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