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1 Tobacco Constituents: Discussion of Abuse Liability Allison C. Hoffman, Ph.D. FDA Center for Tobacco Products July 7-8, 2010.

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Presentation on theme: "1 Tobacco Constituents: Discussion of Abuse Liability Allison C. Hoffman, Ph.D. FDA Center for Tobacco Products July 7-8, 2010."— Presentation transcript:

1 1 Tobacco Constituents: Discussion of Abuse Liability Allison C. Hoffman, Ph.D. FDA Center for Tobacco Products July 7-8, 2010

2 2 Overview Rationale Scope Terminology: Abuse liability Assessment of abuse liability using animal models –Neurobiological assessment –Behavioral assessment Conditioned place preference Drug discrimination Self-administration Withdrawal Assessment of abuse liability using human laboratory studies Summary

3 3 Rationale In the last H/PH Subcommittee meeting (June 8- 9, 2010), the issue of addictive constituents in tobacco products was deferred. This presentation is meant to address questions regarding the abuse liability of specific tobacco product constituents identified by the Subcommittee in the previous meeting.

4 4 Scope Literature examples only for nicotine Comprehensive review of Pub Med peer- reviewed literature of other constituents from June Subcommittee list –Nornicotine –Anabasine –Anatabine –Myosmine –Acetaldehyde –Ammonia

5 5 What is Abuse Liability? Abuse liability = abuse potential Most commonly used by animal researchers Can be meaningfully applied to both animal and human research findings

6 6 Neurobiological Assessment

7 7 Neuronal activation can be detected through the release of chemical messengers in the brain called neurotransmitters The importance of the neurotransmitter dopamine (DA) in abuse liability –When released in the midbrain (incl. nucleus accumbens and striatum), DA is widely thought to be involved in the maintenance of positively reinforced behavior, including feeding and drug taking –Drugs that cause increased DA in these areas are thought to have abuse liability For reviews, see Balfour, 2004; Deadwyler, 2010; Markou, 2008

8 8 http://www.cam.ac.uk/about/scienceseminars/drugs/brain.png Nucleus Accumbens Caudate- Putamen Ventral Tegmental Area - Drugs can go in (local administration) - Fluid samples can come out Striatum

9 9 Example of measuring DA release in the midbrain Dong et al., 2010 Systemic or local injection (via cannula) of nicotine causes DA release in the nucleus accumbens (p<0.05).

10 10 Neurobiological Assessment (cont.) Nicotine –Increases DA in nucleus accumbens 1 –Increases DA in striatum (caudate and putamen) 2 Nornicotine –Increases DA in nucleus accumbens 3 –Increases DA in striatum (caudate and putamen) 4 Anabasine –Increases DA in striatum (caudate and putamen) 5 1 Di Chiara and Imperato 1988; Rowell et al., 1987 2 Balfour, 2004; Dong et al., 2010; Markou, 2008 3 Green et al., 2001; Middleton et al., 2007 4 Dwoskin et al., 1993; Dwoskin et al., 1995; Teng et al., 1997 5 Dwoskin et al., 1995

11 11 Neurobiological Assessment (cont.) Acetaldehyde –Reduced DA in the nucleus accumbens or striatum 1 –When given with nicotine 2 No effect on DA levels in the nucleus accumbens (adult rats) Reduced DA in the nucleus accumbens or striatum when (young rats) Ammonia –Increased DA in striatum and in rat forebrain and midbrain synaptosomes 3 Thought to indicate ammonia toxicity 1 Wang et al., 2007; Ward et al., 1997 2 Sershen et al., 2009 3 Anderzhanova et al., 2003; Erecinska et al., 1987

12 12 Neurobiological Assessment (cont.) No data were found in the review of Pub Med’s peer-reviewed literature on DA in the midbrain and anatabine or myosmine

13 13 Behavioral Assessment: Place Conditioning

14 14 What is Place Conditioning? Two distinct environments (texture, color, smell) Training sessions –Drug pretreatment paired with one environment, saline with other One pretreatment = one side only Test session – not confined to single side (undrugged) Outcome variable = time spent in each environment –If prefer drug-paired environment = conditioned place preference (CPP) –If avoid drug-paired environment = conditioned place aversion (CPA)

