Tibor Harkany1,2 Drogenkonsum und Gehirnentwicklung: Cannabis, Cannabinoide und das Endocannabinoid-System
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Drogenkonsum und Gehirnentwicklung:
Cannabis, Cannabinoide und das Endocannabinoid-System
Tibor Harkany1,2
1KarolinskaInstitutet, Stockholm, Sweden
2Medical University of Vienna, Austria
Wirkungsmechanismen von Drogen
Phasen der Entwicklung des Gehirns
Die Hanfpflanze – vom Himalaya in die Apotheke
Cannabis sativa
- Cannabis indica
- Cannabis ruderalis
Used for:
- Hemp (fibers, non-toxicant or low
amount of phytocannabinoids),
- Marijuana (dried flower buds),
selective cultivation led to
numerous subspecies with
discrete THC/CBD ratios, also for
medical use,
- Hashish (resin) or hashish oils
(extracts).
Gesetzeslage rund um Cannabis - weltweit
Gesetzeslage rund um Cannabis – Europa (speziell medizischer Einsatz von Cannabis)
Unterschied zwischen medizinischer Anwendung
und Genuss-Konsum
Recreational cannabis use:
Impacts an “intact system” (= physiological) in which
additional drug enhances/modulates/disrupts
endocannabinoid signaling.
Risks are from “having too much of a good(?) thing”
particularly in case of a hidden condition.
Medical cannabis use:
Treatment of a “faulty system” (= disease) in which
endocannabinoid signaling is impaired. Benefit is
from compensating an error.Indikationen für medizinische Cannabis
Anwendung
• Nausea and vomiting (including cancer chemotherapy),
• Appetite stimulation (anorexia, cachexia, AIDS, Alzheimer’s),
• Spasticity (Multiplex sclerosis, spinal cord injury),
• Movement disorders,
• Pain (cancer, rheumatoid arthritis, headache, menstruation, chronic
inflammation, neuralgias),
• Glaucoma (intraocular pressure - 30-50% decrease),
• Epilepsy,
• Asthma, allergic reactions,
• Withdrawal in dependency on benzodiazepines, opiates and alcohol,
• Anxiety, depression (and bipolar disorder),
• Inflammatory diseases.Zugelassene Produkte die
Phytocannabinoide beinhalten
• Sativex (GW Pharma), THC/CBD, pain & spasticity,
• Dronabinol/Marinol (Solvay Pharma), synthetic THC,
nausea and vomiting,
• Nabilone / Cesamet (Valeant Pharma), synthetic
cannabinoid, nausea and vomiting,
• Dexanabinol (Solvay Pharma), non-psychotropic
cannabinoids, neuroprotective (TBI),
• CT-3 (ajulemic acid, Indevus Pharma), THC-11-oic acid,
spasticity and pain,
• Cannabinor (Pharmos), pain – not introduced,
• HU 308 (Pharmos), CB2 agonist, hypertension, anti-
inflammatory – not approved,
• HU 331 (Cayman), CB1/CB2 pharmacology, weight loss,
appetite – pre-clinical,
• Acomplia/Rimonabant (Sanofi-Aventis) – CB1 antagonist,
weight loss, appetite – withdrawn,
• Taranabant (Merck) – CB1 antagonist, appetite –
abandoned.Medizinische Verwendung: noch nicht hinreichend beforscht?
Ein Geschichte-Wissenschafts Mix
(von altertümlichen Kräuterbüchern bis zum Klonieren)
time line Shennong bencao jing
2800 BC 1967 Woodstock
1990
Phytocannabinoid 1969
CB1R cloning 1992 – 1995
Endocannabinoids
THC
Anandamide (AEA)
2-Arachidonoyl Glycerol (2-AG)
Gaoni & Mechoulam (1967) Tetrahedron Lett
Devane et al (1988) Mol Pharm
Herkenham et al (1990) PNAS
Ramos et al (2010) Phys. Chem. Chem. Phys.Wie wirkt es im Gehirn?
