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

Ersche et al. (2005) Psychopharmacol., in press (Online First) 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)

Fillmore and Rush (2002) Drug Alcohol Dep., 66: 265-273 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