15 15 Nicotine Place Conditioning Nicotine (0.25 – 2.0 mg/kg) or vehicle pretreatment prior 8 conditioning sessions –4 sessions each Mice display preference (CPP) for nicotine-paired environment at 0.5 mg/kg Mice display aversion (CPA) for nicotine-paired environment at 2.0 mg/kg Nicotine produces an inverted U-shaped dose- response curve –Low to moderate doses are rewarding –High doses are aversive Risinger and Oakes, 1995

16 16 Nicotine Place Conditioning (cont.) Four conditioning sessions each (nicotine, vehicle). Adolescent, but not adult, rats exhibited conditioned place preference to this very low dose of nicotine (p< 0.05) Shram and Le, 2010

17 17 Acetaldehyde Place Conditioning Acetaldehyde produces CPP when administered systemically 1 or directly into the brain 2 Acetaldehyde produces an inverted U- shaped dose-response curve –Low to moderate doses are rewarding (CPP) –High doses are aversive (CPA) 3 1 Quertemont and De Witte, 2001; Quintanilla and Tamper, 2003; Spina et al., 2010 2 Smith et al., 1984 3 Quertemont and De Witte, 2001 Note: Review of neurobiological effects of acetaldehyde by Quertemont et al. (2005)

18 18 Acetaldehyde Place Conditioning (cont.) Quertemont and De Witte, 2001 p<0.001

19 19 Place Conditioning: Other Constituents No data were found in the review of Pub Med’s peer-reviewed literature regarding place conditioning and nornicotine, anabasine, anatabine, myosmine, or ammonia

20 20 Behavioral Assessment: Drug Discrimination

21 21 What is Drug Discrimination? Two lever operant task working for non-drug reinforcer (e.g., sucrose, food) Pretreatment with training drug (one lever active) or vehicle (other lever active) prior to training session –Learn to reliably press one lever when pretreated with drug and the other when pretreated with vehicle Test drug administered prior to test session (neither lever active) –Outcome measure: % training-drug paired lever (not reinforced) –Drug lever = common interoceptive cues Correlated with shared mechanism of action Shared across drug classes (e.g., stimulant drugs partially or fully substitute for each other)

22 22 Nicotine Drug Discrimination Nicotine produces reliable drug discrimination in a variety of animal models (nicotine versus saline; nicotine versus other drugs) –Mice 1 –Rats 2 –Non-human primates 3 1 Jackson et al., 2010 2 Desai et al., 2003; Goldberg et al., 1989 3 Takeda et al., 1989

23 23 Nornicotine Drug Discrimination In rats trained to discriminate nicotine from saline, nornicotine substitutes fully or almost fully for nicotine 1 In rats trained to discriminate between amphetamine and saline, nornicotine partially substitutes for amphetamine (shown) 2 Figure adapted from Bardo et al., 1997 1 Desai et al., 1999; Goldberg et al., 1989; Takada et al., 1989 2 Bardo et al., 1997

24 24 Nornicotine Drug Discrimination Rats trained to discriminate cocaine from saline. Nornicotine partially substituted for cocaine –producing a maximum of 44.3% cocaine-appropriate –Comparison to nicotine: almost fully substituted for cocaine Desai et al., 2003 Nicotine Nornicotine

25 25 Anabasine Drug Discrimination Rats trained to discriminate nicotine from saline Pretreatment with anabasine produced almost full substitution in lever choice (p<0.05) (shown) 1 Others found similar results 2* 1 Brioni et al., 1994 2 Pratt et al., 1983; Stolerman et al., 1984 *Takeda et al., 1989 [only studied in one squirrel monkey, data not included]

26 26 Acetaldehyde Drug Discrimination Rats learned to reliably discriminate acetaldehyde from saline 1 Acetaldehyde produces at least some ethanol-like behavior in some cases 2 but not others 3 (depends on training regimen) 1 Redila et al., 2002 2 Redila et al., 2000; Jarbe et al., 1982 3 Jarbe et al., 1982; Quertemont and Grant, 2002; Quertemont, 2003

27 27 Drug Discrimination: Other Constituents No data were found in the review of Pub Med’s peer-reviewed literature regarding drug discrimination and anatabine, myosmine, or ammonia

28 28 Behavioral Assessment: Drug Self-Administration

29 29 What is Drug Self-Administration? When an animal performs a behavior in order to receive drug, it is “self-administering” that drug –Leverpress or other operant behavior Reliable drug self-administration is considered a robust indication of abuse potential –However, failure doesn’t necessarily indicate lack of abuse potential Dose, scheduling, etc.

