ibogaine analogues: drug development for addictive disorders stanley d. glick, ph.d., m.d. center...
TRANSCRIPT
Ibogaine Analogues: Ibogaine Analogues: Drug Development for Drug Development for
Addictive Disorders Addictive Disorders
Stanley D. Glick, Ph.D., M.D.
Center for Neuropharmacology and Neuroscience
THETHE
NEUROSCIENCESEUROSCIENCESINSTITUTEINSTITUTE
Albany Medical Center
Drug Abuse / Drug Drug Abuse / Drug DependenceDependence
Drug/substance abuse Self-administered use of any drug/substance in a manner
that deviates from the approved medical or social standards within a given culture
Addiction or psychological dependence Repeated, compulsive seeking or use of a substance despite
adverse social, psychological and/ or physical consequences Chronic relapsing disorder
Physical dependence Adaptive, physiological state produced by repeated drug
administration that is manifested as a withdrawal syndrome.
ADDICTION can occur without PHYSICAL DEPENDENCEADDICTION can occur without PHYSICAL DEPENDENCEPHYSICAL DEPENDENCE can occur without ADDICTIONPHYSICAL DEPENDENCE can occur without ADDICTION
July 10, 1996
Dr. M.A. GeyerManaging EditorPsychopharmacologyDepartment of PsychiatrySchool of MedicineUniversity of California San DiegoLa Jolla, CA 92093-0804
Dear Dr. Geyer:
Enclosed are four copies of our revised manuscript (MS96MG-095) entitled, "Ibogaine And The Dopaminergic Response To Nicotine," authored by S.D. Glick, G.L. Mann, C.R. Deibel and myself which we would like to resubmit for publication in Psychopharmacology.
1- We do not think that it would be appropriate to discuss the report of Dworkin et al. (1995) in this manuscript, since we do not report any self-administration results. Dworkin, using Fisher rats, reported that ibogaine alters all reinforcers (food, drug) with limited effects a day later. Our laboratory, using Sprague Dawley rats, showed that ibogaine alters all reinforcers (water, drug) on the day of its administration, but only the drug reinforcers later on (Glick et al. 1991). The strain difference may explain this inconsistency. It should also be noted that Cappendijk and Dzoljic (1993) reported effects of ibogaine on cocaine self-administration that were very similar to our results (Glick et al. 1994). The effects of mecamylamine on DOPAC and HVA increases induced by nicotine are described in the results section and, as requested by the reviewer, plotted as Figure 3. We have incorporated in Figure 2 the dopamine baseline values preceding mecamylamine administration and the 30 min levels prior to nicotine infusion. In the discussion (pages 12-13) the effects of ibogaine and mecamylamine on the dopamine response to nicotine are compared, and the greater efficacy of ibogaine to alter the nicotine-induced increase in dopamine as compared to DOPAC and HVA is addressed. It is true that the phenomenon of nicotine-induced desensitization has been widely studied using numerous techniques. However, direct in vivo neurochemical measurements were made only by Damsma in 1989 who did not observe any acute tolerance to the dopaminergic response to nicotine. In this context, our findings are very interesting.
Thank you for your consideration.
