Download Wenhua Zhou, Ph.D. - Center for Advancing Longitudinal Drug

2015 International Conference on Global
Health, Hangzhou April 22-24, 2015
Cognitive enhancers for the treatment of
heroin relapse:
Preclinical evidence
周文华
Wenhua Zhou Ph.D
Dean & Prof. School of Medicine, Ningbo University
Director, Ningbo Addiction Research & Treatment Cent.
Email:[email protected] or [email protected]
The number of heroin abuser is about 0.2-0.3%
of adults populations in China
Craving in heroin users persistently exist (n=416)
3.0
*
2.8
2.6
*
Craving
2.4
2.2
2.0
1.8
1.6
1.4
1.2
1.0
<3 Month
•
•
•
•
4--6 Month
7--12 Month
>12 Month
Dose:
r = 0.170，P < 0.01
Injection:
r = 0.261，P < 0.01
Abuse durative period: r = 0.239，P < 0.01
The duration of detoxification: r = 0.107，P < 0.05
Animal models of drug reward
Intravenous drug self-administration
model
In this model, animals typically
make a lever press or nose poke to
receive contingent drug injections.
The premise of this procedure is
that drugs of abuse control
behaviour by functioning as operant
positive reinforcers.
Heroin self-administration and relapse model
Animal models of relapse
Reinstatement model
• non-contingent priming injections of the
drug,
• exposure to discrete or contextual cues
that are associated with drug intake,
• exposure to stressors.
Self-administration mimics relapse behavior
Regular taking
Compulsive seeking
Zhou et al., Neuroreport 2004; Zhang et al., Neuroscience Letter 2005； Zhang et al., Pharmacology，Biochemistry and
Behavior，2004; Zhou et al., Psychopharmacology 2005; Liu et al., Brain Research 2005; Zhang. J Neurosci Methods 2006
Inhibitor of acetylcholinase attenuated heroin seeking
behavior
(Zhou et al., Neuroscience,2007)
Galantamine attenuated heroin seeking
galantamine
Liu et al., Neuropharmacology,2012
Reward Pathway of heroin
lateral dorsal tegmental nucleus
Cognitive dysfunction in heroin addicts
Behaviorally, patients took a much shorter time to
complete task but committed more errors,Indicating
that patients tend to be impulsive.The attenuation of
activity in the anterior cingulate, and the additional
recruitment of the right inferior parietal region.
（Neuroscience Letters, 2005）。
Hypothesis:Cognitive dysfunction and relapse
Cognitive function
Disinhibition
Relapse
Drug-associated memory
Drug seeking/
impulsivity
Cognitive enhancers
Targets on anti-relapse
• Acetylcholine: galantamine， huperzine A
• Glutamate: N-acetylcysteine，NAAG
• Dopamine：risperidone
• Phosphodiesterase:rolipram
Risperidone inhibited cue-induced heroin seeking
risperidone
Lai et al.,Int J Neuropsychopharmacology, 2013
Effects of risperidone on heroin SA or locomotor activities
Does dopamine mediate opiate reward?
Neuropsychopharmacology (2008) 33, 166-180
N-acetylcystein inhibited heroin seeking
Zhou et al., Biol Psychiatry, 2008
N-acetyl-aspartyl-glutamate:an anti-relapse peptide
N-acetyl-aspartyl-glutamate: an anti-relapse peptide
Incubation of heroin seeking after long-term withdrawal
(Zhou et al.,Psychopharmacology 2009)
Expression of CREB and AKT during withdrawal
Beta-actin
p-AKT(ser473)
Beta-Actin
160
*
140
normalized p-AKT
(% control)
p-CREB
120
100
80
60
40
20
0
con
cc1
cs1
cc14
cs14
Rolipram inhibited heroin seeking
p-CREB
GAPDH
CON
Rolipram
0.03
0.1
0.3
Normalized of p-CREB(% of contorl)
80
*
*
0.03
0.1
*
60
40
20
0
0
0.3
Rolipram(mg/kg)
Lai et al., Int J Neuropsychopharmacology,2014
Rolipram inhibited heroin seeking
Lai et al., Int J Neuropsychopharmacology,2014
Rolipram in NAc inhibited heroin seeking
Sun et al., Neuroscience Letters ,2015
LY294002, PI3 Kinase inhibitor,decreases heroin seeking
AKT
p-AKT(473)
Beta-actin
LY294002
0
0.34
0.68 μg/ μ l/side
AKT1 siRNA and Ad miR-382 inhibited heroin seeking
miR-382表达减少
AKT3
β-Actin
Summary
Evaluated
drugs
Heroin selfExtinction
administration
Drug seeking Drug seeking
induced by
induced by
cues
heroin
Galantamine or
huperzine A
N-acetylcysteine
NAAG
Risperidone
N
Rolipram
N
N
N
Animal Center and Rats SA chambers
Outpatient
Clinical award
Acknowledgements
Funding supports:
Nature Scientific Foundation of China（ 81471350,U1132602）
National Basic Research Program of China (2009CB522008,
2015CB553504）
Collaborators:
MUSC: Prof.Kalivas
West Virginia University Health Sciences Center: Prof.Zhang
Hangzhou Normal University: Prof. Weng
Medical School of Ningbo University: Yu Liu PhD