multiple neuronal systems thought to be involved in nicotine dependence frank vocci, ph.d. director...
TRANSCRIPT
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
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
0
50
100
150
200
250
300
---------------------------------------------------
time (min)
do
pam
ine
(% o
f b
asal
)
* * *
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• 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
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
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
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
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
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
0
15
30
45
60
Res
pon
ses
in 3
h
(Act
ive
Lev
er)
Veh 3015
**
Veh 15 30
Footshock(10 min)
No stress
* *
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