Sincerely,
Isabelle Maisonneuvebbbbbbb
VTA
December 9, 1999“…I am currently married and have a three year old daughter. I have used heroin on and off since I was 16 years old, more on than off… I have attended numerous substances abuse program and detoxes… I started a business and bought a house with my wife. Unfortunately, I am losing both due to my addiction. I crave heroin constantly, only heroin. I overdosed ten days ago and this wasn’t the first time. I’ll try anything that might help me to stay clean and straight. Please consider me as a candidate for your research protocol…”
February 16, 2000“…I am 63 years old and I have been using heroin for well over 25 years, never having the willpower or success to kick the habit once and for all. At this point I know that I must stop and desperately want to. Somehow, I’ve managed to hold onto my county job for the past 13 years, and must continue to keep it for at least 4 more years. We have recently filed for bankruptcy, and our condo is in foreclosure; yet it can become even worse if I don’t get a grip on this habit. I have many reasons to stop, not least of all for the sake of my children, grandchildren and wife who is not at all that well herself. I would be so very grateful sir, if you could take the time to give me some idea, some direction as to how I might go about signing up or at least trying to participate in your research…”
July 10, 1996
Dr. M.A. GeyerManaging EditdggggggggorPsychopharmacologyUniversity of California Sa
Dear Dr. Geyer:
Enclosed are four copies of our revised manuscript (MS96MG-095) entitled, "Ibogaine And The Dopaminergic Response To Nicotine," authored by S.D. Glick, G.L. Mann, C.R. Deibel and myself which we would like to resubmit for publication in Psychopharmacolog1- We do not think that it would be appropriate to discuss the report of Dworkin et al. (1995) in this manuscript, since we do not report any self-administration results. Dworkin, using Fisher rats, reported that ibogaine alters all reinforcers (food, drug) with limited effects a day later. Our laboratory, using Sprague Dawley rats, showed that ibogaine alters all reinforcers (water, drug) on the day of its administration, but only the drug reinforcers later on (Glick et al. 1991). The strain difference may explain this inconsistency. It should also be noted that Cappendijk and Dzoljic (1993) reported effects of ibogaine on cocaine self-administration that were very similar to our results (Glick et al. 1994). The effects of mecamylamine on DOPAC and HVA increases induced by nicotine are described in the results section and, as requested by the reviewer, plotted as Figure 3. We have incorporated in Figure 2 the dopamine baseline values preceding mecamylamine administration and the 30 min levels prior to nicotine infusion. In the discussion (pages 12-13) the effects of ibogaine and mecamylamine on the dopamine response to nicotine are compared, and the greater efficacy of ibogaine to alter the nicotine-induced increase in dopamine as compared to DOPAC and HVA is addressed. It is true that the phenomenon of nicotine-induced desensitization has been widely studied using numerous techniques. However, direct in vivo neurochemical measurements were made only by Damsma in 1989 who did not observe any acute tolerance to the dopaminergic response to nicotine. In this context, our findings are very interesting.
Thank you for your consideration.
Sincerely,
Isabelle Maisonneuve,
IShofd
Wtray
Addicts are desperate Addicts are desperate for new therapiesfor new therapies
Once upon a time in Once upon a time in Africa…Africa…Tabernanthe iboga shrub
Ibogaine is contained in the roots of the shrubs.
Ibogaine has been used for centuries in rituals of the Bwiti religion.
CameroonEq. GuineaGabon2 Congos
At very high concentrations, At very high concentrations, side effects are present…side effects are present…
Degeneration of Purkinje cells in parasagittal zones of the cerebellar vermis after treatment with ibogaine or harmaline. O'Hearn, E. and Molliver, M.E. Neuroscience 55:303-310 (1993).
The search for a better ibogaine…The search for a better ibogaine…
1. It had to be as effective as ibogaine.
2. It had to lack all the side effects of ibogaine.
Is 18-MC a potential treatmentIs 18-MC a potential treatmentfor drug dependence?for drug dependence?
1. Is 18-MC effective in reducingdrug self-administration?
2. Is 18-MC effective in reducing signs of drug withdrawal?
Drug self-administrationDrug self-administration
Effect of an ideal treatmentEffect of an ideal treatment
Treatment dosage
num
ber
of
resp
on
ses
The ideal treatment will not affect
responding for a non-drug reinforcer (e.g., water, food,
sucrose).
The ideal treatment will depress
responding for a drug of abuse
0 10 20 30 40
0
20
40
60
80
100
120
Perc
ent
of b
asel
ine
18-MC (mg/kg, i.p.)
Water Cocaine Morphine
Effects of 18-MC on respondingEffects of 18-MC on respondingfor morphine, cocaine and waterfor morphine, cocaine and water
18-MC selectively decreases
morphine and cocaine self-
administration.
