Transcript No Slide Title

THE
NEUROSCIENCES
INSTITUTE
Albany Medical Center
Center for
Neuropharmacology
and Neuroscience
Ibogaine Analogues:
Drug Development for
Addictive Disorders
Stanley D. Glick, Ph.D., M.D.
Drug Abuse / Drug Dependence
 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 DEPENDENCE
PHYSICAL DEPENDENCE can occur without ADDICTION
Addicts are desperate
for new therapies
July 10, 1996
Dr. M.A. Geyer
Managing Editor
Psychopharmacology
Department of Psychiatry
School of Medicine
University of California San Diego
La 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 nicotineinduced 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,
IShofd
Isabelle Maisonneuvebbbbbbb
July 10, 1996
Dr. M.A. Geyer
Managing Editdggggggggor
Psychopharmacology
University 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,
Wtray
Isabelle Maisonneuve,
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…”
VTA
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…”
Once upon a time in Africa…
Tabernanthe iboga shrub
Cameroon
Eq. Guinea
Gabon
2 Congos
Ibogaine is contained in
the roots of the shrubs.
Ibogaine has
been used for
centuries in
rituals of the
Bwiti religion.
At very high concentrations,
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…
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 treatment
for drug dependence?
1. Is 18-MC effective in reducing
drug self-administration?
2. Is 18-MC effective in reducing
signs of drug withdrawal?
Drug self-administration
Effect of an ideal treatment
number of responses
The ideal treatment
will not affect
responding for a nondrug reinforcer (e.g.,
water, food, sucrose).
The ideal treatment
will depress responding
for a drug of abuse
Treatment dosage
Effects of 18-MC on responding
for morphine, cocaine and water
18-MC selectively
decreases morphine
and cocaine selfadministration.
120
*
80
Ibogaine also affects
responding for water.
*
60
120
*
Water
40
20
0
Cocaine
100
*
Morphine
0
10
20
30
18-MC (mg/kg, i.p.)
*
*
40
Percent of baseline
Percent of baseline
100
80
60
40
Water
Cocaine
Morphine
20
0
0
10
20
30
Ibogaine (mg/kg, i.p.)
40
Effects of 18-MC on responding
for methamphetamine and nicotine
120
Female rats
Percent of baseline
100
80
60
*
40
*
*
*
20
*
*
Methamphetamine
0
Nicotine
0
*
10
20
30
18-MC (mg/kg, i.p.)
*
40
18-MC selectively
decreases
methamphetamine and
nicotine selfadministration, but is
most potent in
decreasing nicotine
self-administration.
Effects of 18-MC on alcohol intake
50
100
Food intake (g/kg/day)
75
30
*
*
*
20
25
10
0
50
Food intake
0
Alcohol intake
10
20
30
18-MC (mg/kg, i.p.)
40
Alcohol intake (ml/kg/day)
40
18-MC decreases
alcohol intake at
doses that do not
affect food intake.
0
Rezvani et al., Pharmacol. Biochem.
Behav., 58:615-619 (1997).
18-MC reduces
the efficacy of morphine
18-MC produces a
significant downward
shift in the doseresponse curve for
morphine selfadministration.
Infusions/hour
30
20
10
Vehicle
0
0.00
18-MC (40 mg/kg, p.o.)
0.04
0.08
0.12
0.16
Morphine (mg/kg/infusion)
I don’t like
morphine as
much since I
took 18-MC
18-MC’s effects on drug selfadministration are persistent
18-MC decreases
cocaine self-administration
for 24 hours
40
*
20
0
*
60
40*
20
0 3 Day 6 Day 7
Base Day 1 Day 2 Day
Base
Test Session
Control
Cocaine infusions/hour
60
Morphine infusions/hour
Morphine infusions/hour
18-MC decreases
morphine self-administration
for 48 hours
30
20
*
10
0
*
Base
Day 1 Day 2 Day 3 Day 6 Day 7
Day 1 Day 2 Day 3 Day 6 Day 7
Test Session
Control
18-MC (40 mg/kg, i.p.) 18-MC (40 mg/kg, i.p.)
