Neurobiology of Addictionand Therapeutic Strategies
Felice Nava, MD, PhD
Why does the Brain Become Addicted?
ADDICTION IS A COMPLEX ILLNESSADDICTION IS A COMPLEX ILLNESS
NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2003NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2003
AgeAgeAge at tobacco, at alcohol and at cannabis dependence as per DSM IV
0.0%0.0%
0.2%0.2%
0.4%0.4%
0.6%0.6%
0.8%0.8%
1.0%1.0%
1.2%1.2%
1.4%1.4%
1.6%1.6%
1.8%1.8%
55 1010 1515 2121 2525 3030 3535 4040 4545 5050 5555 6060 6565% in
eac
h ag
e gr
oup
who
dev
elop
fir
st ti
me
depe
nden
ce
% in
eac
h ag
e gr
oup
who
dev
elop
fir
st ti
me
depe
nden
ce
THCALCOHOL
TOBACCO
Addiction is a Developmental Disease
Addiction is a “Normal” Disease
The Smokers Body
Smokers have a 35-45% reduction in MAO B
Flower et al., 2003
Effects of Cocaine on Glucose Metabolismin Maternal and Fetal Brain
James Old (1922-1976)
The Pleasure Centers
movement motivation
addiction sex & reward
Dopamine the Molecule of Life
The Brain Reward System
Sampling of Interstitial Neurochemicalsby in vivo Microdialysis
Sampling of Interstitial Neurochemicalsby in vivo Microdialysis
00
5050
100100
150150
200200
00 6060 120120 180180
Time (min)Time (min)
% o
f B
asal
DA
O
utp
ut
% o
f B
asal
DA
O
utp
ut
NAc shellNAc shell
EmptyEmpty
BoxBox FeedingFeeding
Source: Di Chiara et al.Source: Di Chiara et al.
FOODFOOD
100100
150150
200200
DA
Co
nce
ntr
ati
on
(%
Bas
elin
e)D
A C
on
cen
tra
tio
n (
% B
asel
ine)
MountsMountsIntromissionsIntromissionsEjaculationsEjaculations
1515
00
55
1010
Co
pu
latio
n F
req
ue
nc
yC
op
ula
tion
Fre
qu
en
cy
SampleNumberSampleNumber
11 22 33 44 55 66 77 88 99 1010 1111 1212 1313 1414 1515 1616 1717
Female 1 Female 1 Female 2 Female 2
Source: Fiorino and PhillipsSource: Fiorino and Phillips
SEXSEX
The Natural Rewards
0
50
100
150
200
250
F
latency 8'45"30"
amount eaten 20.2g
Fonzies naive
0
50
100
150
200
250
F
latency to eat 15"0
amount eaten 40.2g
1 day post Fonzies
0 60 120 180 2400
50
100
150
200
250
F
amount eaten 4.20.2g
latency to eat 22"0
5 days post Fonzies
time (min)
% o
f b
asa
l D
ATime-course of habituation of NAc shell DA responsiveness to one trial Fonzies feeding
Bassareo and Di Chiara,J.Neurosci.1999
001001002002003003004004005005006006007007008008009009001000100011001100
00 11 22 33 44 5 hr5 hr
Time After AmphetamineTime After Amphetamine
% o
f B
as
al
Re
lea
se
% o
f B
as
al
Re
lea
se
DADADOPACDOPACHVAHVA
AccumbensAccumbens AMPHETAMINEAMPHETAMINE
00
100100
200200
300300
400400
00 11 22 33 44 5 hr5 hrTime After CocaineTime After Cocaine
% o
f B
as
al
Re
lea
se
% o
f B
as
al
Re
lea
se
DADADOPACDOPACHVAHVA
AccumbensAccumbens COCAINECOCAINE
00
100100
150150200200
250250
00 11 22 3 hr3 hr
Time After NicotineTime After Nicotine
% o
f B
as
al
Re
lea
se
% o
f B
as
al
Re
lea
se
AccumbensAccumbensCaudateCaudate
NICOTINENICOTINE
100100
150150
200200
250250
00 11 22 33 4hr4hrTime After EthanolTime After Ethanol
% o
f B
as
al
Re
lea
se
% o
f B
as
al
Re
lea
se
0.250.250.50.5112.52.5
AccumbensAccumbens
00
Dose (g/kg ip)Dose (g/kg ip)
ETHANOLETHANOLETHANOLETHANOL
Source: Di Chiara and Imperato
The Drugs of Abuse and DA Output
Tanda, Pontieri & Di Chiara, Science, 1997
Selective increase of DA in the Nac
shell after i.v.THC and heroin
Fast DA Release is Addictive
Reward Circuit in Addiction: The Role of Dopamine
Methylphenidate Induced Increase in Striatal DA in Controls and in Alcoholics Subjects
Memory/Conditioning: The Role of Dopamine
Dopamine and The Incentive Phase
[11C] Raclopride Binding In Cocaine Abusers (n =18) Viewing a Neutral and a Cocaine-Cue Video
Motivation and Executive Control Circuits: The Role of Dopamine
Dopamine D2 Receptors are Lower in Addiction
Correlations Between D2 Receptors in Striatum and Brain Glucose Metabolism
Actions of Drugs of Abuse on Ventral Tegmental Area and Nucleus Accumbens
Stress and Temperament ModulateDrug Intake Response
Neurochemical Circuitry in Drug Reward
Neurocircuitry of Addiction
Derived from: Koob G, Everitt, B and Robbins T, Reward, motivation, and addiction. In: Squire LR, Berg D, Bloom FE, du Lac S, Ghosh A, Spitzer NC (Eds.), Fundamental Neuroscience, 3rd edition, Academic Press, Amsterdam, 2008, pp. 987-1016.