0 10 20 30 400
20
40
60
80
100
120
Perc
ent
of b
asel
ine
I bogaine (mg/kg, i.p.)
Water Cocaine Morphine
Ibogaine also affects responding
for water.
0 10 20 30 40
0
20
40
60
80
100
120
Perc
ent
of b
asel
ine
18-MC (mg/kg, i.p.)
Methamphetamine Nicotine
Effects of 18-MC on respondingEffects of 18-MC on respondingfor methamphetamine and for methamphetamine and
nicotinenicotineFemale rats 18-MC selectively
decreases methamphetamine and nicotine self-
administration, but is most potent in
decreasing nicotine self-administration.
Effects of 18-MC on alcohol intakeEffects of 18-MC on alcohol intake
0 10 20 30 400
10
20
30
40
50
0 10 20 30 400
25
50
75
100
Food
inta
ke (g
/kg/
day)
18-MC (mg/kg, i.p.)
Food intake Alcohol intake
Alcohol intake (m
l/kg/day)
Rezvani et al., Pharmacol. Biochem. Behav., 58:615-619 (1997).
18-MC decreases alcohol intake at doses that do not
affect food intake.
18-MC reduces 18-MC reduces the efficacy of morphinethe efficacy of morphine
0.00 0.04 0.08 0.12 0.160
10
20
30
Infu
sion
s/ho
ur
Morphine (mg/kg/infusion)
Vehicle 18-MC (40 mg/kg, p.o.)
I don’t like morphine as much since I took 18-MC
18-MC produces a significant downward
shift in the dose-response curve for
morphine self-administration.
18-MC’s effects on drug self-18-MC’s effects on drug self-administration are persistentadministration are persistent
Base Day 1 Day 2 Day 3 Day 6 Day 70
20
40
60
Mor
phin
e in
fusi
ons/
hour
Test Session
Control 18-MC (40 mg/kg, i.p.)
Base Day 1 Day 2 Day 3 Day 6 Day 70
10
20
30
Coca
ine
infu
sion
s/ho
ur
Test SessionBase Day 1 Day 2 Day 3 Day 6 Day 7
0
20
40
60
Mor
phin
e in
fusi
ons/
hour
Test Session
Control 18-MC (40 mg/kg, i.p.)
18-MC decreasescocaine self-
administration for 24 hours
18-MC decreasesmorphine self-administration
for 48 hours
Opioid withdrawalOpioid withdrawal
•weight loss•wet dog shakes•flinching•teeth chattering•grooming•burying•diarrhea
18-MC reduces the intensity of several signs of
morphine withdrawal
Control 10 20 400
5
10
15
Wei
ght
loss
18-MC (mg/kg, i.p.)
Control 10 20 400
20
40
60
80
100
Wet
dog
sha
kes
18-MC (mg/kg, i.p.)Control 10 20 40
0
5
10
15
20
Groo
min
g
18-MC (mg/kg, i.p.)
Control 10 20 400
5
10
Bury
ing
18-MC (mg/kg, i.p.)
Control 10 20 400
1
2
3
Dia
rrhe
a
18-MC (mg/kg, i.p.)
Weig
ht
loss
Wet
dog
shake
s
Control 10 20 400
5
10
15
Flin
chin
g
18-MC (mg/kg, i.p.)Fl
inch
ing
Bu
ryin
gG
room
ing
Control 10 20 400
10
20
30
Teet
h ch
atte
ring
18-MC (mg/kg, i.p.)
Teeth
chatt
eri
ng
Dia
rhea
Effects of 18-MCEffects of 18-MCon opioid withdrawal signson opioid withdrawal signs
18-MC is a potentially effective 18-MC is a potentially effective anti-addictive treatmentanti-addictive treatment
1. 18-MC decreases the self-administration of multiple drugs of abuse.
2. 18-MC alleviates several signs of morphine withdrawal.
Does 18-MC have side effects?Does 18-MC have side effects?
