Addiction Neurobiology

Addiction Neurobiology Stephen Jurd University of Sydney Australia

Richard W is sick Apology

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!!!

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!