Test Session
Opioid withdrawal
•weight loss
•wet dog shakes
•flinching
•teeth chattering
•grooming
•burying
•diarrhea
Effects of 18-MC
on opioid withdrawal signs
3
*
10
5
0
10
20
18-MC (mg/kg, i.p.)
Control
10
20
18-MC (mg/kg, i.p.)
40
Grooming
Grooming
60
*
40
20
*
1
0
Control
10
20
18-MC (mg/kg, i.p.)
40
Control
10
20
15
10
5
0
40
Control
10
20
18-MC (mg/kg, i.p.)
40
30
*
20
10
0
2
20
18-MC (mg/kg, i.p.)
Teeth
chattering
Teeth chattering
5
0
40
80
0
10
Control
10
20
18-MC (mg/kg, i.p.)
*
40
Burying
Burying
Wet dog
shakes
Wet dog shakes
100
Control
Diarhea
Diarrhea
15
Flinching
Flinching
Weight
loss
Weight loss
15
10
5
0
Control
10
20
18-MC (mg/kg, i.p.)
*
40
18-MC reduces
the intensity of
several signs of
morphine
withdrawal
18-MC is a potentially effective
anti-addictive treatment
1. 18-MC decreases the selfadministration of multiple drugs
of abuse.
2. 18-MC alleviates several signs of
morphine withdrawal.
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 toxicity
Ibogaine
18-MC
One month after
3x100mg/kg, i.p.
Ibogaine at very
high doses
damages
Purkinje cells.
18-MC at very
high doses does
not produce any
Purkinje cell
damage.
Percent of baseline
Effects of 18-MC and ibogaine
on heart rate and blood pressure
Systolic
125
Diastolic
Heart rate
100
75
18-MC
vehicle
0
20
40
60
80
100
120
140
160
18-MC (200
mg/kg, ip) has
no apparent
effects on
heart rate and
blood pressure.
180 200 220 240
Percent of baseline
Time (minutes)
Systolic
125
Diastolic
Heart rate
Ibogaine (200
mg/kg, ip)
decreases heart
rate without
altering blood
pressure.
100
75
vehicle
0
20
ibogaine
40
60
80
100
120
140
Time (minutes)
160
180 200 220 240
18-MC does not increase
extracellular serotonin levels
3000
Ibogaine
Percent of Baseline
2500
*
18-MC
(40 mg/kg, i.p.)
**
2000
*
1500
*
1000
Ibogaine, but not
18-MC, increases
extracellular
serotonin levels in
the nucleus
accumbens.
*
*
*
500
0
-60
0
60
Time (minutes)
120
180
So I won’t
hallucinate?
Cumulative responses
cocaine
saline
18-MC
40
saline
30
20
10
0
0
10
20
30
40
Time (min)
50
60
Cumulative
responses
Cumulativeresponses
responses
Cumulative
Cumulative responses
18-MC itself is not reinforcing
40
40
cocaine (0.4 mg/kg/infusion)
30
20
10
0
0
10
20
30
40
Time (min)
50
60
cocaine
(0.4mg/kg/infusion)
mg/kg/infusion)
saline
18-MC (0.8
30
20
10
0
0
10
20
30
40
Time (min)
50
60
18-MC has no apparent
side 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
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
(40 mg/kg, i.v.)
6000
n=5
Plasma (±)-18-MC (ng/ml)
one-compartment fit
T1/2 = 10.2 min
5000
The data do not fit a
one-compartment
model.
two-compartment fit
T1/2a = 6.2 min
4000
T1/2b = 109.4 min
3000
2000
1000
0
0
20
40
60
80
Time (minutes)
100
120
Tissue distribution of 18-MC
(4 hr)
2000
p.o.
i.p.
