similar to the effect of nicotine. Tolerance did not develop to any nAChR drug over the course of the study (3-4 months). NAChR drug treatment did not worsen parkinsonism or cognitive ability. These data suggest that nAChR agonists may be useful for the management of dyskinesias in L-dopa treated Parkinson's disease patients.
    Journal of Pharmacology and Experimental Therapeutics 07/2013; · 3.89 Impact Factor
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    ABSTRACT: (+)-Methamphetamine (METH) addiction is a chronic disease that interferes with fundamental brain-mediated behaviors and biological functions like eating. These studies present preclinical efficacy and safety profiles for a METH conjugate vaccine (ICKLH-SMO9) designed to treat METH abuse. ICKLH-SMO9 efficacy and safety were assessed over a 16-week period by monitoring general health and stability of responding in a food maintained behavioral paradigm. Male Sprague-Dawley rats were trained to lever press for food reinforcers until stable behavior was established. Rats (n=9/group) were then immunized with 100μg of a control antigenic carrier protein (ICKLH-Cys) or ICKLH-SMO9 in Alhydrogel® adjuvant, with booster immunizations at 4, 8 and 12weeks. Health, immunization site and behavior were assessed daily. No adverse effects were found. During weeks 14-16, when antibody titers and METH affinity (Kd=13.9±1.7nM) were maximal, all rats received progressively higher METH doses (0.3-3.0mg/kg) every 3-4days, followed by behavioral testing. Even though the lower METH doses from 0.3 to 1.0mg/kg produced no impairment in food maintained behavior, 3.0-mg/kg in control rats showed significantly (p<0.05) reduced response rates and number of reinforcers earned, as well as reduced food intake. In sharp contrast, the ICKLH-SMO9 group showed no changes in food maintained behavior at any METH dose, even though METH serum concentrations showed profound increases due to anti-METH antibody binding. These findings suggest the ICKLH-SMO9 vaccine is effective and safe at reducing adverse METH-induced effects, even at high METH doses.
    Vaccine 07/2013; · 3.49 Impact Factor
  • K Freitas, SS Negus, FI Carroll, MI Damaj
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    ABSTRACT: Background and PurposeThe α7 nicotinic ACh receptor subtype is abundantly expressed in the CNS and in the periphery. Recent evidence suggests that α7 nicotinic ACh receptor (nAChR) subtypes, which can be activated by an endogenous cholinergic tone comprising ACh and the α7 agonist choline, play an important role in chronic pain and inflammation. In this study, we evaluated whether type II α7 positive allosteric modulator PNU-120596 induces antinociception on its own and in combination with choline in the formalin pain model. Experimental ApproachWe assessed the effects of PNU-120596 and choline and the nature of their interactions in the formalin test using an isobolographic analysis. In addition, we evaluated the interaction of PNU-120596 with PHA-54613, an exogenous selective α7 nAChR agonist, in the formalin test. Finally, we assessed the interaction between PNU-120596 and nicotine using acute thermal pain, locomotor activity, body temperature and convulsing activity tests in mice. Key ResultsWe found that PNU-120596 dose-dependently attenuated nociceptive behaviour in the formalin test after systemic administration in mice. In addition, mixtures of PNU-120596 and choline synergistically reduced formalin-induced pain. PNU-120596 enhanced the effects of nicotine and α7 agonist PHA-543613 in the same test. In contrast, PNU-120596 failed to enhance nicotine-induced convulsions, hypomotility and antinociception in acute pain models. Surprisingly, it enhanced nicotine-induced hypothermia via activation of α7 nAChRs. Conclusions and ImplicationsOur results demonstrate that type II α7 positive allosteric modulators produce antinociceptive effects in the formalin test through a synergistic interaction with the endogenous α7 agonist choline.