30 30 Nicotine Self-Administration Rats press a lever to self-administer intravenous nicotine Inverted U-shaped dose-response curve Maximum level of intake (plateau) Corrigall and Coen, 1989

31 31 Nornicotine Self-Administration Rats learn to self- administer intravenous nornicotine Produces similar inverted U-shaped dose-response curve Bardo et al., 1999 p<0.001

32 32 Acetaldehyde Self-Administration Rats self-administer acetaldehyde administered systemically 1 Rats self-administer acetaldehyde into the brain’s cerebral ventricles 2 or ventral tegmental area 3 1 Myers et al., 1982; Myers et al., 1984a, Myers et al., 1984b, Myers et al., 1984c 2 Amit et al., 1977 3 Rodd-Henddricks et al., 2002

33 33 Acetaldehyde Self-Administration (cont.) Dose-dependent interaction (p<0.05) between nicotine plus acetaldehyde in adolescent, but not adult, rats. Beluzzi et al., 2005; figure adapted

34 34 Self-Administration: Other Constituents No data were found in the review of Pub Med’s peer-reviewed literature regarding self-administration and anabasine, anatabine, myosmine, or ammonia

35 35 Behavioral Assessment: Withdrawal

36 36 What is Withdrawal? Withdrawal is a phenomenon that occurs following exposure to a drug. –Somatic withdrawal characterizes physical dependence In animals chronically exposed to a drug, physical dependence is evaluated following either cessation of drug administration (spontaneous withdrawal) or with treatment with a drug blocker (precipitated withdrawal).

37 37 Nicotine Withdrawal In rats exposed to chronic nicotine, then withdrawn from nicotine (spontaneous or precipitated withdrawal), overt somatic signs of withdrawal, including: –Body shakes, chews, cheek tremors, escape attempts, foot licks, gasps, writhes, headshakes, ptosis, teeth chattering, yawns Often given as a composite score O’Dell et al., 2004

38 38 Nicotine Withdrawal (cont.) Rats given chronic nicotine (7 days), followed by precipitated withdrawal Adolescent rats show –Significant, but less withdrawal (p<0.05) 1 or –No significant withdrawal 2. Adult rats show significant withdrawal (p<0.05) 1,2 1 Natividad et al. 2010 (figure) 2 O’Dell et al., 2004

39 39 Other Constituents: Withdrawal No data were found in the review of Pub Med’s peer-reviewed literature regarding withdrawal and nornicotine, anabasine, anatabine, myosmine, acetaldehyde, or ammonia

40 40 Human Laboratory Studies: Subjective Effects

41 41 Human Laboratory Studies: Subjective effects of nicotine Nicotine produces positive subjective ratings –High, stimulated, rush, drug effect, etc. 1 Humans choose to administer intravenous nicotine 2 People self-administer nicotine every time they take a puff of a cigarette 1 Chausmer et al., 2003 2 Rose et al., 2010

42 42 Human Laboratory Studies: Subjective Effects of Other Constituents No data were found in the review of Pub Med’s peer-reviewed literature regarding human laboratory studies and nornicotine, anabasine, anatabine, myosmine, acetaldehyde, or ammonia

43 43 Summary Nicotine has robust abuse liability –Increases DA in the midbrain (esp. nucleus accumbens) –Produces CPP –Maintains self-administration in animals –Produces withdrawal symptoms –Positive ratings in human laboratory studies

44 44 Summary (cont.) Nornicotine has likely abuse liability –Increases DA in the midbrain (esp. nucleus accumbens) –No data on place conditioning –Substitutes for nicotine in drug discrimination testing Partially substitutes for cocaine and amphetamine –Maintains self-administration in animals