1. Nerve cell damage?
2. Cardiovascular toxicity?
3. Is 18-MC likely to cause hallucinations?
4. Is 18-MC addictive (i.e., reinforcing)?
18-MC has no cerebellar toxicity18-MC has no cerebellar toxicity
Ibogaine 18-MC
One month after 3x100mg/kg, i.p.
18-MC at very high doses does not
produce any Purkinje cell
damage.
Ibogaine at very high
doses damages Purkinje cells.
Effects of 18-MC and ibogaineEffects of 18-MC and ibogaineon heart rate and blood pressureon heart rate and blood pressure
18-MC (200 mg/kg, ip) has no apparent effects on
heart rate and blood pressure.
0 20 40 60 80 100 120 140 160 180 200 220 240
75
100
125
Per
cent
of
base
line
18-MCvehicle
Time (minutes)
Systolic Diastolic Heart rate
0 20 40 60 80 100 120 140 160 180 200 220 240
75
100
125
ibogainevehicle
Time (minutes)
Systolic Diastolic Heart rate
Per
cent
of
base
line
Ibogaine (200 mg/kg, ip) decreases heart rate without
altering blood pressure.
-60 0 60 120 1800
500
1000
1500
2000
2500
3000
Per
cent
of
Base
line
Time (minutes)
I bogaine 18-MC
(40 mg/kg, i.p.)
18-MC does not increase18-MC does not increaseextracellular serotonin levelsextracellular serotonin levels
Ibogaine, but not 18-MC, increases
extracellular serotonin levels in
the nucleus accumbens.
So I won’t hallucinate
?
0 10 20 30 40 50 600
10
20
30
40
Time (min)
saline
Cu
mu
lati
ve r
esp
on
ses
0 10 20 30 40 50 600
10
20
30
40
Time (min)
18-MC (0.8 mg/kg/infusion)
Cu
mu
lati
ve r
esp
on
ses
18-MC itself is not reinforcing18-MC itself is not reinforcing
0 10 20 30 40 50 600
10
20
30
40
Time (min)
cocaine (0.4 mg/kg/infusion)
Cu
mu
lati
ve r
esp
on
sescocaine
0 10 20 30 40 50 600
10
20
30
40
Time (min)
cocaine (0.4 mg/kg/infusion)
Cum
ula
tive r
esp
onse
s
saline
0 10 20 30 40 50 600
10
20
30
40
Time (min)
saline
Cum
ula
tive r
esp
onse
s
18-MC
18-MC has no apparent18-MC has no apparentside effectsside effects
1. Unlike ibogaine, 18-MC does not induce tremors and does not damage the cerebellum.
2. Unlike ibogaine, 18-MC has no ill effect on the heart.
3. 18-MC may not be hallucinogenic.
4. 18-MC is not reinforcing and should not be liable to abuse.
What are the pharmacokinetic What are the pharmacokinetic properties of 18-MC?properties of 18-MC?
1. What is its half-life?
2. Is it uniformly distributed throughout the body?
3. Does it have any metabolites?
Pharmacokinetics of 18-MC Pharmacokinetics of 18-MC (40 mg/kg, i.v.)(40 mg/kg, i.v.)
0 20 40 60 80 100 1200
1000
2000
3000
4000
5000
6000
n=5 one-compartment fit
T1/2
= 10.2 min two-compartment fit
T1/2a = 6.2 min
T1/2b = 109.4 min
Plas
ma
(±)-
18-M
C (n
g/m
l)
Time (minutes)
The data do not fit a one-
compartment model.
Tissue distribution of 18-MCTissue distribution of 18-MC(4 hr)(4 hr)
Plasma Brain Fat0
500
1000
1500
2000
ng/g
or
ng/m
l
p.o. i.p.
Plasma Brain0
20
40
60
18-MC is sequestered in fat.
18-MC metabolites18-MC metabolites(TLC)(TLC)
Volume (l)of sample spotted
18-MC may have several
metabolites; the most important one has been shown to be
18-OH-coronaridine.
