Dopamine, Craving, the Cerebellar Vermis, and Ibogaine

1. Dopamine, Craving, the Cerebellar Vermis, and Ibogaine Carl Anderson, Ph.D., Harvard Medical School & The Brain Imaging Center, McLean Hospital, Belmont, MA

2. 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

3. Overview Role of the cerebellar vermis in cognitive-motor integration Human vermis [11C]Altropanebinding: Implications in craving and reward Implications for thearpy: C.C.Naranjo & movement

4. Vermis Anterior FN Vermis Posterior

5. 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.

6. Cerebellar vermis is positioned to integrate food reward with coordination of movement Reward-Evoked Bipedal Locomotion

7. movement Vermis Cog-Emotion Fig 5 from Mori et al., 2000

8. 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

9. 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)

10. neutralscenes cocainescenes neutralscenes cocainescenes 0 5 10 2 1/2 7 1/2 time (minutes) From Maas et al. 1998 • 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

11. Role of the Cerebellar Vermis In Cue-Induced Cocaine Craving From Anderson et al. in submission

12. Anterior Posterior Macaque Adult Human DAT-IR in the PrimateVermis • Melchitzky and Lewis (2000) observed dopamine transporter immunoreactivity (DAT-IR) in macaque cerebellar midline (anterior- and posterior-inferior vermis, AVand PIV, respectively), implying the possible presence of functional DAT in homologous regions of the human vermis.

13. 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

14. 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 DAT-selective ligand accumulation in the posterior-inferior vermis (lobules VIII-IX), suggesting the presence of DAT in this region.

15. 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.

16. Implications for Ibogaine Therapy • Ibogaine appears to specifically target regions of the vermisinvolved 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.

17. 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.

18. Funding for this work was provided in partby 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)

19. 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 Transporter-Immunoreactive Axons in the Primate Cerebellum: Evidence for a Lobular- and Laminar-Specific 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.