Multiple Neuronal Systems Thought to be Involved in

Nicotine Dependence

Frank Vocci, Ph.D.

Director

Division of Treatment Research and Development

National Institute on Drug Abuse

Nicotinic Cholinergic Receptors

• nAChRs span the cell membrane

• binding of nicotine / other ligands alters configuration

• permeability to ions changes

Nicotine Partial Agonist

Treatments for Nicotine Dependence

• Inhibition of nicotine metabolism• Based on observations of differences in

nicotine metabolism ( CYP 2A6) and risk of dependence formation – Pianezza et al Nature (1998)

• Clinical study with Methoxsalen ( CYP2A6 inhibitor ) reduced CO and smoking – Sellers et al CPT (2000)

Mesolimbic Dopamine System

dopamine antagonists systemically

dopamine antagonist in nucleus accumbens

6-OHDA lesion of mesolimbic projection

DHβE into ventral tegmental area (VTA)

nicotine self-administration in laboratory animals altered by:

Mesolimbic Dopamine System

DHβE into VTA-40 -20 0 20 40 60 80 100120140160

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time (min)

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nic+DHβE 200 μMnic+DHβE 10 μMnicotine

VTA manipulations alter nicotine-evoked dopamine release in ACC

systemic nicotine

GABA Mechanisms

VTAACC

GABA

nAChRs exist on VTA GABA circuitry and dopamine neurons

dopamine neurons are influenced by GABA-containing neurons

GABA Mechanisms

• GABA agonists into the VTA or administered systemically reduce self-administration of nicotine by animals

• GVG decreases nicotine-induced dopamine release in ACC and nicotine self-administration

Descending Glutamate Projections

VTA

glutamate

GABA

ACC

mPFCx

Descending Glutamate Projections

VTA

glutamate

GABA

ACC

mPFCx• nicotine GABA transmission• nAChRs on GABA processes desensitize• GABA transmission

• nicotine Glu transmission• nAChRs on Glu processes desensitize less• Glu transmission remains elevated

facilitation of synaptic

transmission

Preclinical Approaches- Excitation and Inhibition

Produced by Nicotine

Brain Mechanisms in Summary

VTA

ACh

glutamate

GABA

mesopontine nuclei

glutamate

GABA

ACC

mPFCx

dopamine

norepinephrine system

cannabinoid system

CRF system

others …

Preclinical Approaches- Excitation and Inhibition

Produced by Nicotine

• Three approaches are apparent in terms of modulation of nicotine– Reduce the glutamatergic excitation through

blockade of glutamate receptors… or– Increase the GABAergic inhibition by

increasing GABA or administering GABA-like drugs

– Reduce glutamate excitation and increase GABA activity

Modulation of Glutamatergic Transmission by an MGluR5

Antagonist

GVG ( GABA B) and Nicotine

Vigabatrin and Smoking Cessation

• Visual Field Defects have been reported in @ 30 % of individuals taking between 110 and 1500 grams of vigabatrin

• Effects may start as a bi-concave nasal lesion and progress to concentric circles

• Would have to be relegated to smokers who had failed to quit with other behavioral and pharmacological means

• Would have a time-limited therapy;e.g., facilitation of smoking cessation

Simultaneous Modulation of GABAergic Transmission-Topiramate ( TOPAMAX)

Galantamine-Potentiation of Synaptic Transmission

Treatment Approaches- Preclinical Studies

• Based on altering neurobiological processes that may be involved in maintenance of dependence or reinstatement

• Nicotine or smoking –related cues

• Nicotine-priming

• Stress- induced increases in nicotine intake

• Effects on frontal cortex inhibitory systems

Treatment Approaches- Preclinical Studies

• Based on altering neurobiological processes that may be involved in maintenance of dependence or reinstatement

• Nicotine or smoking –related cues

• Nicotine-priming

• Stress- induced increases in nicotine intake

• Effects on frontal cortex inhibitory systems

Grant

Positive Correlation with Cravingin Left Amygdala/Perirhinal Cortex

p<0.005, uncorrected. Extent = 10 pixels. N = 11p<0.005, uncorrected. Extent = 10 pixels. N = 11

Alterations in Conditioned Cueing: Two Phases of a Second-Order

Schedule Reinforcement

Pilla et al., 1999

D3 Partial Agonist Blocks Responses to Conditioned Cues

Priming

• “Priming” is a function of the rate and extent of drug into the CNS

• Reducing rate and extent of uptake could block priming … and relapse

• Pharmacological alterations of priming mechanisms

Session

Res

pon

ses

Initiation

Maintenance

Extinction

Saline

PrimingDrug Injection

Testing

Hypothetical Time Course in the Reinstatement Procedure

Erb, Shaham & Stewart 1996

Nicotine Vaccine and Priming

DAS 431

Blockade of Stress-Induced Responses

Medications Development for the Treatment of Abuse and Dependence

Footshock Stress-Induced Responses

Medications Development for the Treatment of Abuse and Dependence

B. Heroin-trained rats A. Cocaine-trained rats

Effects of SC Injections of the Non-Peptide CRF Antagonist, CP-154,526, on

Stress-Induced Reinstatement

Shaham et al

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CP-154,526 Dose (mg/kg, SC)

No stressFootshock (15 min)

Medications Development for Smoking Cessation

• Multiple clinical targets available that go beyond manipulation of the nicotinic cholinergic system

• Decisions on which clinical targets to pursue

• Multiple preclinical targets in discovery and preclinical testing that need priority ranking

Treatments for Nicotine Dependence

• MAO inhibitors

• Noted that a constituent in cigarette smoke is an MAO ( A and B) inhibitor- Fowler et al PNAS (1996) and Fowler et al Nature (1996)

• Suggests that MAO inhibition may assist smokers in quitting

Source: Fowler, J.S. et al., Inhibition of monoamine oxidase in the brains of smokers.Nature 379, pp. 733-736, February 22, 1996.

Treatments for Nicotine DependenceBrain MAO B and Smoking Status

Treatments for Nicotine Dependence- MAO A Inhibition

Selegiline as a Possible Treatment

Selegiline for Smoking Cessation