    British Journal of Pharmacology 06/2013; 169(3). · 5.07 Impact Factor
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    ABSTRACT: There is continuing interest in the discovery and development of new κ opioid receptor antagonists. We recently reported that N-substituted 3-methyl-4-(3-hydroxyphenyl)piperazines were a new class of opioid receptor antagonists. In this study we report the syntheses of two piperazine JDTic-like analogues. Evaluation of the two compounds in an in vitro [(35)S]GTPγS binding assay showed that neither compound showed the high potency and κ opioid receptor selectivity of JDTic. A library of compounds using the core scaffold 21 was synthesized and tested for their ability to inhibit [(35)S]GTPγS binding stimulated by the selective κ opioid agonist U69,593. These studies led to N-[(1S)-1-{[(3S)-4-(3-hydroxyphenyl)-3-methylpiperazin-1-yl]methyl}-2-methylpropyl]-4-phenoxybenzamide (11a), a compound that showed good κ opioid receptor antagonist properties. An SAR study based on 11a provided 28 novel analogues. Evaluation of these 28 compounds in the [(35)S]GTPγS binding assay showed that several of the analogues were potent and selective κ opioid receptor antagonists.
    Journal of Medicinal Chemistry 05/2013; · 5.48 Impact Factor
  • F Ivy Carroll, William Anthony Carlezon
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    ABSTRACT: Kappa opioid receptors (KORs) belong to the G-protein coupled class of receptors (GPCRs). They are activated by the endogenous opioid peptide dynorphin (DYN) and expressed at particularly high levels within brain areas implicated in modulation of motivation, emotion, and cognitive function. Chronic activation of KORs in animal models has maladaptive effects including increases in behaviors that reflect depression, the propensity to engage in drug-seeking behavior, and drug craving. The fact that KOR activation has such a profound influence on behaviors often triggered by stress has led to interest in selective KOR antagonists as potential therapeutic agents. This perspective provides a description of preclinical research conducted in the development of several different classes of selective KOR antagonists, a summary of the clinical studies conducted thus far, and recommendations for the type of work needed in the future to determine if these agents would be useful as pharmacotherapies for neuropsychiatric illness.
    Journal of Medicinal Chemistry 01/2013; · 5.48 Impact Factor
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    ABSTRACT: BACKGROUND: Tobacco cessation pharmacotherapies currently are limited to nicotine itself, the partial nicotine agonists varenicline and cytisine, and the antidepressant bupropion. Compared with agonists, nicotinic antagonists such as the noncompetitive, nonselective compound mecamylamine, and the competitive, α4β2-preferring antagonist dihydro-β-erythroidine (DHβE) may be a novel approach to the treatment of tobacco smoking as both are effective antagonists of nicotine's central effects. Considering nicotinic acetylcholine receptors mediate critical peripheral effects of acetylcholine, such as cardiovascular effects, it is important to study how nicotinic antagonists would alter the cardiovascular system and the cardiovascular changes induced by nicotine. METHODS: The effects of several nicotinic agonists and antagonists on blood pressure and heart rate were measured in conscious, unrestrained rats following parenteral administration using a telemetry system. RESULTS: Nicotine and other nicotinic receptor agonists (epibatidine, varenicline, and cytisine) produced similar increases in blood pressure, whereas their effects on heart rate were biphasic. The cardiovascular changes were attenuated by the nonselective nicotine antagonist, mecamylamine, but the peripherally restricted antagonist hexamethonium blocked only the agonist-induced changes in blood pressure. The α7-preferring antagonist, MLA, and the α4β2-preferring antagonist, DHβE, were much less effective in blocking the agonist-induced cardiovascular changes, indicating that nicotine's cardiovascular effects, are due to activation at autonomic ganglia involving nicotinic receptor subtypes other than α4, α7, or β2. CONCLUSIONS: The data indicate that the cardiovascular effects of nicotine and nicotine-like agents are mediated through receptor mechanisms that are distinct from those that mediate the central effects of nicotine.