45 45 Summary (cont.) Anabasine may have some abuse liability –Increases DA in the midbrain (striatum) –Partially substitutes for nicotine in drug discrimination testing

46 46 Summary (cont.) Acetaldehyde has likely abuse liability –No consistent effects on midbrain DA levels (age related?) –Produces CPP –Partially substitutes for ethanol (not reliable) –Maintains self-administration in animals

47 47 Summary (cont.) There is not enough data to assess anatabine, myosmine, or ammonia

48 48 Clarifying Questions? References are listed in subsequent slides

49 49 References Amit Z, Brown ZW, Rockman GE. Possible involvement of acetaldehyde, norepinephrine and their tetrahydroisoquinoline derivatives in the regulation of ethanol seld-administration. Drug Alcohol Depend. 1977 Sep-Nov;2(5-6):495-500. Anderzhanova E, Oja SS, Saransaari P, Albrecht J. Changes in the striatal extracellular levels of dopamine and dihydroxyphenylacetic acid evoked by ammonia and N-methyl-D-aspartate: modulation by taurine. Brain Res. 2003 Jul 11;977(2):290-3. Balfour DJ. The neurobiology of tobacco dependence: a preclinical perspective on the role of the dopamine projections to the nucleus accumbens Nicotine Tob Res. 2004 Dec;6(6):899-912. Review. Bardo MT, Bevins, RA, Klebaur JE, Crooks PA, Dwoskin LP. (-)-Nornicotine partially substitutes for (+)-Amphetamine in a drug discrimination paradign in rats. Pharm Bio Behav. 1997; 58(4): 1083-1087. Belluzzi JD, Wang R, Leslie FM. Acetaldehyde enhances acquisition of nicotine self-administration in adolescent rats. Neuropsychopharmacology. 2005 Apr;30(4):705-12. Brioni JD, Kim DJ, O'Neill AB, Williams JE, Decker MW. Clozapine attenuates the discriminative stimulus properties of (-)-nicotine. Brain Res. 1994 Apr 18;643(1-2):1-9. Chausmer AL, Smith BJ, Kelly RY, Griffiths RR. Cocaine-like subjective effects of nicotine are not blocked by the D1 selective antagonist ecopipam (SCH 39166). Behav Pharmacol. 2003 Mar;14(2):111-20.

50 50 References (cont.) Corrigall WA, Coen, KA. Nicotine maintains robust self-administration in rats on a limited access schedule. Psychopharm. 1989; 99: 473-478. Deadwyler SA. Electrophysiological correlates of abused drugs: relation to natural rewards. Ann N Y Acad Sci. 2010 Feb;1187:140-7. Desai RI, Barber DJ, Terry P. Behav Pharmacol. 1999 Nov;10(6-7):647-56. Asymmetric generalization between the discriminative stimulus effects of nicotine and cocaine. Desai RI, Barber DJ, Terry P. Dopaminergic and cholinergic involvement in the discriminative stimulus effects of nicotine and cocaine in rats. Psychopharmacology (Berl). 2003 Jun;167(4):335-43. Di Chiara G, Imperato A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci. 1988; 85: 5274-5278. Dong Y, Zhang T, Li W, Doyon WM, Dani JA. Route of nicotine administration influences in vivo dopamine neuron activity: habituation, needle injection, and cannula infusion. J Mol Neurosci. 2010 Jan;40(1-2):164-71. Dwoskin LP, Buxton ST, Jewell AL, Crooks PA. S(-)-nornicotine increases dopamine release in a calcium-dependent manner from superfused rat striatal slices. J Neurochem. 1993 Jun;60(6):2167-74. Dwoskin LP, Teng L, Buxton ST, Ravard A, Deo N, Crooks PA. Minor alkaloids of tobacco release [3H]dopamine from superfused rat striatal slices. Eur J Pharmacol. 1995 Mar 24;276(1-2):195-9.