(Physiologische Basis - Endocannabinoide)
Human cerebral cortex Networks Synapses
(A) Get excited! (Glu)
(B) Slow down! (GABA)
5 cm
Neuron: 2 x 1010
Synapse: 1.5 x 1014
Give me a break!!!Meilensteine der CB1R Pharmakologie
(Ligand-Entdeckung, Verteilung)
Gaoni & Mechoulam (1967) Tetrahedron Lett
Devane et al (1988) Mol Pharm
Herkenham et al (1990) PNASPhysiologische Bedeutung des Endocannabinoid-Signals
(2-AG & AEA)
step
50 pA
10s
Control DSI/DSE Recovery
Wilson & Nicoll (2001) NatureBedeutung im Menschen
(Bevölkerungsstatistik)
7 - 17% of women were estimated to use
marijuana during pregnancy (SAMHSA, 2002).
Mulder et al. (2008) Proc. Natl. Acad. Sci. USAEndocannabinoid signals contribute to: (a) Stem cell proliferation, (b) Stem cell survival, (c) Neuron vs. glia fate decision, (d) Neuronal migration, (e) Synaptogenesis, axonal growth. This is achieved through the likely existence of endocannabinoid gradients and a mixture of cell autonomous / intercellular signaling events.
Klaudia Barabas Endocannabinoid Signale bestimmen Spezifizierung von Pyramidenzellen und lang-reichweitige Axonen
rompted the vibrant discipline of contempo- Neurogenesis: the process by which neurons are created, irrespective of the
logy. Developmental biology studies con- specific region where these cells are generated or their specific functions
he formation of endocannabinoid signaling
, the role of endocannabinoids [10–19] and,
within the nervous system.
Progenitor cell: an early descendant of a stem cell that can proliferate and Molecular model of cannabis
differentiate. A progenitor cell is more limited than a stem cell in the lineages
the molecular blueprint of prenatal cannabis
Review
23] in the developing
Review nervous system soon
of cells it can generate.
Retrograde signaling: a phenomenon during which a signal molecule travels
sensitivity in developing
present understanding is that endocannabi-
Molecular model of cannabis
from the postsynaptic neuron toward the presynaptic neuron in a direction
opposing that of the relevant synaptic neurotransmitter. neuronal circuits
Molecular
sensitivity model
uthor: Harkany, T. (Tibor.Harkany@ki.se) in developing of cannabis Synaptogenesis: the formation of functional synapses.
Erik Keimpema1, Ken Mackie2 and Tibor Harkany1,3
sensitivity
neuronal
t matter ! 2011 Elsevier
in
circuits
Ltd. All rights reserved.
developing
doi:10.1016/j.tips.2011.05.004 Trends in Pharmacological Sciences, September 2011, Vol. 32, No. 9
1
551
European Neuroscience Institute at Aberdeen, University of Aberdeen, Aberdeen AB25 2ZD, UK
neuronal circuits
1
Erik Keimpema , Ken Mackie and Tibor Harkany 2 1,3 2
Gill Center for Neuroscience and Department of Psychological and Brain Sciences, Indiana Univ
1 Institute at Aberdeen, IN 47405, USA
, Ken Mackie2 and 1,3
1
Erik Keimpema
European Neuroscience Tibor
University Harkany
of Aberdeen, Aberdeen AB25 2ZD,
3 UK
2
Gill Center for Neuroscience and Department of Psychological and Brain Sciences, Indiana Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karo
University, Bloomington,
1
INEuropean
47405, USA
3
2
Stockholm,
Neuroscience Institute at Aberdeen, University of Aberdeen, Aberdeen AB25 2ZD, UK Sweden
Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177
Gill Center for Neuroscience and Department of Psychological and Brain Sciences, Indiana University, Bloomington,
Stockholm,
IN Sweden
47405, USA
3
Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177
Stockholm, Sweden
Prenatal cannabis exposure can complicate in utero de- Prenatal
noids can act as focal instructive cannabis
signals that affect exposure
neural can complicate in utero de- noids can act as focal instruc
velopment of the nervous system. Cannabis impacts the progenitor proliferation [18] and neuron versus glia fate
Prenatal
formationcannabis exposure
and functions can complicate
of neuronal circuitries in by
utero de-
target- noids can [24],
decisions act asasfocal velopment
wellinstructive signalsof
as the differentiation thatthe nervous
affect neural
programs of system. Cannabis impacts the progenitor proliferation [18
velopment
ing cannabinoidof the receptors.
