Stimulant Drugs & the Brain
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Methylphenidate (MP) is a stimulant used to treat ADHD that works by blocking the dopamine transporter. This causes increased tonic dopamine levels in the striatum. In cocaine addicts, MP activated the orbitofrontal cortex and medial prefrontal cortex, but not in controls. This suggests MP may increase craving and drug-seeking behavior by dysregulating dopamine signaling in brain regions involved in reward processing and decision making. A dopaminergic model of drug abuse proposes that blocking the dopamine transporter initially increases dopamine, but prolonged use leads to dopamine deficits that drive further drug use.
Stimulant Drugs & the Brain
- 1. What we know about Dopamine, Methylphenidate & 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).
- 2. Methylphenidate (MP) ≒ Stimulant used to treat ADHD ≒ Oral dose: 10-60mg; peak brain levels 1-2 hours ≒ Mechanism: Blocks Dopamine Transporter (DAT)
- 3. DA in the Striatum Phasic: transient burst firing Tonic: background firing Schultz, Ann Rev Psychol, 2006. Tonic regulates phasic via DA autoreceptors; inverse relationship
- 4. DA Circuitry ≒ PFC (corticostriatal) - inhibit VP - disinhibit VTA + + - phasic DA - novelty response, flexibility, SNR + - ≒ Tonic DA - phasic DA - mesocortical DA - - perseveration ≒ permissive gate Grace et al. TINS (2007).
- 5. DA & MP MP blocks DAT - in DRD2 availability indicates in extracellular (tonic) DA Volkow et al., Biol Psychiatry (2005).
- 6. DAT effects of MP predict subjective effects Positive Effects Pleasurable Mood Happiness Desire Displeasurable Negative Effects Distrust Annoyance Anxiety Volkow et al. Am J Psychiatry (1999). Change in Euphoria Leyton et al. Neuropsychopharm (2002). Drevets et al. Biol Psychiatry (2001).
- 7. DA & Drug Abuse DA metabolism and high are ~50% higher when MP expected Volkow et al., J Neurosci (2003).
- 8. A Dopaminergic Model of Drug Abuse - Block DAT: - Tonic DA (35-fold!!) - Phasic - Withdrawal: corticostriatal input - Further Tonic DA in VTA - Phasic DA positive affect, reinforcement (dysphoria) - DA deficit state requires additional drug to achieve normality phasic-tonic equilibrium Grace Addiction (2000).
- 9. 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) Rate Drug Effects ≒ Single blind - High ≒ Fixed order - Desire for cocaine - Desire for MP - Restlessness - Mood
- 10. Results
- 11. Addicts exhibit oppossit OFC pattern PFC lesions in rats increase sensitivity to cocaine (Schenk, 1991).
- 12. ?
- 13. 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