What is the mechanism What is the mechanism of action of 18-MC?of action of 18-MC?
PFC = prefrontal cortexNAC = nucleus accumbensVTA = ventral tegmental area
VTANAC
PFC
18-MC may interact with the “reward pathways”.
dopaminergic neurons
In vivo In vivo microdialysismicrodialysis
Effect of 18-MC on sensitized Effect of 18-MC on sensitized cocaine-induced dopamine cocaine-induced dopamine
releaserelease
-60 0 60 120 1500
500
1000
1500
2000
2500
Perc
ent
of b
asel
eine
Cocaine(20 mg/kg, i.p.)
Acute
Time (min)-60 0 60 120 150
0
500
1000
1500
2000
2500
Perc
ent
of b
asel
eine
Cocaine(20 mg/kg, i.p.)
AcuteChronic cocaine:
Vehicle- pretreated
Time (min)
Acute cocaine increases dopamine
release in the nucleus accumbens.
-60 0 60 120 1500
500
1000
1500
2000
2500
Perc
ent
of b
asel
eine
Cocaine(20 mg/kg, i.p.)
AcuteChronic cocaine:
Vehicle- pretreated
18-MC- pretreated
Time (min)
After chronic administration
cocaine releases much more
dopamine in the nucleus accumbens.
This is called sensitization.
18-MC abolishes the sensitization of cocaine-induced
dopamine release.
18-MC abolishes drug 18-MC abolishes drug sensitization.sensitization.
Why is this important?Why is this important?
abuse addiction
abstinencerelapse
usecraving
Drug sensitization may underlie craving and the cyclic nature of addiction.
By abolishing drug sensitization 18-MC may prevent relapse and promote
abstinence.
Ibogaine and 18-MC binding affinities(Ki in M)
18-MC has no affinity for NMDA receptors.
18-MC has no affinity for 5-HT uptake
sites.
18-MC has very low affinity for sigma
receptors.
With which With which receptorsreceptors
does 18-MC does 18-MC interact?interact?
-30 0 30 6050
100
150
200
250
300
350
Nicotine (80 g, i.v., 5 min)
Per
cent
of
Base
line
Time (minutes)
Vehicle 18-MC (40 mg/kg, i.p.)
Effect of 18-MCEffect of 18-MCon nicotine-induced dopamine releaseon nicotine-induced dopamine release
18-MC, administered 19 hours beforehand, abolishes nicotine-induced dopamine
release in the nucleus accumbens.
So 18-MC may block nicotinic
receptors. But which
ones?
Patch-clamp electrophysiologyPatch-clamp electrophysiologyWhole-cell recordingWhole-cell recording
Patch-pipette
Cell Receptor
Recording system
Whole-cell recordingWhole-cell recording
In the presence of receptor agonist
Movement of positive ions from the outside to the inside of the
cell is an INWARD current and is shown as a DOWNWARD
deflection.
This is due to receptor
desensitization.
18-MC interacts with 18-MC interacts with aa33bb4 nicotinic receptors4 nicotinic receptors
18-MC and ibogaine block the
nAch receptor currents in cells co-transfected
with rat a3 andb4 receptor subunits.
20
0 p
A
20
0 p
A
20
0 p
A
1 sec 1 sec 1 sec
Ach 1 mM18-MC 20 MIBO 20 M
18-MC does not interact with 18-MC does not interact with aa44bb2 nicotinic receptors2 nicotinic receptors
Ibogaine, but not 18-MC, blocks the
nAch receptor currents in cells co-transfected
with rat a4 andb2 receptor subunits.