nervous system. Cannabis impacts
Endocannabinoid signalingthe progenitor proliferation
forebrain neurons [18] and
formation
(including butneuron
notand versus
restricted glia
to fate
functions cell of neuronal circuitries by target- decisions [24], as well as th
formation
emerges asand functionscassette
a signaling of neuronalthat circuitries
orchestrates by target-
neuro- decisions
migration,[24],
axonalas well
growthas and
the differentiation
synapse development)programs of
[24].
ing cannabinoid receptors.
nal differentiation Endocannabinoid
programs through the precisely signaling
timed forebrain
Here, we neurons ingmolecular
ask: are(including
the cannabinoid
but not mechanisms receptors.
restrictedof toendo-
cell Endocannabinoid signaling forebrain neurons (includin
emerges
interactionasof a endocannabinoid
signaling cassetteligandsthat orchestrates neuro-
with their cognate migration,
cannabinoid axonal growth
signaling and
emerges
(that is, synapse as
the dynamic development)
a signaling
arrangements[24]. cassette that orchestrates neuro- migration, axonal growth an
nal differentiation
cannabinoid programs
receptors. through the precisely
By indiscriminately prolonging timed
the Here,
of the we ask: are
enzymatic the molecular
control mechanisms of avail-
of focal endocannabinoid endo-
interaction
‘switched-on’ of endocannabinoid
period of cannabinoid ligands with theircannabis
receptors, cognate cannabinoid signalingatnal
ability and signaling (that differentiation
is, 1the
the CB dynamic arrangements
R) necessary programs through the precisely timed
and sufficient Here, we ask: are the m
cannabinoid receptors. By indiscriminately prolonging the of
to the enzymatic control of focal in endocannabinoid avail-
can hijack endocannabinoid signals to evoke molecular establish
ability
cannabis
and signaling
sensitivity
interaction
the CB1R) necessary
atarguments
developing neurons?
of endocannabinoid
and
ligands with their cognate cannabinoid signaling (that
‘switched-on’
rearrangements, period of cannabinoid
leading to the erroneous receptors,
wiring cannabis
of neu- We present a series of to pinpoint thesufficient
nascent
can
ronalhijack endocannabinoid
networks. Here, we formulatesignals to evoke molecular
a hierarchical network to establish
axon as a cannabis
structural cannabinoid
sensitivity
substrate receptors.
in developing actionBy indiscriminately prolonging the
of cannabisneurons? of the enzymatic control of
rearrangements,
design necessary leading to the to
and sufficient erroneous
describewiring of neu-
the molecular We present aand
[6,13,15,17], series
to of arguments
suggest a causal to pinpoint the nascent
link between com-
ronal
underpinnings of cannabis-induced neural network
networks. Here, we formulate a hierarchical growth axon as a structural
partmentalized
‘switched-on’
substrate
endocannabinoid signaling
period
of cannabis
and cannabis
of cannabinoid receptors, cannabis
action
ability and signaling at the C
design necessary and sufficient to describe
defects. We integrate signalosome components, deduced the molecular [6,13,15,17], and to can
suggest hijack
a causal endocannabinoid
link
(or cannabinomimetic)-driven modifications to the wiringbetween com- signals to evoke molecular to establish cannabis sensi
underpinnings
from genome- and of proteome-wide
cannabis-induced arraysneural growth
and candidate partmentalized endocannabinoid
of emergent neuronal networks in signaling and cannabis
the fetal brain [6,7,13].
defects.
