Addiction Neurobiology

Stephen Jurd University of Sydney

Australia

Apology

• Richard W is sick

The site of pathology

IF

• Addiction has a neurobiological basis

• THEN we should be able to:

• Define addiction AND

• Identify relevant neurological systems AND

• Their molecular pathology AND

• Manipulate it pharmacologically AND

• Identify mechanisms of recovery

Addiction

• Not simply withdrawal

• Persists well after use has stopped – DSM says

‘early remission’ to 12 months

• Common problem

• Social impact

• Medical impact

• Many psychiatric complications

Alcohol Dependence Syndrome

• Tolerance

• Repeated withdrawal symptoms

• Relief of withdrawal by further drinking

• Salience of drink seeking behaviour

• Subjective awareness of a compulsion to drink

• Narrowing of the drinking repertoire

• Reinstatement after abstinence

Substance Dependence – DSM

IV

• Maladaptive pattern of substance use

• Leading to clinically significant impairment or

distress

• Manifested by three or more criteria

• Occurring at any time in the same 12 month

period

DSM IV Dependence criteria

• Tolerance

• Withdrawal

• Substance taken more or longer than intended

• Problem cutting down or controlling use

• Great deal of time spent obtaining, using, recovering from substance

• Important activities given up or reduced

• Continued use despite knowledge of harm

DSM 5

• Not abuse (1 criterion) v dependence (3) but

• Substance use disorder (2 criteria) also including

• Craving or a strong desire or urge to use a substance AND

• 2–3 criteria = mild

• 4–5 = moderate

• 6+ = severe

• NB no physiological dependence

The Brain

• Obviously the site of addiction

• Subtle interplay between various brain functions

• Wise old Griffith Edwards: “salience”

• Responds to stimuli not consciously encoded

(Childress et al 2008)

Reward

• There must be a system of reward, hard wired

into mammalian brains

• Attempts to track it down have identified

dopamine as the relevant neurotransmitter

The “new” dopamine hypothesis

• DA is not merely a vector for the production of

psychosis

• DA is crucial for all reinforcement

• DA in the shell of the nucleus accumbens causes

reward = attention, memory and learning

• Addiction subsumes this basic mechanism

Schematic diagram that

represents the dopamine

pathway projecting from the

ventral tegmental area (VTA)

to the nucleus accumbens

(NAcc), indicating how

substances of abuse can

alter the activity of this

pathway to produce their

rewarding effects.

What causes relapse?

• Stress

• Cues

• Priming dose

• In animals!!!

Am J Psychiatry. 2012;169(4):351-353. doi:10.1176/appi.ajp.2012.12010041

Copyright © American Psychiatric Association. All rights reserved.

Neural circuitry mediating drug seeking

Prelude to Passion (Childress 2008)

fMRI showed limbic activation to “unseen” cocaine and sexual images of 33 milliseconds duration in 22 male cocaine patients.

• Brain reward circuitry responds to drug and sexual cues presented outside awareness.

• 48 hours later, addict ‘liked’ visible versions of the same cues.

• This study displays unconscious vulnerability in addiction.

Genetics 1

• Twin studies (Kaij 1961, Prescott 1999)

• Adoptee studies ( Goodwin 1973, Cloninger

1979, Sigvaardson 1996, Cadoret 1995)

• Long term follow up (Vaillant 1983, 1995, 2003)

Nano evidence

• GABA a2 receptor subtypes associated with alcohol dependence (Soyka 2008)

• A1 allele of D2 DA receptor (Blum & Noble 1990)

• Serotonin transporter gene(Lichterman 2000, Herman et al 2003)

• Alcohol dehydrogenase (protective)

Old Effective Treatments

• Opioid substitution (‘done, bupe, LAAM)

• Disulfiram

Newer Treatments

• Naltrexone

• Acamprosate (rat model = alcoholisation)

• Nalmefene

• Ondansetron

• Topiramate

• Baclofen

Latt, Jurd et al (2002)

Sass, Soyka et al

“Oh, wait! Wait, Cory! . . .

Add the cereal first and then the milk!”

New Drugs - Old Concepts

• Addiction is a disease

• Craving is a physical phenomenon

• Addicts reward themselves chemically

New Drugs - New Concepts

• Several neurotransmitters are relevant

• Combination drug treatment may be appropriate

• There may be pharmacological subtypes of

alcohol dependence

Brewster, Kaufmann et al (2008)

• Ontario PHP, 5 year follow up of 100 physicians

• AA/NA a required component

• 71% no relapse

• 85% completed program with a good outcome

McLellan, Skipper et al (2008)

• 5 year follow up data from 16 separate PHPs in

USA

• 75% good outcome at 5 years

• Much residential treatment and AA

Huh?

• Yes, two slides document

• 80% recovery • How?

• Close monitoring

• Big carrots

• Solid stick

Key components

• Contingency management

• Frequent random drug testing

• Tight links with AA/NA = abstinence

• Intensified treatment and monitoring follows

relapse

• Continuing care approach

• Lifelong recovery focus

Brain Plasticity

• Synaptic structures are highly dynamic

• Synapse count per cell body changes from 2,500

in infants to 15,000 in adolescents to 7,500 in

adults

• Mature brains can generate new neurones

• Exercise increases neural production

• Cells move within the CNS

Recovery

• The previous slide outlined a mechanism for the

biological basis of recovery:

• New behaviours

• New thoughts

• New feelings

• In new cells, synapses and pathways

• Ultimately, new microscopic neural architecture

SO

• Addiction lives in the brain

• And we can:

• Agree on a definition of addiction AND

• The relevance of the reward pathway AND

• Its biochemistry and pathology AND

• Manipulate it pharmacologically AND

• Recognise the relevance of plasticity to recovery

Demonstration

Scattered through the original presentation were multiple random pictures of my grandchildren.

My obsession with my grandchildren is

• Illogical - irrational

• Self-serving - egocentric

• Intrusive - distracting

• Salient – dominating

• Enjoyed – egosyntonic

• Defended – I hereby rationalise it!

• But positive (in my special case)– not all addictions destroy!