25
0 p
A
25
0 p
A
10 sec 10 sec
Ach 300 M18-MC 5 MIBO 5 M
50% inhibition
Where are Where are aa33bb4 nicotinic 4 nicotinic receptorsreceptors located ?located ?
interpeduncular nucleus
medial habenula
IP
mHb
VTANAC
Connections between habenulo-interpeduncular and mesolimbic
systems
mHb = medial habenula IP = interpeduncular nucleus VTA = ventral tegmental areaNAC = nucleus accumbensR = raphe nucleiPFC = prefrontal cortexMD = medial dorsal thalamic nucleus
IP
mHb
VTANAC
PFC
IP
mHb
VTANACR
MD
Is 18-MC blockade of Is 18-MC blockade of aa33bb4 nicotinic 4 nicotinic receptors relevant toreceptors relevant to
its anti-addictive effects?its anti-addictive effects?
1. Effects of combination of low doses of non-specific a3b4 nicotinic receptors on drug self-administration
2. Effects of interpeduncular administration of 18-MC on drug self-administration
3. Correlations between potencies of 18-MC congeners to block a3b4 nicotinic receptors and their effects on drug self-administration
Non-specific Non-specific aa33bb4 nicotinic 4 nicotinic antagonistsantagonistsDRUG IC50 (M)
mecamylamine 0.09-1.0 (Papke et al., 2001; Hernandez et al.,
2000) bupropion 1.4 (Fryer and Lukas, 1999)
dextromethorphan 8.9 (Hernandez et al., 2000)
18-MC 0.75 (Glick et al., 2002)
Mecamylamine, an antihypertensive agent (Inversine®), is a non-specific nicotinic receptor antagonist.
Bupropion, an antidepressant (Wellbutrin®) and an anti-smoking aid (Zyban®), is also a dopamine uptake blocker.
Dextromethorphan, an antitussive in many OTC cough medicines (Benylin®, Delsym®, DexAlone™, Pertussin®, Robitussin®, Sucrets®), is also a NMDA receptor antagonist.
Effects of Effects of aa33bb4 drug combinations4 drug combinationson morphine self-administrationon morphine self-administration
All drug combinations
REDUCED morphine self-administration.
Mec1 Bup5 DM5 MC1 Mec1 Mec1 Mec1 DM5 DM5 MC1 + + + + + + Bup5 DM5 MC1 Bup5 MC1 Bup5
Mec1 = mecamylamine (1 mg/kg, i.p.)Bup5 = bupropion (5 mg/kg, i.p.)
0
5
10
15
20
25
30
35
40
45
Mor
phin
e In
fusi
ons/
hour
Baseline Treatment
DM5 = dextromethorphan (5 mg/kg, s.c.) MC1 = 18-methoxycoronaridine (1 mg/kg, i.p.)
At low doses, NONE of these agents affected morphine self-administration.
0
5
10
15
20
25
30
35
Met
ham
phet
amin
e In
fusi
ons/
hour
Baseline Treatment
Effects of Effects of aa33bb4 drug combinations4 drug combinationson methamphetamine self-on methamphetamine self-
administrationadministration
All drug combinations
REDUCEDmethamphetami
ne self-administration.
Mec1 Bup10 DM10 MC5 Mec1 Mec1 Mec1 DM10 DM5 MC5 + + + + + + Bup10 DM5 MC2 Bup10 MC2 Bup10
Mec1 = mecamylamine (1 mg/kg, i.p.)Bup10 = bupropion (10 mg/kg, i.p.)DM5 = dextromethorphan (5 mg/kg, s.c.)
DM10 = dextromethorphan (10 mg/kg, s.c.) MC2 = 18-methoxycoronaridine (2 mg/kg, i.p.)MC5 = 18-methoxycoronaridine (5 mg/kg, i.p.)
0
5
10
15
20
25
30
35
40
Nic
otin
e In
fusi
ons/
hour
Baseline Treatment
Effects of Effects of aa33bb4 drug combinations4 drug combinationson nicotine self-administrationon nicotine self-administration
All drug combinations
REDUCEDnicotine self-
administration.
Mec.1 Bup5 DM.5 MC.1 Mec.1 Mec.1 Mec.1 DM.5 DM.5 MC.1 + + + + + + Bup5 DM.5 MC.1 Bup5 MC.1 Bup5
Mec.1 = mecamylamine (0.1 mg/kg, i.p.)Bup5 = bupropion (5 mg/kg, i.p.)
