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Tobacco Constituents: Discussion of Abuse Liability

Tobacco Constituents: Discussion of Abuse Liability. Allison C. Hoffman, Ph.D. FDA Center for Tobacco Products July 7-8, 2010. Overview. Rationale Scope Terminology: Abuse liability Assessment of abuse liability using animal models Neurobiological assessment Behavioral assessment

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Tobacco Constituents: Discussion of Abuse Liability

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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

  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. 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. 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. 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. Neurobiological Assessment

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

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

  10. Neurobiological Assessment (cont.) • Nicotine • Increases DA in nucleus accumbens1 • Increases DA in striatum (caudate and putamen)2 • Nornicotine • Increases DA in nucleus accumbens3 • 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. Neurobiological Assessment (cont.) • Acetaldehyde • Reduced DA in the nucleus accumbens or striatum1 • When given with nicotine2 • 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 synaptosomes3 • 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. 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. Behavioral Assessment: Place Conditioning

  14. 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) What is Place Conditioning?

  15. 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 Nicotine Place Conditioning Risinger and Oakes, 1995

  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. Acetaldehyde Place Conditioning • Acetaldehyde produces CPP when administered systemically1 or directly into the brain2 • Acetaldehyde produces an inverted U- shaped dose-response curve • Low to moderate doses are rewarding (CPP) • High doses are aversive (CPA)3 Note: Review of neurobiological effects of acetaldehyde by Quertemont et al. (2005) 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

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

  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. Behavioral Assessment:Drug Discrimination

  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. Nicotine Drug Discrimination • Nicotine produces reliable drug discrimination in a variety of animal models (nicotine versus saline; nicotine versus other drugs) • Mice1 • Rats2 • Non-human primates3 1 Jackson et al., 2010 2 Desai et al., 2003; Goldberg et al., 1989 3 Takeda et al., 1989

  23. Nornicotine Drug Discrimination • In rats trained to discriminate nicotine from saline, nornicotine substitutes fully or almost fully for nicotine1 • 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. 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 Nornicotine Drug Discrimination Nicotine Nornicotine Desai et al., 2003

  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 results2* 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. Acetaldehyde Drug Discrimination • Rats learned to reliably discriminate acetaldehyde from saline1 • Acetaldehyde produces at least some ethanol-like behavior in some cases2 but not others3 (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. 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. Behavioral Assessment:Drug Self-Administration

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

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

  32. Acetaldehyde Self-Administration • Rats self-administer acetaldehyde administered systemically1 • Rats self-administer acetaldehyde into the brain’s cerebral ventricles2 or ventral tegmental area3 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. 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. 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. Behavioral Assessment: Withdrawal

  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. 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. Rats given chronic nicotine (7 days), followed by precipitated withdrawal Adolescent rats show Significant, but less withdrawal (p<0.05)1 or No significant withdrawal2. Adult rats show significant withdrawal (p<0.05) 1,2 Nicotine Withdrawal (cont.) 1 Natividad et al. 2010 (figure) 2 O’Dell et al., 2004

  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. Human Laboratory Studies: Subjective Effects

  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 nicotine2 • People self-administer nicotine every time they take a puff of a cigarette 1 Chausmer et al., 2003 2 Rose et al., 2010

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

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

  48. Clarifying Questions? References are listed in subsequent slides

  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. 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.

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