Activation of OFC and mPFC by Methylphenidate in Cocaine Addicted Subjects But Not in Controls: Relevance to Addiction (Volkow et al., J Neuroscience, 2005).

What we know about Dopamine, Methylphenidate & the Brain

Methylphenidate (MP)

•  Stimulant used to treat ADHD

•  Oral dose: 10-60mg; peak brain levels 1-2 hours

•  Mechanism: Blocks Dopamine Transporter (DAT)

DA in the Striatum Phasic: transient burst firing

Tonic: background firing

Tonic regulates phasic via DA autoreceptors; inverse relationship

Schultz, Ann Rev Psychol, 2006.

DA Circuitry

Grace et al. TINS (2007).

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+ -

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•  ↑ PFC (corticostriatal) - inhibit VP - disinhibit VTA - ↑ phasic DA - ↑ novelty response,

flexibility, SNR

•  Tonic DA - ↓ phasic DA - ↓ mesocortical DA - ↑ perseveration

•  “permissive gate”

DA & MP

Volkow et al., Biol Psychiatry (2005).

MP blocks DAT -↓ in DRD2 availability indicates ↑ in extracellular (tonic) DA

DAT effects of MP predict subjective effects

Volkow et al. Am J Psychiatry (1999).

Leyton et al. Neuropsychopharm (2002). Drevets et al. Biol Psychiatry (2001).

Change in Euphoria

Pleasurable

Displeasurable

Positive Effects Mood Happiness Desire

Negative Effects Distrust Annoyance Anxiety

DA & Drug Abuse

Volkow et al., J Neurosci (2003).

DA metabolism and “high” are ~50% higher when MP expected

A Dopaminergic Model of Drug Abuse

Grace Addiction (2000).

-  Block DAT: - ↑ Tonic DA (35-fold!!) - ↓ Phasic

-  Withdrawal: ↑ corticostriatal input

-  Further ↑ Tonic DA in VTA

-  ↓ Phasic DA à ↓ positive affect, reinforcement (dysphoria) - DA deficit state requires additional drug to achieve “normality” – phasic-tonic equilibrium

Methods •  21 male cocaine addicts •  ≥ 3g/ week for 6 months •  No other addiction except

nicotine

•  15 male controls •  No substance abuse or

dependence (except nicotine)

•  Single blind •  Fixed order

Rate Drug Effects -  High -  Desire for cocaine -  Desire for MP -  Restlessness -  Mood

Results

Addicts exhibit oppossit OFC pattern

PFC lesions in rats increase sensitivity to cocaine (Schenk, 1991).

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Discussion •  OFC/ ACC abnormalities in cocaine, meth,

heroine, marijauna & alcohol addiction •  Conditioned stimuli activate OFC/ ACC in

addicts; blunted response to other rewards •  Discrepancy: ↓ in NAcc and INS contrasts with

cocaine – induced ↑ (subjects, drugs, methods . . .)

•  BA 25 – emotional reactivity; BA11 – motivational salience –  Maybe common substrates for compulsive disorders