51 51 References (cont.) Erecińska M, Pastuszko A, Wilson DF, Nelson D. Ammonia-induced release of neurotransmitters from rat brain synaptosomes: differences between the effects on amines and amino acids. J Neurochem. 1987 Oct;49(4):1258- 65. Goldberg SR, Risner ME, Stolerman IP, Reavill C, Garcha HS. Nicotine and some related compounds: effects on schedule-controlled behaviour and discriminative properties in rats. Psychopharmacology (Berl). 1989;97(3):295- 302. Green TA, Crooks PA, Bardo MT, Dwoskin LP. Contributory role for nornicotine in nicotine neuropharmacology: nornicotine-evoked [3H]dopamine overflow from rat nucleus accumbens slices. Biochem Pharmacol. 2001 Dec 15;62(12):1597-603. Green TA, Phillips SB, Crooks PA, Dwoskin LP, Bardo MT. Nornicotine pretreatment decreases intravenous nicotine self-administration in rats. Psychopharmacology (Berl). 2000 Oct;152(3):289-94. Jackson KJ, Marks MJ, Vann RE, Chen X, Gamage TF, Warner JA, Damaj MI. Role of {alpha}5 Nicotinic Acetylcholine Receptors in Pharmacological and Behavioral Effects of Nicotine in Mice. J Pharmacol Exp Ther. 2010 Jul;334(1):137-46. Järbe TU, Hiltunen AJ, Swedberg MD. Ethanol as a discriminative stimulus: effects of cyanamide, acetaldehyde and chlormethiazole. Med Biol. 1982 Dec;60(6):298-306. Markou A. Review. Neurobiology of nicotine dependence. Philos Trans R Soc Lond B Biol Sci. 2008 Oct 12;363(1507):3159-68.

52 52 References (cont.) Myers WD, Ng KT, Singer G. Intravenous self-administration of acetaldehyde in the rat as a function of schedule, food deprivation and photoperiod. Pharmacol Biochem Behav. 1982 Oct;17(4):807-11. Myers RD, Hepler JR, Schwartzwelder HS, Noto T, Denbow DM. Changes in Ca2+ ion activity within unrestrained rat's hippocampus perfused with alcohol or acetaldehyde. Neuroscience. 1984 Oct;13(2):355-65. Myers W, Ng K, Singer G. Ethanol preference in rats with a prior history of acetaldehyde self-administration. Experientia. 1984 Sep 15;40(9):1008-10. Myers WD, Ng KT, Singer G. Effects of naloxone and buprenorphine on intravenous acetaldehyde self-injection in rats. Physiol Behav. 1984 Sep;33(3):449-55. Myers WD, Ng KT, Marzuki S, Myers RD, Singer G. Alteration of alcohol drinking in the rat by peripherally self- administered acetaldehyde. Alcohol. 1984 May-Jun;1(3):229-36. Middleton LS, Crooks PA, Wedlund PJ, Cass WA, Dwoskin LP. Nornicotine inhibition of dopamine transporter function in striatum via nicotinic receptor activation. Synapse. 2007 Mar;61(3):157-65. O'Dell LE, Bruijnzeel AW, Ghozland S, Markou A, Koob GF. Nicotine withdrawal in adolescent and adult rats. Ann N Y Acad Sci. 2004 Jun;1021:167-74.

53 53 References (cont.) Pratt JA, Stolerman IP, Garcha HS, Giardini V, Feyerabend C. Discriminative stimulus properties of nicotine: further evidence for mediation at a cholinergic receptor. Psychopharmacology (Berl). 1983;81(1):54-60. Quertemont E. Discriminative stimulus effects of ethanol with a conditioned taste aversion procedure: lack of acetaldehyde substitution. Behav Pharmacol. 2003 Jul;14(4):343-50. Quertemont E, De Witte P. Conditioned stimulus preference after acetaldehyde but not ethanol injections. Pharmacol Biochem Behav. 2001 Mar;68(3):449-54. Quertemont E, Grant KA.Role of acetaldehyde in the discriminative stimulus effects of ethanol. Alcohol Clin Exp Res. 2002 Jun;26(6):812-7. Quertemont E, Tambour S, Tirelli E. The role of acetaldehyde in the neurobiological effects of ethanol: A comprehensive review of animal studies. Prog Neurobiol. 2005; 75: 247-274. Quintanilla ME, Tampier L. Acetaldehyde-reinforcing effects: differences in low-alcohol-drinking (UChA) and high- alcohol-drinking (UChB) rats. Alcohol. 2003 Aug-Oct;31(1-2):63-9.