Reward Transmitters Implicated in the Motivational Effects of Drugs of Abuse
Dopamine … “dysphoria”
Opioid peptides ... pain
Serotonin … “dysphoria”
GABA … anxiety, panic attacks
Dopamine
Opioid peptides
Serotonin
GABA
Positive Hedonic Effects
Negative Hedonic Effectsof Withdrawal
Extracellular DA and 5-HT in the Nucleus Accumbens During Cocaine Self-Administration and Withdrawal
Stress and Anti-stress Neurotransmitters Implicated in the Motivational
Effects of Drugs of Abuse
Corticotropin-releasing factor
Norepinephrine
Vasopressin
Orexin (hypocretin)
Dynoprhin
Neuropeptide Y
Nociceptin (orphanin FQ)
CNS Actions ofCorticotropin-Releasing Factor (CRF)
Neurochemical Changes Associated with Drug Use, Dependence and Relapse
Molecular Targets of Drug Action
??Inhalants
Serotonin receptors
Serotonin receptors
NMDA receptors
NMDA receptors
Hallucinogens
LSD
MDMA
PCP
Ketamine
Dopamine transporters
Dopamine/NE release
Stimulants
Cocaine
Amphetamines
Opioid receptorsOpioids
Cannabinoid receptorsMarijuana/THC
GABA receptors
GABA receptors
Depressants
Barbiturates
Benzodiazepines
Nicotinic Ach receptorNicotine
Adenosine ReceptorsCaffeine
Classes of Drugs Primary Target
NMDA receptors (blocked)
Kainate receptors (blocked)
GABA receptors (stimulated)
Glycine receptors (stimulated)
Nicotinic Ach receptors (stimulated)
Serotonin receptors (stimulated)
Calcium channels (blocked)
Potassium channels (blocked)
Protein Kinase C
Protein Kinase A
DARPP-32
Phosphatases
Neurosteriods
Alcohol Targets
The Aims of the Pharmacological Treatment of Addiction
• The management of the withdrawal syndrome;
• The achiment of abstinence and its maintenance
• The reduction of harms associated with drug use
• The treatment of complications of drug use
Principles of Actions of the Drugs for Addiction
• Agonists e.g. methadone, buprenorphine
• Antagonists e.g. naltrexone
• Inhibitory drugs e.g. disulfiram
Nava et al., 2010
Marie Nyswander & Vincent P. Dole
Methadone an Example of Serendipidy
Heroin Addiction: Functional State of aTypical Addict
"High"
"Straight"
"Sick"
Days
AM PM AM PM AM
Fu
nct
ion
al S
tate
Dole, Nyswander and Kreek, 1966
(ove
rdo
se)
(arrows indicate times of injection)
Methadone Maintenance: Functional State of a Former Addict Treated With
Methadone Maintenance
Fu
nct
ion
al S
tate
Dole, Nyswander and Kreek
"High"
"Straight"
"Sick"
AM PM AM PM AM
Days
“Functional state of a patient blockaded with methadone (a single oral dose each morning). The effect of an intravenous injection of heroin in the blocked patient is shown
in the second day. The dotted line (---) indicates the course if methadone is omitted.”
M MH
Wong et al., 2004
GHB The Anti-Alcohol Agent:An Italian Discovery
New Therapeutic Strategies Against Addiction
• GABAA and GABAB enhancing agents able to contrast alcoholism and other forms of addiction;
• Nicotine antagonists able to treat tobacco dependency;
• New formulations of opioid-modulating drugs able to favourite the compliance and the efficacy of the heroin treatment;
• Dopamine D3 receptor antagonists and dopamine-reuptake inhibitors able to reduce cocaine and psychostimulant
• CB1 cannabinoid antagonists able to reduce cannabis or polydrugs intake
• Active vaccination against nicotine, cocaine, ect. able to minimize the harmful drug effects and to alleviate the intoxication state
New Therapeutic Agents Against Addiction•Learning and ant-learning agents (e.g. the glutamatergic agents);
• Agents able to oppose in drug users the switch from a normal to a dependent state (e.g. the GABA and the cannabinoids);
• Anti-stress agents (e.g. CRF antagonists);
• Molecules able to reduce the sensivity of the reward (e.g. SSRIs, dopamine antagonists);
• Agents able to act on new pharmacological targets controlling the drug taking behaviour and relapse (e.g. agonists of the NOP receptors);
• Gene-silencing or tur-on (gene therapies) of endogenouscompounds (e.g. endorphins, dynorphins or endocannabinoids)
Felice Nava, MD, PhD
Direttore Comitato Scientifico FeDerSerDwww.federserd.it
Felice Nava, MD, PhD
Responsabile UOS Sanità PenitenziariaDistretto 2Via Tommaso Temanza, 135134 PadovaTel. 049-8214904Fax [email protected]
Direttore Comitato Scientifico FeDerSerDwww.federserd.it
http://[email protected]
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