Transcript statins

Statins Reduce the Risks of
Relapse to Addiction in Rats
Neuropsychopharmacology
2015 Oct 15. doi: 10.1038/npp.2015.317.
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指導老師:
報告學生:
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林宏榮老師.鄭伯智老師
胡喬雅
NA3H0004
2015.12.12
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Introduction
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Cocaine
Cocaine is the most powerful stimulant
commonly inhaled or injected into the veins
Mental effects may include loss of contact with
reality, an intense feeling of happiness, or agitation.
Physical symptoms may include a fast heart rate,
sweating, and large pupils.
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https://en.wikipedia.org/wiki/Cocaine
https://www.discoveryplace.info/effects-cocaine-addict-graduate
http://www.drugabuse.gov/publications/research-reports/cocaine/how-does-cocaine-produce-its-effects
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cocaine and nicotine alter the brain’s dopamine levels
in highly similar ways.
https://www.bibalex.org/supercourse/lecture/lec29291/033.htm
http://www.promises.com/articles/smoking/is-nicotine-a-gateway-drug-for-cocaine/
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http://www.hazeldenbettyford.org/articles/bcr-update-brain-and-dopamine-oct-2015
Relapse Rate
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http://www.futuresofpalmbeach.com/drug-rehab/statistics/
addiction relapse
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 a study in humans has found that increase in
transcripts related to cholesterol biosynthesis
and trafficking is a common feature of
cocaine,cannabis, and phencyclidine abuse.
(Lehrmann et al, 2006).
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http://www.hazeldenbettyford.org/articles/bcr-update-brain-and-dopamine-oct-2015
statin
 HMG-CoA reductase inhibitors
 inhibition of cholesterol synthesis
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http://www.alzforum.org/news/research-news/statins-boost-growth-factors-mouse-brain-improve-memory
statins can directly bind to histone deacetylation
enzymes, key enzymes in promoting epigenetic
modifications (Tsankova et al,2007), and inhibit their function
(Lin et al, 2008),an effect that has been shown to reduce
addiction-related behaviors of cocaine (Romieu et al, 2008).
Trends Pharmacol Sci. 2015 Apr;36(4):226-35.
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HYPOTHESIS
cocaine or nicotine
cocaine or nicotine
Statin
?
the Risks of Relapse to Addiction
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http://www.janvier-labs.com/rodent-research-models-services/research-models/per-species/outbred-rats/product/sprague-dawley.html
Aim of the study
Positive effects of statins are reminiscent
to those obtained with the enriched environment,
an experimental paradigm that was also shown to
be beneficial in reducing risks of relapse to
cocaine addiction in models of relapse.
(Solinas et al, 2008; Chauvet et al, 2009; Thiel et al, 2009; Chauvet et al, 2012).
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Methods & Result
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self-administration
Adult male Sprague Dawley rats
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Proc Natl Acad Sci U S A. 2012 Dec 11;109(50):20703-8.
Experimental design
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Cocaine (0.6 mg/kg )
FR1
 Statins or vehicle were always injected between
10 AM and 12 AM and tests for relapse
Veh–Veh
Veh–Sim
Sim–Veh
Sim–Sim
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Experimental design
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Atorvastatin (1 mg/kg i.p.)
Pravastatin (2 mg/kg i.p.)
vehicle
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simvastatin (1 mg/kg i.p.)
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Part I
Simvastatin Decreases Cocaine Seeking
After Abstinence
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Results 1:
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Results 1:
$$, P<0.01 Sim-treated different from veh-treated control **,
P<0.01 active different from inactive nose-pokes.
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Part II
The Effects of Simvastatin are Long Lasting
Veh–Veh
Veh–Sim
Sim–Veh
Sim–Sim
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Results 2:
Veh–Veh
Veh–Sim
Sim–Veh
Sim–Sim
$ and $$P<0.05 and P<0.01 Sim-treated different from veh-treated control;
**P<0.01 active different from inactive nose-pokes.
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Part III
Only Statins that Pass the Blood–Brain Barrier
(BBB) Reduce Cocaine-Seeking Behavior
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Results 3:
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Results 3:
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Part IV
Simvastatin Does not Affect Cocaine-Taking
Behavior
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Results 4:
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Part V
Simvastatin Decreases Relapse to Nicotine
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Results 5:
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Results 5:
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Discussion
The effects of simvastatin were dose dependent
with doses of 1 mg/kg, but not 0.1 mg/kg, being
effective in decreasing drug seeking.
only lipophilic statins that pass the BBB such as
simvastatin and atorvastatin reduce drug-seeking
behavior, whereas hydrophilic statins such as
pravastatin had no effect.
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Discussion
 Further studies are necessary to determine the
neurobiological mechanisms underlying the
effects of statins and to determine whether statins
would also be effective in reducing drug seeking
after acute administration.
 despite the good safety profile of statins, the risks
to develop side effects with these drugs seem to
increase over time.
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Conclusion
 a chronic treatment with brain-penetrating
statins decreases the risk of relapse to cocaine
and nicotine.
 brain-penetrating statins such as simvastatin and
atorvastatin could be useful pharmacological
tools for the treatment of addiction.
 statin treatment may be effective only in
reducing relapse but not in facilitating quitting.
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statins
upregulate
vascular endothelial growth factor
brain-derived neurotropic factor (BDNF)
hippocampal neurogenesis
interact
PI3K/Akt and ras/ERK pathways
beneficial of neurological conditions
Lu et al, 2007; Wu et al,2008
http://www.nature.com/jcbfm/journal/v30/n3/full/jcbfm2009255a.html
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