analyses,We tointegrate
proposesignalosome
a mechanistic components,
hypothesisdeduced of how Our
rearrangements,
(or cannabinomimetic)-driven
molecular model reconcilesmodifications
competing and
leading
toprovocative
the wiring
to the erroneous wiring of neu- We present a series of argum
from genome- andectopic
cannabis-induced proteome-wide
cannabinoid arrays and candidate
receptor activity of emergenton
hypotheses neuronal
the modes ronal
networks
of actionnetworks.
inofthe fetal brainHere,
endocannabinoids, we formulate a hierarchical network
[6,7,13].
the axon as a structural su
analyses, to propose a neurodevelopmental
mechanistic hypothesis of how Our molecular
cellular model reconciles
configuration competing machinery,
of their metabolic and provocative
overrides physiological
cannabis-induced ectopic
binoid signals, affecting thecannabinoid
timely formation receptor
endocanna-
activity
of synapses. hypotheses
signaling byonintracellular
design
the modes ofversus
action of
necessary
endocannabinoids,
extracellular
andand
CB1Rs. the
sufficient to describe the molecular [6,13,15,17], and to suggest
overrides physiological neurodevelopmental endocanna- cellular configuration underpinnings
of their metabolic machinery, of and cannabis-induced neural growth partmentalized endocannab
Endocannabinoids:
binoid signals, affectinggatekeepers
the timelyof neuronalof synapses.
formation signaling by intracellular versus extracellular CB1Rs.
development Glossary defects. We integrate signalosome components, deduced (or cannabinomimetic)-drive
Endocannabinoids:
Molecular cloning of gatekeepers of neuronal
the CB1 cannabinoid receptor (CB1R) from genome- and proteome-wide arrays and candidate
Cell cycle exit: the event when a cell permanently leaves the cell cycle to adopt of emergent neuronal netwo
development
[1] and its functional characterization as the major target Glossary
a terminal differentiation program. To achieve this, cells become refractory to
9
Molecular cloning of the CB(THC)
of D -tetrahydrocannabinol 1 cannabinoid receptor
from cannabis [2](CB
led1R)
to proliferative signals. analyses, to propose a mechanistic hypothesis of how
Cell cycle exit: the event when a cell permanently leaves the cell cycle to adopt
Our molecular model reconci
Fate decision: the point when a progenitor cell commits toward and initiates an
[1] and its functional
a sea-change
9
characterization
in the understanding as molecular
of the the major target
mech- cannabis-induced ectopic cannabinoid receptor activity
a terminal differentiation program. To achieve this, cells become refractory to
intrinsic specification program to generate a terminally differentiated cell.
proliferative signals.
hypotheses on the modes of a
of D -tetrahydrocannabinol
anisms of this psychoactive (THC)
drug’sfrom cannabis
actions [2] led to
on neuronal Lateral geniculate nucleus: resides within the thalamus and functions as the
a sea-change
structure andin the understanding
function in brain regions of thecontrolling
molecularmemo- mech- overrides physiological neurodevelopmental endocanna-
Fate decision: the point when a progenitor cell commits toward and initiates an
primary relay center for visual information received from the retina of the eye.
intrinsic specification program to generate a terminally differentiated cell.
cellular configuration of the
Growth cone: a specialized region at the tip of a growing neurite that is
anisms of this psychoactive drug’s actions
ry, cognition, movement and pain perception [3]. These on neuronal binoid signals, affecting the timely formation of synapses.
Lateral geniculate nucleus: resides within the thalamus and functions as the
responsible for sensing the local environment and for guiding the axon signaling by intracellular ve
primary relay center for visual information received from the retina of the eye.
structure and function
findings, coupled with in
thebrain regions
discovery thatcontrolling
the CB1Rmemo- func- through the transduction of attractive and repulsive extracellular guidance
Growth cone: a specialized region at the tip of a growing neurite that is
ry, cognition, movement and transducer
pain perception cues toward a target cell.
