Transcript Beyond BP. New ways to detect release of dopamine with PET.

Imaging Drugs in the Brain
ENAS 880 / NSCI 523
Fall 2010
Morris/Cosgrove
[email protected]
kelly [email protected]
http://tauruspet.med.yale.edu/staff/edm42/courses/ENAS_880/index.html
Quiz 1
Course business
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info posted on Evan’s website
a few classes in N203 at end of semester
lectur-ettes, followed by…
paper discussions – participation expected
paper synopses to be written, emailed
collaborative presentation or other work
what are your interests?
what are your goals?
Terms in first papers
dopamine
neuroleptic
tomographic method
spatial resolution
cyclotron (‘in-hospital’… why)
specific activity
specific binding
attentuation correction
septa
reference region
recovery coefficient
ligand vs tracer vs isotope
contrast
noise
model
compartments
steady state
structural vs functional
caudate, cerebellum
Warmup: What is this?
http://www.cscs.umich.edu/~crshalizi/
OK, start with this…
now this
functional image overlaid
on a structural image:
the ‘pixels’ in a structural image
convey some physical,
anatomical, or geographical
information about the object.
http://www.cscs.umich.edu/~crshalizi/election/
now this
functional image:
the color and size of the ‘pixels’
convey some functional
information about how the object
WORKS.
http://www.cscs.umich.edu/~crshalizi/election/
Electoral Map (Cartogram)
Every county is displayed in color according to vote (in
2004) of the majority of the voters. The size of the county
represents the number of voters. (Note that the western
plain states are smaller than the east coast.)
In this case, the cartogram shows us that –contrary to
popular belief- the country’s distribution of Dems and
Repubs was reasonably heterogeneous.
http://www.cscs.umich.edu/~crshalizi/
but do “functional images” of the
brain ever change the apparent
shape of the brain?
..actually, yes…
perhaps we’ll get to this advanced topic this semester
Our goal: Understand how
functional maps of the human brain
are used to study drugs and drug
action
what’s going on here?
Christian et al.
which ones are…functional vs structural
which ones do “detection” vs “characterization”
Fowler et al., Science & Practice Perspectives, April 2007, 4-16
what’s the modality?
what is the orientation of
the brain?
what is the orientation of
the person?
what’s the yellow stuff?
is this a single subject?
Fowler et al., Science & Practice Perspectives, April 2007, 4-16
what’s the prominent neurotransmitter in the nucleus accumbens?
Fowler et al., Science & Practice Perspectives, April 2007, 4-16
Many drugs cause release of dopamine
“… cocaine, morphine, nicotine, and ethanol share the property of increasing DA
transmission in the BNST. This effect may be related to an action at the level of
neuronal circuits activated by natural reinforcers … suggest[ing] that DA
transmission of the BNST plays a role in the mechanism of drug abuse and
addiction.”
Carboni et al, J Neurosci 20:RC102(1-5), 2000
is everyone
familiar with
this diagram?
to what other
site(s) could
we direct a
tracer?
Fowler et al., Science & Practice Perspectives, April 2007, 4-16
which one is specific for
neurotransmitter system?
which one is a non-specific
marker of ‘activation’?
what are they ‘tracing’
are these molecules
biologically the same as their
tracees?
is there a mistake on this
slide?
Fowler et al., Science & Practice Perspectives, April 2007, 4-16
which end is up?
which end has high uptake
in healthy controls?
how do you know?
what does that mean?
why are these images so
blurry?
Fowler et al., Science & Practice Perspectives, April 2007, 4-16
what is the claim here?
what assumption(s) is(are)
at work?
are they measuring the
phenomenon or something
related to it?
Fowler et al., Science & Practice Perspectives, April 2007, 4-16
why is most of the brain blue?
are these “early” or “late”
images?
is this structural or functional?
is this a ‘detection’ or a
‘characterization’ experiment?
Fowler et al., Science & Practice Perspectives, April 2007, 4-16
Schematic Diagram of Ligand Binding
“Rest” condition
BP = B/F
at steady state
endogenous NT
unlabeled tracer
radiolabeled tracer
Schematic Diagram of Ligand Binding
“Rest” condition
loss of receptors
BP ↓
endogenous NT
unlabeled tracer
radiolabeled tracer
Schematic Diagram of Ligand Binding
DA-release condition
DA ↑
BP ↓
endogenous NT
unlabeled tracer
radiolabeled tracer
DBP is the (fractional) difference in BP
between conditions
DBP= (BP1-BP2)/BP1
questions/thoughts on the review article by Fowler et al.
1. What is functional imaging and how is it different from structural imaging?
a. sort of related: detection (as in tumor…but could be simply distribution of receptors) vs
characterization (as in kinetic characterization… requires modeling)
2. Are effects of chronic drug use permanent?
3. How can I get my basal ganglia to grow larger?
4. Is there really such a thing as a functional MRI machine? Is there a forward-moving car a
different thing than a car going in reverse? Bottom line: is fMRI really a different modality than
MRI?
5. what is wrong with this statement: “Biologically, the more oxygen that cells in a region utilize,
the more oxygen-carrying hemoglobin molecules will be found in the blood vessels responsible
for supplying them”?
6. a big potential use of imaging is to predict vulnerability to addiction… but I am not sure it is
being done successfully yet.
7. in Wexler 2001 (see Figure 4) why is there so much activity in visual cortex in healthy volunteers
but not in cocaine addicts.
8. why is fMRI not “specific” like PET or SPECT or even MRS? cannot differentiate
neurotransmitters or circuits or even inhibitory vs excitatory activity.
questions (2)
1. fMRI and MRS image endogenous materials. PET and SPECT (in most basic mode) image
exogenous tracers. PET and SPECT can be used to image effects of endogenous chemicals…
2. compare relative SENSITIVITIES of MRS and PET
3. Not clear if MRS observations of NAA indicate increased glial activity or something else…
possible contradictions on pages 8 & 9
4. can’t we make images from MRS… not just spectra
5. could use MRS to look at exogenous alcohol.
6. PET/SPECT require injection of radiotracers
7. A little overstatement: “series of images taken at appropriate intervals provides stop-action
record of a drug’s movement into and out of the brain”
8. can you find the mistake in figure 5… F18 replaces OH not F19
questions (3)
1. Figure 5 legend leaves out a key step…”annihilation”
2. is there a difference between imaging dopamine receptors and dopamine transporters?
a. how ‘bout dopamine receptors and dopamine? How would you do it?
b. is there a difference between imaging cocaine effects on dopamine system and cocaine
effects on mu-opioid system? What?
3. there are inherent ambiguities in PET data … such as the inability (in most cases) to separate the
effects of change in affinity of receptor for ligands vs change in number of receptors.
a. how do people deal with such ambiguities?
4. we want to “exacerbate nicotine-induced dopamine dysregulation… how should we do it? Give
MAO inhibitors that are present in tobacco smoke? If so, why is selegiline (MAO inhibitor) used
(tried) as a smoking cessation treatment?
5. what imaging work has actually affected design/development of smoking and other addiction
treatments?
6. “dopamine spikes underlie drug euphoria” has this ever been proved?
7. Treatment strategies. Paper by Kreek is cited to support: “third strategy… utilizes a medication
that activates the same neurotransmitter system as an abused drug, but produces no shart
dopamine spike”… this sounds like Chantix. Authors claim it is methadone and bupremorphine.
8. detox’d methamphet users who stayed abstinent for 9 months recovered dopamine
transporters. but they did not recover the same degree of cognitive and motor function. why
not?