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Impaired Prefrontal Cortex Function
Seminars in Addiction
J. David Jentsch, Ph.D.Department of Psychology (Behavioral
Neuroscience)
Early Neurobiological/Psychological Models of Addiction
• Locus coeruleus– Somatic and affective withdrawal
• Dopamine and nucleus accumbens– Reinforcement learning/instrumental models– Opponent process theories
• Extended amygdala– Incentive motivation/cue control
• None emphasize, nor even directly address, the concept of conflict.
Why Conflict?
• "continued [substance abuse] despite knowledge of having a recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance" (DSM-IV)
Important Types of Conflict
• Immediate (“go”)– Regulating pre-potent responses– Evaluating USs and actions that have mixed effects or
consequences– Determining how to spend limited resources on the
reinforcers available (closed economy system)
• Delayed (“stop”/”wait”)– Appreciating delayed outcomes (whether positive or
negative)– “Trickle down” effects; temporal competition between
reinforcers/saturation effects– Balancing long-term gains and costs
Conflict Resolution
• "continued [substance abuse] despite knowledge of having a recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance" (DSM-IV)
• Interaction between declarative and implicit memory systems– Knowing versus doing– Gating conditioned, habitual behavior based upon
declarative knowledge, conditional rules, working memory, attentional sets, etc.
Prefrontal Cortex
• Lesions of PFC lead to dissociable forms of failure to resolve conflict– Medial frontal cortex: failure to extinguish a
conditioned response; abolishment of food preferences
– Orbitofrontal cortex: impairments in reversal learning, go/no-go, stop signal RT tasks, decision making
– DLPFC: attentional set shifting; WCST
Prefrontal Cortex is Abnormal in Addicts
• Metabolically
• Structurally
• Neurochemically
• Functionally
• Particularly, medial and orbital cortices
An “Inhibitory Control” Model for Addiction
Theoretical Construct
• Incentive sensitization (mediated by extended amygdala and striatal circuits) is not tempered or suppressed by descending cortical fibers normally required for the suppression of habitual, reward-related responses.
Drug Abusers Can Not Use Conflict to Guide their Decision Making
• Young polysubstance abusers
• Iowa Gambling Task• “Optimal”
performance requires switching from selecting high gain/high loss decks to low gain/low loss (but more profitable) decks.
Grant, Contoreggi, London (2000) Neuropsychologia 38: 1180-1187
Cambridge Risk Task
• Requires the subject to balance risk versus likelihood of reward.
• Control tasks include a working memory loaded task and a visuomotor control procedure.
• Amphetamine abusers exhibited somewhat less optimal responses in the risk task and somewhat poorer accuracy in the working memory task.
• Opiate abusers did not differ from controls.
Ersche et al. (2005) Psychopharmacol., in press (Online First)
Cambridge Risk Task
• Higher right DLPFC blood flow in controls.• Higher left orbitofrontal blood flow in addicts
(including “ex”-addicts.• Also from Ersche et al. (2005)
Stop-Signal RT Task
• Chronic cocaine abusers are impaired on the SSRTT.
• They are less capable of “stopping” a response when cued to do so.
• This mirrors the pattern of effects seen in individuals with damage to right inferior frontal cortex.
Fillmore and Rush (2002) Drug Alcohol Dep., 66: 265-273
Multiple Forms of Inhibitory Control Loss in Addiction
• Attention set shifting
• Decision making
• Reversal learning (response switching)
• SSRTT (response stopping)
Dackis and O’Brien (2005)
• “Denial, a hallmark of cocaine addiction, classically involves minimization, rationalization, and poor insight into cocaine-related hazards.”
• “These examples of nonadaptive executive function could stem from cocaine-induced PFC imbalances, as might problems with decision-making, impulse control, and motivation that are characteristic of cocaine-addicted patients.”
• “we believe that PFC dysfunction may also be a core component of cocaine addiction, and contribute to many baffling characteristics of addicted patients that were once thought to be purely psychological.”
Unanswered Questions
• Do impairments of PFC function represent an underlying dispositional factor that acts as a risk factor for substance abuse?
• Or is it a consequence of usage, in turn supporting the compulsiveness of the disease?
Inhibitory Control Deficits RESULT from Stimulant Exposure
• Young, adult Vervet monkeys
• Two weeks exposure to cocaine (BID dosing)
• Tested on a three object visual discrimination task, with reversal
• These data represent performance 30 days displaced from the drug
Jentsch et al. (2002) Neuropsychopharmacol., 26:
183-190
Effects of Orbitofrontal Cortex Lesions are Mimicked by:
• Chronic cocaine
• Chronic amphetamine
• Chronic methamphetamine
• Chronic MDMA
• Chronic phencyclidine
• Chronic delta-9-tetrahydrocannabinol
• Chronic alcohol
Neurochemical Substrates of Impaired PFC Function
• Cortical dopamine depletion
• Partial serotonin depletion
• Striatal dopamine hyperactivity– Consequence of both
Cortical Dopamine Depletion
• Deficits in inhibitory control are associated with a decrease in cortical dopamine tone in chronic PCP treated monkeys.
• Activation of dopamine transmission, cortically, remediates these deficits. Jentsch et al. (1999) Neurosci.,
90: 823-832
Cortical Monoamine Depletion
• Visuospatial attention deficits (associated with more dorsomedial frontal cortex) in chronic delta-9-THC-exposed rats were ameliorated by activation of monoamine systems.
Verrico, Jentsch, et al. (2004) Neuropsychopharmacol., 29:
522-529
Dopamine D1 Agonists
• Reduce relapse in animal models of cocaine abuse
• Block sensitization when infused directly into the PFC of cocaine-exposed rats
• Remediate cognitive deficits in certain animal models of addiction
Limitations
• All dopamine D1 receptors are catechols and have extraordinarily poor pharmacokinetic profiles
• D1 receptor agonists produce desensitization of post-synaptic receptors after only a few administrations
• D1 agonists can be emetic
ABT-431 (Adrogolide)
• Pro-drug for A-86929
• About 400x more potent for the D1 vs. D2 family
• Low oral availability (<4%)
• Little tolerance