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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

Tobacco Constituents: Discussion of Abuse Liability

Allison C. Hoffman, Ph.D.

FDA Center for Tobacco Products

July 7-8, 2010

overview
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
rationale
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.
scope
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
what is abuse liability
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
neurobiological assessment7
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

slide8

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

example of measuring da release in the midbrain
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

neurobiological assessment cont
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

neurobiological assessment cont11
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

neurobiological assessment cont12
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
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)

What is Place Conditioning?
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

Nicotine Place Conditioning

Risinger and Oakes, 1995

nicotine place conditioning cont
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

acetaldehyde place conditioning
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

acetaldehyde place conditioning cont
Acetaldehyde Place Conditioning (cont.)

p<0.001

Quertemont and De Witte, 2001

place conditioning other constituents
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
what is drug discrimination
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)
nicotine drug discrimination
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

nornicotine drug discrimination
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

nornicotine drug discrimination24
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

anabasine drug discrimination
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]

acetaldehyde drug discrimination
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

drug discrimination other constituents
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
what is drug self administration
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.
nicotine self administration
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

nornicotine self administration
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

acetaldehyde self administration
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

acetaldehyde self administration cont
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

self administration other constituents
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
what is withdrawal
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).
nicotine withdrawal
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

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 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

other constituents withdrawal
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
human laboratory studies subjective effects of nicotine
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

human laboratory studies subjective effects of other constituents
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
summary
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
summary cont
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
summary cont45
Summary (cont.)
  • Anabasine may have some abuse liability
    • Increases DA in the midbrain (striatum)
    • Partially substitutes for nicotine in drug discrimination testing
summary cont46
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
summary cont47
Summary (cont.)
  • There is not enough data to assess anatabine, myosmine, or ammonia
slide48

Clarifying Questions?

References are listed in subsequent slides

references
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.

references cont
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.

references cont51
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.

references cont52
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.

references cont53
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.

references cont54
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.

references cont55
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.

harman and norharman
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).