    Drug and alcohol dependence 01/2013; · 3.60 Impact Factor
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    ABSTRACT: Pain is associated with stimulation of some behaviors (eg, withdrawal reflexes) but depression of many other behaviors (eg, feeding, locomotion, positively reinforced operant behavior). Drugs that block reuptake of serotonin, norepinephrine, and/or dopamine are widely used to treat depression, and they have also emerged as useful drugs for treatment of pain. This study compared effects of selective and mixed-action inhibitors of serotonin, norepinephrine, and/or dopamine reuptake in assays of acute pain-stimulated and pain-depressed behavior. Intraperitoneal injection of dilute acid served as a noxious stimulus to stimulate a writhing response or depress intracranial self-stimulation (ICSS) in Sprague Dawley rats. Selective reuptake inhibitors of serotonin (citalopram, clomipramine) and norepinephrine (nisoxetine, nortriptyline) and a mixed-action reuptake inhibitor of serotonin and norepinephrine (milnacipran) blocked acid-stimulated writhing but failed to block acid-induced depression of ICSS. Selective dopamine reuptake inhibitors (RTI-113 [3ß-(4-chlorophenyl)tropane-2ß-carboxylic acid phenyl ester hydrochloride], bupropion) and a triple reuptake inhibitor of dopamine, serotonin, and norepinephrine (RTI-112 [3ß-(3-methyl-4-chlorophenyl)tropane-2ß-carboxylic acid methyl ester hydrochloride]) blocked both acid-stimulated writhing and acid-induced depression of ICSS, although these drugs also produced an abuse-related facilitation of ICSS in the absence of the noxious stimulus. These results support further consideration of dopamine reuptake inhibitors as candidate analgesics, although abuse liability remains a concern. PERSPECTIVE: Monoamine reuptake inhibitors are used to treat depression and some forms of pain. This study examined effects of monoamine reuptake inhibitors in a preclinical assay of pain-related behavioral depression. The results support further consideration of dopamine reuptake inhibitors as candidate analgesics under selected circumstances, although abuse liability remains a concern.
    The journal of pain: official journal of the American Pain Society 01/2013; · 4.22 Impact Factor

Publication Stats

8k Citations
1,539.86 Total Impact Points


  • 1999–2014
    • Emory University
      • • Department of Radiology
      • • Department of Neuroscience and Behavioral Biology
      Atlanta, Georgia, United States
  • 1976–2014
    • Research Triangle Park Laboratories, Inc.
      Raleigh, North Carolina, United States
  • 2013
    • Harvard Medical School
      • Department of Psychiatry
      Boston, Massachusetts, United States
  • 2007–2013
    • McLean Hospital
      • Behavioral Genetics Laboratory
      Cambridge, Massachusetts, United States
  • 2009–2011
    • RTI International
      • Division of Organic and Medicinal Chemistry
      Durham, North Carolina, United States
  • 2010
    • Barrow Neurological Institute
      • Division of Neurobiology
      Phoenix, AZ, United States
  • 2003–2009
    • University of Arkansas at Little Rock
      Little Rock, Arkansas, United States
  • 2004–2006
    • Virginia Commonwealth University
      • Department of Pharmacology and Toxicology
      Richmond, VA, United States
  • 2000–2001
    • University of California, Los Angeles
      • Department of Psychiatry and Biobehavioural Sciences
      Los Angeles, CA, United States
  • 1996–1999
    • Brookhaven National Laboratory
      • • Chemistry Department
      • • Medical Department
      New York City, NY, United States
  • 1996–1997
    • Johns Hopkins Medicine
      • Division of Nuclear Medicine
      Baltimore, MD, United States
  • 1995–1997
    • Johns Hopkins University
      • • Department of Radiology
      • • Department of Environmental Health Sciences
      Baltimore, MD, United States
  • 1990–1996
    • National Institute on Drug Abuse
      • Division of Intramural Research (IRP)
      Maryland, United States
    • University of Maryland, Baltimore
      Baltimore, Maryland, United States
  • 1994
    • University of North Carolina at Chapel Hill
      • Department of Psychiatry
      North Carolina, United States
  • 1993
    • Brown University
      Providence, Rhode Island, United States
  • 1992
    • University at Buffalo, The State University of New York
      Buffalo, New York, United States
    • Bristol-Myers Squibb
      New York City, New York, United States
  • 1986
    • Walter Reed Army Institute of Research
      Silver Spring, Maryland, United States