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

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fir

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me

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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 049-8214906felicealfonso.nava@sanita.padova.it

Direttore Comitato Scientifico FeDerSerDwww.federserd.it

http://felicenava.splinder.comfelnava@tin.it