Neurobiology of addiction and why it is important

Neurobiology of addiction and why it is important Stephen Jurd University of Sydney 2016

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 AND Not treat addicts as bad people

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

Reward There is a system of reward, hard wired into mammalian brains Attempts to track it down have identified dopamine as the relevant neurotransmitter

The role of dopamine 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.

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)

What causes relapse? Stress Cues Priming dose In animals!!!

The drivers (Volkow, Kob and McLellan 2016) Acutely the experience goes from euphoria to feeling good to escaping dysphoria Abstinence effects go from less energy to less excitement to depression, anxiety, restlessness Preoccupation goes from anticipation to desire to obsession and planning

Behavioural effects Voluntary action with abstinence or control Becomes Flawed control with occasional lapses of taking more than intended, using when unintended Becomes Impulsive action with relapse and compulsive use

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.

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 criteria As above, but All SUD, no abuse/dependence distinction Only 2 items required Legal consequences out (RBT) Craving in

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

1976 status 1992 Status Abstinent Controlled drinking Relapse Dropped out or lost 3+ yrs abs 3+ yrs rtsd 18 3 1 8* 1 7 1 4

NESARC Relapse 2109 people Full remission from alcohol dependence Interviewed 3 years later Recurrence of AUD symptoms in: 51% of asymptomatic risk drinkers 27.2% of low risk drinkers 7.3% abstainers Dawson Goldstein and Grant (2007)

Domino et al (2005) Long term follow up of 292 addict physicians 75% had no relapse over 5 years Relapse more likely if: FH of addiction Dual diagnosis and opioid use Previous relapse

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, four slides document 80% recovery How? Close monitoring Big carrots Solid stick

Key components (DuPont) Contingency management Frequent random drug testing Tight links with AA/NA = abstinence Intensified treatment and monitoring follows relapse Continuing care approach Lifelong recovery focus

Independent Factors Substitute Dependencies i.e.habit 53 & 67% New love relationship i.e.love 32 & 38% Religious Involvement i.e.god 49 & 57% Behaviour Modification i.e.control 73 & 49% Percentages for 1 and 3 years abstinent

Full recovery is a reality Securely abstinent subjects had mental health outcomes comparable with those who had never had a drinking problem (Vaillant 1983)

Mental health outcomes HSRS Score Low risk drinker N=227 Abstinent >3 years N=20 Abstinent 1-3 years N=12 0-60 8 0 25 38 Progressiv e alcoholic N=29 60-70 16 30 33 34 70-80 29 40 25 28 80-100 47 30 17 0

Mapping the recovery journeys of former drinkers in recovery Hibbert and Best (2011, Drug and Alcohol Review)

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 mechanisms 1 Fellowship Oxytocin Feelgood

Recovery mechanisms 2 Mirror neurones Passive learning Comfort Normalising new behaviour

Recovery mechanisms 3 Anxiety reduction through meditation Chanting Structure Prayer

Recovery The previous slides outline 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 Identify a variety of mechanisms relevant to recovery