54 54 References (cont.) Redila VA, Aliatas E, Smith BR, Amit Z. Effects of ethanol on an acetaldehyde drug discrimination with a conditioned taste aversion procedure. Alcohol. 2002 Oct;28(2):103-9. Risinger FO, Oakes RA. Nicotine-induced conditioned place preference and conditioned place aversion in mice. Pharmacol Biochem Behav. 1995 Jun-Jul;51(2-3):457-61. Rodd-Henricks ZA, Melendez RI, Zaffaroni A, Goldstein A, McBride WJ, Li TK. The reinforcing effects of acetaldehyde in the posterior ventral tegmental area of alcohol-preferring rats. Pharmacol Biochem Behav. 2002 May;72(1- 2):55-64. Rose JE, Salley A, Behm FM, Bates JE, Westman EC. Reinforcing effects of nicotine and non-nicotine components of cigarette smoke. Psychopharmacology (Berl). 2010 May;210(1):1-12. Rowell PP, Carr LA, Garner AC. Stimulation of [3H]dopamine release by nicotine in rat nucleus accumbens. J Neurochem. 1987 Nov;49(5):1449-54. Sershen H, Shearman E, Gallon S, Chakroborty G, Smiley J, Lajtha A. The effects of acetaldehyde on nicotine-induced neurotransmitter levels in young and adult brain areas. Br Res Bull. 2009; 79: 458-462. Spina L, Longoni R, Vinci S, Ibba F, Peana AT, Muggironi G, Spiga S, Acquas E. Role of dopamine D1 receptors and extracellular signal regulated kinase in the motivational properties of acetaldehyde as assessed by place preference conditioning. Alcohol Clin Exp Res. 2010 Apr 1;34(4):607-16.

55 55 References (cont.) Stairs DJ, Neugebauer NM, Wei X, Boustany C, Hojahmat M, Cassis LA, Crooks PA, Dwoskin LP, Bardo MT. Effects of nornicotine enantiomers on intravenous S(-)-nicotine self-administration and cardiovascular function in rats. Psychopharmacology (Berl). 2007 Feb;190(2):145-55. Stolerman IP, Garcha HS, Pratt JA, Kumar R. Role of training dose in discrimination of nicotine and related compounds by rats. Psychopharmacology (Berl). 1984;84(3):413-9. Pratt JA, Stolerman IP, Garcha HS, Giardini V, Feyerabend C. Discriminative stimulus properties of nicotine: further evidence for mediation at a cholinergic receptor. Psychopharmacology (Berl). 1983;81(1):54-60. Takada K, Swedberg MD, Goldberg SR, Katz JL. Discriminative stimulus effects of intravenous l-nicotine and nicotine analogs or metabolites in squirrel monkeys. Psychopharmacology (Berl). 1989;99(2):208-12. Teng L, Crooks PA, Buxton ST, Dwoskin LP. Nicotinic-receptor mediation of S(-)nornicotine-evoked -3H-overflow from rat striatal slices preloaded with -3H-dopamine. J Pharmacol Exp Ther. 1997 Nov;283(2):778-87. Wang W, Ameno K, Jamal M, Kumihashi M, Uekita I, Ameno S, Ijiri I. Effect of direct infusion of acetaldehyde on dopamine and dopamine-derived salsolinol in the striatum of free-moving rats using a reverse microdialysis technique. Arch Toxicol. 2007 Feb;81(2):121-6. Ward RJ, Colantuoni C, Dahchour A, Quertemont E, De Witte P. Acetaldehyde-induced changes in monoamine and amino acid extracellular microdialysate content of the nucleus accumbens. Neuropharmacology. 1997 Feb;36(2):225-32.

56 56 Harman and norharman Beta-carbolines are monoamine oxidase inhibitors (MAOI) Harman is formed from tryptamine or tryptophan and acetaldehyde, and is present in tobacco smoke (see review by Talhout et al., 2007).


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