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Tobacco Constituents: Discussion of Abuse Liability

Allison C. Hoffman, Ph.D.

FDA Center for Tobacco Products

July 7-8, 2010

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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

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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.

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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

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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

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Neurobiological Assessment

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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

8http://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

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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).

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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

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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

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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

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Behavioral Assessment: Place Conditioning

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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)

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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

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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

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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

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)

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Acetaldehyde Place Conditioning (cont.)

Quertemont and De Witte, 2001

p<0.001

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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

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Behavioral Assessment:Drug Discrimination

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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)

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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

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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

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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

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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]

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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

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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

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Behavioral Assessment:Drug Self-Administration

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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.

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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

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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

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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

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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

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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

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Behavioral Assessment: Withdrawal

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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).

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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

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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

1 Natividad et al. 2010 (figure) 2 O’Dell et al., 2004

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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

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Human Laboratory Studies: Subjective Effects

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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

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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

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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

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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

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Summary (cont.)

• Anabasine may have some abuse liability– Increases DA in the midbrain (striatum)– Partially substitutes for nicotine in drug

discrimination testing

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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

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Summary (cont.)

• There is not enough data to assess anatabine, myosmine, or ammonia

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Clarifying Questions?

References are listed in subsequent slides

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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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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).