Download Medications Development for Nicotine Dependence

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
nicotine self-administration in
laboratory animals altered by:
dopamine antagonists
systemically
dopamine antagonist
in nucleus accumbens
6-OHDA lesion of
mesolimbic projection
DHβE into ventral
tegmental area (VTA)
Mesolimbic Dopamine System
dopamine (% of basal)
VTA manipulations alter nicotineevoked dopamine release in ACC
300
250
nic+DHβE 200 μM
nic+DHβE 10 μM
nicotine
systemic
nicotine
200
150
100
* * *
---------------------------------------------------
50
0
-40 -20 0 20 40 60 80 100 120 140 160
time (min)
DHβE into VTA
GABA Mechanisms
dopamine neurons are
influenced by GABAcontaining neurons
nAChRs exist on VTA
GABA circuitry and
dopamine neurons
ACC
VTA
GABA
GABA Mechanisms
• GABA agonists into the VTA or
administered systemically reduce selfadministration of nicotine by animals
• GVG decreases nicotine-induced
dopamine release in ACC and nicotine
self-administration
Descending Glutamate
Projections
mPFCx
glutamate
GABA
ACC
VTA
Descending Glutamate
Projections
mPFCx
glutamate
• nicotine GABA transmission
• nAChRs on GABA processes desensitize
•  GABA transmission
VTA
GABA
facilitation of
synaptic
transmission
ACC
• nicotine  Glu transmission
• nAChRs on Glu processes desensitize less
• Glu transmission remains elevated
Preclinical ApproachesExcitation and Inhibition
Produced by Nicotine
Brain Mechanisms in Summary
mPFCx
norepinephrine system
glutamate
cannabinoid system
CRF system
dopamine
VTA
others …
GABA
ACC
mesopontine
nuclei
GABA
glutamate
ACh
Preclinical ApproachesExcitation 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 TransmissionTopiramate ( TOPAMAX)
Galantamine-Potentiation of
Synaptic Transmission
Treatment ApproachesPreclinical 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 ApproachesPreclinical 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
Positive Correlation with Craving
in Left Amygdala/Perirhinal Cortex
p<0.005, uncorrected. Extent = 10 pixels. N = 11
Grant
Alterations in Conditioned Cueing:
Two Phases of a Second-Order
Schedule Reinforcement
D3 Partial Agonist Blocks Responses to
Conditioned Cues
Pilla et al., 1999
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
Hypothetical Time Course
in the Reinstatement Procedure
Responses
Maintenance
Initiation
Priming
Drug Injection
Saline
Extinction
Testing
Session
Erb, Shaham & Stewart 1996
Nicotine Vaccine and Priming
DAS 431
Medications Development for the
Treatment of Abuse and Dependence
Blockade of Stress-Induced Responses
Medications Development for the
Treatment of Abuse and Dependence
Footshock Stress-Induced Responses
Effects of SC Injections of the Non-Peptide CRF
Antagonist, CP-154,526, on
Stress-Induced Reinstatement
Responses in 3 h
(Active Lever)
A. Cocaine-trained rats B. Heroin-trained rats
60
45
No stress
Footshock (15 min)
No stress
Footshock
(10 min)
*
30
*
15
0
Veh
15
*
*
30
Veh 15
30
CP-154,526 Dose (mg/kg, SC)
Shaham et al
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
Treatments for Nicotine Dependence
Brain MAO B and Smoking Status
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
Dependence- MAO A Inhibition
Selegiline as a Possible
Treatment
Selegiline for Smoking
Cessation