18-MC is sequestered
in fat.
ng/g or ng/ml
1500
60
1000
40
20
0
Plasma
Brain
500
0
Plasma
Brain
Fat
18-MC metabolites
(TLC)
Volume (ml)
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
of action of 18-MC?
PFC
NAC
18-MC may interact with
the “reward pathways”.
VTA
PFC = prefrontal cortex
NAC = nucleus accumbens
VTA = ventral tegmental area
dopaminergic
neurons
In vivo
microdialysis
Effect of 18-MC on sensitized
cocaine-induced dopamine release
2500
2500
Percent of baseleine
Acute
Chronic cocaine:
2000
2000
Vehiclepretreated
18-MC1500
1500
pretreated
1000
1000
After chronic
administration cocaine
Acute
cocainethe
18-MC
abolishes
releases
much more
increases
dopamine
sensitization
of
dopamine in the
release
in the nucleus
cocaine-induced
nucleus
accumbens.
accumbens.
dopamine
This is release.
called
sensitization.
Cocaine
(20 mg/kg, i.p.)
500
500
0
-60
0
60
60
Time (min)
(min)
120
120
150
150
18-MC abolishes drug sensitization.
Why is this important?
relapse
craving
abstinence
use
abuse
addiction
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 mM)
Ibogaine
18-MC
Kappa opioid
2.2 ± 0.10 5.1 ± 0.50
Mu opioid
2.0 ± 0.15 1.1 ± 0.30
Delta opioid
>10 3.5 ± 0.05
Nociceptin
>100
>100
NMDA
3.1 ± 0.30
>100
D1
>10
>100
D2
>10 16 ± 0.60
D3
70 ± 1.7
25 ± 2.5
M1
16 ± 1.0
32 ± 3
M2
31 ± 3.4
>100
5-HT1A
>100
46 ± 4.9
5-HT1B
>100
>100
5-HT1C
>100
>100
5-HT1D
>100
>10
5-HT2A
16
40 ± 3.4
5-HT2C
>10
>100
5-HT3
2.6 ± 0.23 3.8 ± 0.067
Sodium channel
3.6 ± 0.35 6.4 ± 0.68
Sigma 1
2.5 ± 0.6
>100
Sigma 2
0.4 ± 0.036
13 ± 1.2
GABA B
>100
>100
NE uptake
>100
>10
5-HT uptake
4.1 ± 0.83
>10
With which
receptors
does 18-MC
interact?
18-MC has no affinity
for NMDA receptors.
18-MC has very low
affinity for sigma
receptors.
18-MC has no affinity
for 5-HT uptake sites.
Effect of 18-MC
on nicotine-induced dopamine release
350
Vehicle
18-MC, administered 19
hours beforehand,
abolishes nicotine-induced
dopamine release in the
nucleus accumbens.
18-MC (40 mg/kg, i.p.)
Percent of Baseline
300
250
200
*
*
*
150
So 18-MC may
block nicotinic
receptors. But
which ones?
100
50
Nicotine (80 mg, i.v., 5 min)
-30
0
30
Time (minutes)
60
Patch-clamp electrophysiology
Whole-cell recording
Recording
system
Patch-pipette
Cell
Receptor
Whole-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
a3b4 nicotinic receptors
1 sec
Ach 1 mM
18-MC 20 mM
IBO 20 mM
200 pA
200 pA
200 pA
1 sec
1 sec
18-MC and ibogaine
block the nAch
receptor currents
in cells cotransfected with
rat a3 and b4
receptor subunits.
18-MC does not interact with
a4b2 nicotinic receptors
50% inhibition
Ach 300 mM
18-MC 5 mM
IBO 5 mM
10 sec
250 pA
250 pA
10 sec
Ibogaine, but not
18-MC, blocks the
nAch receptor
currents in cells
co-transfected
with rat a4 and b2
receptor subunits.
