Stimulant Drugs & the Brain
-
Upload
dharol -
Category
Health & Medicine
-
view
506 -
download
1
description
Transcript of Stimulant Drugs & the Brain
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).
+ +
+ -
-
• ↑ 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).
?
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