Neurochemical Basis and Pharmacological Interventions in Addictive Disease
James D. Stoehr, Ph.D.
Professor, Midwestern University PA Program, Glendale, AZ

Take home points:
1. The reinforcing and rewarding properties of all drugs of abuse are due to enhancements in the dopaminergic system. 2. The behavioral loss of control associated with dependence and addiction involves dysfunctions in the ventromedial orbitofrontal and dorsolateral prefrontal cortices. 3. Current neuropharmacologic treatment for drug dependence and relapse prevention include aminergic, GABAergic, and cholinergic medications, as well as peripherally acting medications.
Learning Objectives

• Indentify the neurobiological steps involved in the behavioral progression from drug-induced euphoria, substance use and abuse, chemical dependency, to addiction • Review the neurochemical basis of behavioral reward, reinforcement, compulsion and loss of executive control, using examples of alcohol, amphetamine and opiate dependency • Review the neural structures implicated in relapse and recovery from drug • Explain the neurochemical mechanisms of action of recent medication approved to treat addictive disorders and the role of PAs in overall case management of chemically dependent patients
Signs and Symptoms associated with Substance Abuse

• Loss of natural rewards, Escalation, Loss of control, Time devoted to drug
increases, Tolerance, Withdrawal, Continued harm

Review of Escalation of Use Scale

• Abstinence, experimentation, social/recreational use, habituation, abuse, addiction
Identification of reward pathways

• Intracranial self-stimulation paradigm in laboratory experiments o Electrodes placed in various forebrain areas
o Led to discovery of reward pathways

Ventral Tegmental Area (VTA)
• Axons divide extensively throughout forebrain • Dopamine as neurotransmitter (D1, D2, D3, D4 receptors) • Projections into amygdala, septum, hippocampus, prefrontal cortex and nucleus • All shown to be sensitive to reinforcing brain stimulation Nucleus Accumbens (NAc)
• Located in basal forebrain, rostral to preoptic area, adjacent to septum • Dopamine release associated with subjective experience of pleasure • Involved with reward and reinforcement of ‘survival behaviors’ • In addicted state, is also associated with stress and craving in absence of drug
Review: Mechanisms of action of specific drugs of abuse
• Nicotine, alcohol, cocaine, amphetamines, opiates § VTA, NAc dopamine transporter (DAT), etc. o Psychoactive drugs / other neurotransmitter interactions Summary of regions involved in addiction
• Rate of progression from use to addiction o Depends on genetics (DAT in NAc) o Depends on childhood abuse (corticosteroids) o Depends on specific drug (rate of rise of DA) • Continued use impairs prefrontal cortex o Loss of behavioral control o No regard for consequences of actions
Overview of frontal cortex involvement
o Lesions associated with irresponsible behavior, poor judgment o Cognitive correlates of drug use • Tracking, updating, modulating salience of reinforcement o Controls and inhibits behavioral output • Dysfunctional ventromedial orbitofrontal cortex: o Overvaluing drug reinforcement / reward o Undervaluing alternative reinforcement or consequences of actions / risk • Dysfunctional dorsolateral prefrontal cortex: o Sense of immediate gratification o Overactive in craving state
Limbic Structures implicated in addiction
o Learns about social context associated with drug use o Stimulus / reward associations o May assign motivation value to stimulus o Memories associated with reinforcement o Euphoric recall o Organizes subjective experience of craving o Activated by drug associated cues o Lesions associated with ease of drug discontinuation Integrated Model of Neural Substrates
Neurobiological Correlates of Steps Involved with Addiction and Recovery
Limbic drives supersede cortical control Internal or external signals cause change Drug free state (anti-craving compounds)
Current Biomodel of Relapse

• Stress activates NAc through PFC regions • Context activates NAc through limbic areas (amygdale) Treatment
o Primary care physician or Crisis Center assessment o Specialists: Addictionist (ASAM certified), CSAC o In-patient o Detox (hospital setting) o Rehab (14-28 days or more) o Out-patient o Rehab (Intensive Out-Patient) • Support (family, friends, coworkers)
• Anti-craving compounds (maintenance) Anti-Craving Medication
Mechanism of Action
LAAM burprenorphine/naloxone (Suboxone, Subutex) partial D3 agonists immunological agents
More information on substance abuse:

• National Institute on Alcohol Abuse and Alcoholism • Substance Abuse and Mental Health Services Administration

Source: http://web1.aapa.org/aapaconf2008/syllabus/8096StoehrNeuroaddiction.pdf

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