Where are a3b4 nicotinic
receptors located ?
medial habenula
interpeduncular nucleus
Connections between habenulointerpeduncular and mesolimbic systems
mHb
NAC
IP
VTA
PFC
NAC
mHb
MD
VTA
IP
NAC
mHb
R
VTA
IP
mHb = medial habenula
IP = interpeduncular nucleus
VTA = ventral tegmental area
NAC = nucleus accumbens
R = raphe nuclei
PFC = prefrontal cortex
MD = medial dorsal thalamic nucleus
Is 18-MC blockade of a3b4 nicotinic
receptors relevant to
its anti-addictive effects?
1. Effects of combination of low doses of nonspecific a3b4 nicotinic receptors on drug selfadministration
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 a3b4 nicotinic antagonists
DRUG
IC50 (mM)
mecamylamine
bupropion
dextromethorphan
0.09-1.0 (Papke et al., 2001; Hernandez et al., 2000)
1.4 (Fryer and Lukas, 1999)
8.9 (Hernandez et al., 2000)
18-MC
0.75
(Glick et al., 2002)
Mecamylamine, an antihypertensive agent (Inversine®), is a nonspecific 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 a3b4 drug combinations
on morphine self-administration
45
40
Baseline
Treatment
Morphine Infusions/hour
35
30
*
25
*
*
20
15
*
10
*
*
5
0
Mec1 Bup5 DM5 MC1
Mec1 = mecamylamine (1 mg/kg, i.p.)
Bup5 = bupropion (5 mg/kg, i.p.)
Mec1 Mec1 Mec1 DM5 DM5 MC1
+
+
+
+
+
+
Bup5 DM5 MC1 Bup5 MC1 Bup5
DM5 = dextromethorphan (5 mg/kg, s.c.)
MC1 = 18-methoxycoronaridine (1 mg/kg, i.p.)
At low doses,
NONE of these
agents affected
morphine selfAll drug
administration.
combinations
REDUCED
morphine selfadministration.
Effects of a3b4 drug combinations
on methamphetamine self-administration
Methamphetamine Infusions/hour
35
30
Baseline
Treatment
25
20
* * * * * *
15
All drug
combinations
REDUCED
methamphetamine
selfadministration.
10
5
0
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.)
Effects of a3b4 drug combinations
on nicotine self-administration
40
Nicotine Infusions/hour
35
Baseline
Treatment
30
25
*
20
15
* * * *
*
All drug
combinations
REDUCED
nicotine selfadministration.
10
5
0
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.)
Effects of a3b4 drug combinations
on water responding
1200
Baseline
Treatment
Water Bar Presses/hour
1000
NONE of the drug
combinations
had an effect on
responding for
water.
800
600
400
200
0
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.)
Morphine Infusions/hour
35
30
Effects of interpeduncular
administration of 18-MC
on drug self-administration
Vehicle (n=8)
18-MC (n=10)
25
20
15
10
5
0
*
interpeduncular
nucleus
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%.
100
80
60
40
20
morphine
r = -.67
p < 0.05
85
90
95
100
Percent of a3b 4 inhibition
Percent of baseline: self-administration
Percent of baseline: self-administration
Correlations between
blockade of a3b4 nicotinic receptors
and drug self-administration
100
80
How much a
congener of 18-MC
decreases drug
self-administration
is related to how
well it can block
a3b4 nicotinic
receptors.
60
40
20
methamphetamine
r = -.75
p < 0.02
85
90
95
100
Percent of a3b 4 inhibition
Is 18-MC blockade of a3b4 nicotinic
receptors relevant to
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.
Conclusions
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. 18-MC should lack all of ibogaine’s prominent side
effects.
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 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.
COLLABORATORS
Isabelle Maisonneuve
PFC
Martin Kuehne
VTA
Lindsay Hough
Milt Teitler
NAC
Katharine Herrick-Davis
Helen Molinari
Mark Fleck