Transcript [11C]ALTROPANE, A HIGHLY SELECTIVE LIGAND FOR THE DOPAMINE

Dopamine, Craving,
the Cerebellar Vermis,
and Ibogaine
Carl Anderson, Ph.D.,
Harvard Medical School
&
The Brain Imaging Center,
McLean Hospital, Belmont, MA
My Interest in Ibogaine
1993 – First heard about ibogaine from Drs. Mash and Staley.
1995 – Finished my Ph.D on Ontogeny of REM sleep.
http://remfractal.mclean.org/Disseration.pdf
1998 – MAPS article on Ibogaine, REM sleep & PTSD.
http://www.maps.org/news-letters/v08n1/08105and.html
1998 – Cerebellar vermis connection with stimulants & ADHD.
http://remfractal.mclean.org/ADHD_vermis.pdf
2000 – Vermis, childhood sexual abuse and drug use.
http://remfractal.mclean.org/vermis-abuse.pdf
2003 – Cerebellar Doorways to Addiction, Hallucinogenesis,
REM sleep and Trauma: How the Ibogaine Key Might Work the
Vermal lock-Talk at NYC Ibogaine meeting, May 2003.
http://remfractal.mclean.org/NYC_Ibogaine.ppt
Overview
Role of the cerebellar vermis in
cognitive-motor integration
Human vermis [11C]Altropane binding:
Implications in craving and reward
Implications for thearpy:
C.C.Naranjo & movement
Vermis Anterior
FN
Vermis Posterior
The Cerebellar Vermis:
Cognitive-Motor Integration
“..the fastigal nucleus plays a particularly
important role in the control of
locomotion… and the merging of
anticipatory and reactive CNS processes.”
Mori et al. (2004)
Studies of bipedal walking in primates.
Reward-Evoked Bipedal Locomotion
Cerebellar vermis is positioned to integrate
food reward with coordination of movement
Cog-Emotion
movement
Fig 5 from Mori et al., 2000
The Vermis as a Center of
Emotional-Motor Coordination
-Balance
-Eye movements
-Cerebral BF
-Orienting
*NE, DA, 5-HT
*CRF, T4, NO
*GABA, Glu, Ach
• LC, DR, SNR
•Vest. Nuc.
•PPT, NTS, RF
•PAG, IL, AH
•ACC, BN
Lobule VIII enlarged in echo-locating
carnivorous mammals (M.G. Paulin, 1993 &1997)
Modified version of figure 55-D (p. 45) from Larsell and Jansen (1972)
- Crack cocaine-dependent [6 Males:4 Females] 36.1 ± 7.0
years of age and comparison subjects [3 Males:5 Females] 29.8
± 6.8 years of age.
Sections from
videotape
described by
Childress et
al. 1996
neutral
scenes
0
time (minutes)
cocaine
scenes
2 1/2
neutral
scenes
5
From Maas et al. 1998
cocaine
scenes
7 1/2
10
Role of the Cerebellar Vermis In
Cue-Induced Cocaine Craving
From Anderson et al. in submission
DAT-IR in the PrimateVermis
Anterior
Posterior
Macaque
Adult Human
Melchitzky and Lewis (2000) observed dopamine
transporter immunoreactivity (DAT-IR) in macaque
cerebellar midline (anterior- and posterior-inferior vermis,
AV and PIV, respectively), implying the possible presence
of functional DAT in homologous regions of the human
vermis.
Summary So Far…
The cerebellum typically is excluded from the circuitry
considered to mediate stimulant-associated behaviors
since it is low in dopamine.
Yet, parts of the primate cerebellar vermis have been
reported to contain axonal dopamine transporter
immunoreactivity (DAT-IR), suggesting that they may
be part of the reward circuitry
Summary So Far…
Using fMRI, we found that cocaine-related cues
selectively activated DAT-IR-enriched lobules II-III and
VIII-IX in cocaine users.
PET imaging of healthy human subjects detected DATselective ligand accumulation in the posterior-inferior
vermis (lobules VIII-IX), suggesting the presence of
DAT in this region.
Summary So Far…
In light of prior findings illustrating connections
between vermis and midbrain dopamine cell body
regions, established roles for the vermis as a locus of
sensorimotor integration and motor planning, and
increased vermis activation in substance abusers during
reward-related and other cognitive tasks, we propose
that the vermis be considered one of the structures
involved in cocaine- and other incentive-related
behaviors.
Implications for Ibogaine
Therapy
Ibogaine appears to specifically target regions of the
vermis involved in drug- and other incentive-related
behaviors.
Transient ataxia and vestibular disorders that
accompany ibogaine administration could indicate the
induction of compensation within the vermis-fastigial
system.
Movement could facilitate ibogaine-induced
compensation.
Claudio Naranjo on Movement During
Ibogaine Therapy
“A comfortable couch or bed must be considered
part of the setting for the treatment, for most
patients want to lie down during the first few
hours, or even throughout most of their session,
and feel nauseated when they get up or move.
However, others feel the desire to move or even
dance at some point in the session (35 per cent in
my data), and this may prove a very significant
aspect of their experience that will be elaborated
upon later. For this reason some degree of space to
move about is desirable.” *
*From The Healing Journey, chapter 5, Pantheon Books, New York, 1974.
Funding for this work was provided in part by
DA016222 (to Carl M. Anderson),
DA017324 & DA014674 (to Marc J. Kaufman),
DA09448 & DA14178 (to Perry F. Renshaw)
DA15305, DA11558 (to Bertha K. Madras)
from the National Institute on Drug Abuse (NIDA)
References:
Larsell O, Jansen J, Korneliussen H, Mugnaini E (1972): The comparitive anatomy and
histology of the cerebellum: the human cerebellum, cerebellar connections, and cerebellar
cortex. Minneapolis: The University of Minnesota Press.
Maas LC, Lukas SE, Kaufman MJ, et al (1998): Functional magnetic resonance imaging of
human brain activation during cue-induced cocaine craving. American Journal of Psychiatry
155:124-6.
Melchitzsky DS, Lewis DA (2000): Tyrosine Hydrolase- and Dopamine TransporterImmunoreactive Axons in the Primate Cerebellum: Evidence for a Lobular- and LaminarSpecific Dopamine Innervation. Neuropsychopharmacology 22:466-72.
Mori F, Nakajima K, Tachibana A, et al (2004): Reactive and anticipatory control of posture
and bipedal locomotion in a nonhuman primate. Prog Brain Res 143:191-8.
Mori S, Matsui T, Mori F, Nakajima K, Matsuyama K (2000): Instigation and control of
treadmill locomotion in high decerebrate cats by stimulation of the hook bundle of Russell in
the cerebellum. Canadian Journal of Physiology & Pharmacology 78:945-57.