tions as an essential signal in an [3]. These
elaborate responsible for sensing the local environment and for guiding the axon
Intercellular (synaptic) communication: information exchange between neu-
findings, coupled
molecular network with the discovery
relying that the
on ‘endogenous CB1R func-
cannabinoids’ Endocannabinoids: gatekeepers of neuronal
through the transduction of attractive and repulsive extracellular guidance
rons via neurotransmitter release at a specialized junction, the synapse.
cues toward a target cell.
tions as an essential
(endocannabinoids) to signal
modulate transducer in an elaborate
the plasticity of many Neurite outgrowth: sequential process including the specification, elongation
molecular
synapses [4], network
promptedrelying on ‘endogenous
the vibrant disciplinecannabinoids’
of contempo- development
Intercellular (synaptic) communication: information exchange between neu-
and branching of developing axons and dendrites.
rons via neurotransmitter release at a specialized junction, the synapse.
Glossary
Neurogenesis: the process by which neurons are created, irrespective of the
(endocannabinoids) to modulate thebiology
rary neurobiology. Developmental plasticity of many
studies con- Molecular cloning of the CB1 cannabinoid receptor (CB1R)
Neurite outgrowth: sequential process including the specification, elongation
specific region where these cells are generated or their specific functions
and branching of developing axons and dendrites. Cell cycle exit: the event when a cell p
synapses
cerned with[4], the
prompted
formationthe vibrant discipline of contempo-
of endocannabinoid signaling within the nervous system.
rary neurobiology.
networks Developmental
[5–9], the role biology studies
of endocannabinoids [10–19] and,con- [1] and its functional characterization as the major target
Neurogenesis: the process by which neurons are created, irrespective of the
Progenitor cell: an early descendant of a stem cell that can proliferate and
specific region where these cells are generated or their specific functions
differentiate. A progenitor cell is more limited than a stem cell in the lineages
a terminal differentiation program. To
9 proliferative signals.
cerned with the
consequently, theformation
molecular of endocannabinoid
blueprint of prenatal signaling
cannabis within the nervous system.
of cells it can generate. of D -tetrahydrocannabinol (THC) from cannabis [2] led to
Progenitor cell: an early descendant of a stem cell that can proliferate and
networks
abuse [5–9], the
[16,20–23] inrole
the of endocannabinoids
developing [10–19] soon
nervous system and, Retrograde signaling: a phenomenon during which a signal molecule travels
differentiate. A progenitor cell is more limited than a stem cell in the lineages Fate decision: the point when a progen
from the postsynaptic neuron toward the presynaptic neuron in a directionCB1 Rezeptor Antagonisten induzieren
Entwicklungsstörungen
SR141716 SR141716
Hui-Chen Lu & Klaudia BarabasTHC reduziert SCG10/stathmin-2 Inhalt im
embryonalen Gehirn
Giuseppe TortorielloBedeutung im Menschen
(muetterlicher Cannabiskonsum)
Claudia Morris
Yasmin L. HurdTHC-induzierte Änderungen persistieren im Gehirn
des betroffenen Nachwuchs
Janos Fuzik & Giuseppe TortorielloMedizinisches Cannabis: Therapie der Zukunft,
wenn wir die Pflanze verstehen
(Schlussfolgerungen)
Medical cannabis:
• More than 400 phytocannabinoids exist in the
plant – this suggests tremendous therapeutic
potential,
• The combination and ratios of these
components can be used successfully in
many, and most diverse, medical conditions,
• Research must be directed to understand
when, at which combination, and doses
cannabis constituents should/could be
applied,
• The study of cannabis already led to the
discovery of an ancient and fundamental
system endogenous to our body – what
awaits next?Danksagung
Katarzyna Malenczyk, Giuseppe Tortoriello,
Erik Keimpema, Alan Alpar, Daniela Calvigioni, Janos Fuzik
novo nordisk fonden
International collaborators:
Vincenzo Di Marzo, ERG, CNR, Naples, Italy
Yasmin L. Hurd, Mount Sinai School of Medicine, USA
Ken Mackie, Indiana University, Bloomington, USA
Pat Doherty, King’s College London, London, United KingdomYou can also read