DM.5 = dextromethorphan (0.5 mg/kg, s.c.) MC.1 = 18-methoxycoronaridine (0.1 mg/kg, i.p.)
0
200
400
600
800
1000
1200
Wat
er B
ar P
ress
es/h
our
Baseline Treatment
Effects of Effects of aa33bb4 drug combinations4 drug combinationson water respondingon water responding
NONE of the drug
combinations had an effect on responding for
water.
Mec1 Bup10 DM10 MC5 Mec1 Mec1 Mec1 DM10 DM5 MC5 + + + + + + Bup10 DM5 MC2 Bup10 MC2 Bup10
Mec1 = mecamylamine (1 mg/kg, i.p.)Bup10 = bupropion (10 mg/kg, i.p.)DM5 = dextromethorphan (5 mg/kg, s.c.)
DM10 = dextromethorphan (10 mg/kg, s.c.)MC2 = 18-methoxycoronaridine (2 mg/kg, i.p.)MC5 = 18-methoxycoronaridine (5 mg/kg, i.p.)
0
5
10
15
20
25
30
35
Mor
phin
e In
fusi
ons/
hour
Vehicle (n=8) 18-MC (n=10)
Effects of interpeduncular Effects of interpeduncular administration of 18-MC administration of 18-MC
on drug self-administrationon drug self-administration
Local administration of 18-MC (10 µg in 1 µl) into both
interpeduncular nuclei, immediately prior to the session,
decreased responding for morphine by 35%.
interpeduncular nucleus
20
40
60
80
100
85 90 95 100
20
40
60
80
100
85 90 95 100
Percent of a3b4 inhibition
Perc
ent of
bas
elin
e: sel
f-ad
min
istr
atio
n
morphiner = -.67p < 0.05
methamphetaminer = -.75p < 0.02
Per
cent
of
base
line:
sel
f-ad
min
istr
atio
n
Percent of a3b4 inhibition
Correlations between Correlations between blockade of blockade of aa33bb4 nicotinic receptors4 nicotinic receptors
and drug self-administrationand drug self-administration
How much a congener of 18-MC decreases
drug self-administration is related to how
well it can block a3b4 nicotinic
receptors.
Is 18-MC blockade of Is 18-MC blockade of aa33bb4 nicotinic 4 nicotinic receptors relevant toreceptors relevant to
its anti-addictive effects?its anti-addictive effects?
1. Combinations of low doses of non-specific a3b4 nicotinic receptor antagonists decrease drug self-administration.
2. Interpeduncular administration of 18-MC decreases morphine self-administration.
3. There are significant correlations between potencies of 18-MC congeners to block a3b4 nicotinic receptors and their effects on drug self-administration.
ConclusionsConclusions1.1. 18-MC may be useful in treating many forms of drug addiction, including opioid (e.g., heroin) and stimulant (e.g., cocaine, methamphetamine) abuse, alcoholism and smoking.
2.2. 18-MC should lack all of ibogaine’s prominent side effects.
3.3. 18-MC abolishes the dopamine sensitization that occurs with chronic drug administration and that may underlie craving and relapse.
4. An antagonist action at a3b4 nicotinic receptors appears to be 18-MC’s most important action. 18-MC has greater selectivity for this site than either ibogaine or other existing agents.
Clinical applicationClinical application
Antagonism of acetylcholine’s actions at a3b4 nicotinic receptors may constitute a novel mechanism and strategy for reducing addiction to multiple drugs.
Low dose combinations of existing agents (i.e., dextromethorphan, mecamylamine and bupropion) may be viable therapies, and readily testable, in lieu of single agents acting specifically at this site.
VTA
NAC
PFC
COLLABORATORS
Isabelle Maisonneuve
Martin Kuehne
Lindsay HoughMilt Teitler
Katharine Herrick-Davis
Helen MolinariMark Fleck