Neurobiologia delle Dipendenze

1. Neurobiology of Addiction
and Therapeutic Strategies
Felice Nava, MD, PhD

2. Why does the Brain Become Addicted?

3. ADDICTION IS A COMPLEX ILLNESSADDICTION IS A COMPLEX ILLNESS

4. NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2003
Age
Age at tobacco, at alcohol and at cannabis dependence as per DSM IV
0.0%
0.2%
0.4%
0.6%
0.8%
1.0%
1.2%
1.4%
1.6%
1.8%
5 10 15 2125 30 35 40 45 50 55 60 65
%ineachagegroupwhodevelop
firsttimedependence
THC
ALCOHOL
TOBACCO
Addiction is a Developmental Disease

5. Addiction is a “Normal” Disease

6. The Smokers Body
Smokers have a 35-45% reduction in MAO B
Flower et al., 2003

7. Effects of Cocaine on Glucose Metabolism
in Maternal and Fetal Brain

8. James Old (1922-1976)
The Pleasure Centers

10. movement motivation
addiction sex & reward
Dopamine the Molecule of Life

11. The Brain Reward System

12. Sampling of Interstitial Neurochemicals
by in vivo Microdialysis

13. 0
50
100
150
200
0 60 120 180
Time (min)
%ofBasalDA
Output
NAc shell
Empty
Box Feeding
Source: Di Chiara et al.
FOOD
100
150
200
DAConcentration(%Baseline)
Mounts
Intromissions
Ejaculations
15
0
5
10
CopulationFrequency
Sample
Number
1 2 3 4 5 6 7 8 9 1011 1213 1415 1617
Female 1 Female 2
Source: Fiorino and Phillips
SEX
The Natural Rewards

14. 0
50
100
150
200
250
F
latency 8'45"± 30"
amount eaten 2± 0.2g
Fonzies naive
0
50
100
150
200
250
F
latency to eat 15"± 0
amount eaten 4± 0.2g
1 day post Fonzies
0 60 120 180 240
0
50
100
150
200
250
F
amount eaten 4.2± 0.2g
latency to eat 22"± 0
5 days post Fonzies
time (min)
%ofbasalDA Time-course of habituation
of NAc shell DA
responsiveness to one trial
Fonzies feeding
Bassareo and Di Chiara,J.Neurosci.1999

15. 0
100
200
300
400
500
600
700
800
900
1000
1100
0 1 2 3 4 5 hr
Time After Amphetamine
%ofBasalRelease
DADOPACHVA
Accumbens
AMPHETAMINE
0
100
200
300
400
0 1 2 3 4 5 hr
Time After Cocaine
%ofBasalRelease
DA
DOPAC
HVA
Accumbens COCAINE
0
100
150
200
250
0 1 2 3 hr
Time After Nicotine
%ofBasalRelease
Accumbens
Caudate
NICOTINE
100
150
200
250
0 1 2 3 4hr
Time After Ethanol
%ofBasalRelease
0.25
0.5
1
2.5
Accumbens
0
Dose (g/kg ip)
ETHANOLETHANOL
Source: Di Chiara and Imperato
The Drugs of Abuse and DA Output

16. Tanda, Pontieri & Di Chiara, Science, 1997
Selective increase of DA in the Nac
shell after i.v.THC and heroin

17. Fast DA Release is Addictive

18. Reward Circuit in Addiction:
The Role of Dopamine

19. Methylphenidate Induced Increase in Striatal
DA in Controls and in Alcoholics Subjects

20. Memory/Conditioning:
The Role of Dopamine

21. Dopamine and The Incentive Phase

22. [11C] Raclopride Binding In Cocaine Abusers
(n =18) Viewing a Neutral and a Cocaine-Cue
Video

23. Motivation and Executive Control Circuits:
The Role of Dopamine

24. Dopamine D2 Receptors are Lower
in Addiction

25. Correlations Between D2 Receptors in
Striatum and Brain Glucose Metabolism

27. Actions of Drugs of Abuse on Ventral
Tegmental Area and Nucleus Accumbens

28. Stress and Temperament Modulate
Drug Intake Response

29. Neurochemical Circuitry in Drug Reward

30. 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.

31. 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 Effects
of Withdrawal

32. Extracellular DA and 5-HT in the Nucleus
Accumbens During Cocaine Self-
Administration and Withdrawal

33. 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)

34. CNS Actions of
Corticotropin-Releasing Factor (CRF)

35. Neurochemical Changes Associated with
Drug Use, Dependence and Relapse

36. 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
CannabinoidreceptorsMarijuana/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

39. 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

40. Principles of Actions
of the Drugs for Addiction
• Agonists e.g. methadone, buprenorphine
• Antagonists e.g. naltrexone
• Inhibitory drugs e.g. disulfiram

41. Nava et al., 2010

42. Marie Nyswander & Vincent P. Dole
Methadone an Example of Serendipidy

43. Heroin Addiction: Functional State of a
Typical Addict
"High"
"Straight"
"Sick"
Days
AM PM AM PM AM
FunctionalState
Dole, Nyswander and Kreek, 1966
(overdose)
(arrows
indicate
times of
injection)

44. Methadone Maintenance: Functional State
of a Former Addict Treated With
Methadone Maintenance
FunctionalState
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 M
H

45. Wong et al., 2004
GHB The Anti-Alcohol Agent:
An Italian Discovery

46. 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

48. 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 endogenous
compounds (e.g. endorphins, dynorphins or endocannabinoids)

50. Felice Nava, MD, PhD
Direttore Comitato Scientifico FeDerSerD
www.federserd.it
Felice Nava, MD, PhD
Responsabile UOS Sanità Penitenziaria
Distretto 2
Via Tommaso Temanza, 1
35134 Padova
Tel. 049-8214904
Fax 049-8214906
felicealfonso.nava@sanita.padova.it
Direttore Comitato Scientifico FeDerSerD
www.federserd.it
http://felicenava.splinder.com
felnava@tin.it