The Neuroscience of Addiction: A mini-review Jim Morrill, MD, PhD MGH Charlestown HealthCare Center Massachusetts General Hospital
Disclosures Neither I nor my spouse/partner has a relevant financial relationship with a commercial interest to disclose.
Why review addiction neurobiology? 1) To better understand the complex relationship between addiction and free choice in our patients 2) To understand (and innovate) effective treatments 3) To continue changing the culture toward clinical and scientific optimism!
Framework for addiction Genetic Loading Physiologic Tolerance and Withdrawal Impaired Cognition and Control Risk and Protective Factors Choice Drug Use Neurobiological Changes Environment Medical Drug-related Morbidity Hijacked Salience Detection Psychosocial Substance Use Disorder
Framework for recovery Genetic Loading Physiologic Tolerance and Withdrawal Impaired Cognition and Control Risk and Protective Factors Choice Drug Use Neurobiological Changes Environment Medical Drug-related Morbidity Hijacked Salience Detection Psychosocial Substance Use Disorder
Anatomy of the salience (wanting) pathway Human brain, midline view Brain showing corpus striatum Head of caudate nucleus Thalamus Globus pallidus Putamen Amygdaloid nucleus Tail of caudate nucleus Biological Psychology, Sinauer Associates, 2010 http://medicalterms.info/anatomy/basal-nuclei/
Prefrontal cortex Human Brain Nucleus accumbens Ventral tegmental area Cortex Rat Brain Anatomy of the salience (wanting) pathway From Hyman and Malenka (2001) Nat Rev: Neurosci 2: 695. Nucleus accumbens Ventral tegmental area
The ventral striatum may be the seat of decisions about salience Striatal medium spiny neurons receive wide input from the cortex and limbic system Medium Spiny Neurons These neurons give output to the motive centers of the basal ganglia (the ancient brain which drives motor activation) They integrate information into a neural decision to allow or inhibit action Cellular basis of memory for addiction. Eric J. Nestler, MD, PhD. Dialogues Clin Neurosci. 2013;15(4):431-443. http://www.dialogues-cns.com/?post_type=publication&p=34119
The ventral striatum may be the seat of decisions about salience Rat Brain The brain reward circuitry in mood disorders. Scott J. Russo & Eric J. Nestler. Nature Reviews Neuroscience 14, 609 625 (2013) doi:10.1038/nrn3381. http://www.nature.com/nrn/journal/v14/n9/abs/nrn3381.html
The ventral striatum may be the seat of decisions about salience The function of ventral striatal neurons is modulated by dopamine supplied by midbrain neurons Dopamine provides a salience signal to highlight survival-relevant natural stimuli In rats, the behavior-shaping properties of addictive drugs depends on dopamine signaling in this brain region.
Natural stimuli evoke controlled dopamine signals Dopamine secretion in the nucleus accumbens after a food stimulus Shutterstock stock photo From Di Chiara et al. (1999) Eur J Pharmacol 375: 13.
From Di Chiara and Imperato (1988) PNAS 85: 5274. Addictive drugs evoke exaggerated dopamine signals Response to amphetamine Dopamine vs. control dialysate Response to cocaine
Why do addictive drugs become more compelling than natural stimuli? Natural Stimulus DRUG Processing Dopamine Signaling Shaping of Behavior Context
Changes in neuronal structure and function Repetitive Dopamine input to striatal neurons can evoke long lasting modifications of their synaptic connections through changes in gene expression. From Chao and Nestler (2004) Annu Rev Med 55: 113. Changes in neuron structure Changes in neuron communication From Robinson and Kolb (1999) Eur J Neurosci 11: 1598. From Nicola et al. (1996) J Neurosci 16: 1591.
Persistence of addiction may depend on very long-lasting molecular signals FOS-related antigens (FRAs), such as ΔFosB : Very long-lasting proteins induced inside neurons by exposure to dopamine Last for weeks to months, and correlate with changes in neuron structure and function When activated in the neurons of transgenic mice, these proteins can transplant cocaine-addicted behavior into unexposed mice (Kelz et al., 1999) From Nestler (2001) Nature Rev: Neurosci 2: 119.
Epigenetics and molecular memory in addiction DNA Modifiers From Nestler (2013) Dialogues in Clinical Neuroscience 15: 431.
Epigenetic changes and synergistic effects of nicotine and cocaine Summary slide used with persmission from Dr. Susan Weiss, NIDA.
Addictive substances activate the human salience (wanting) pathway Mapping the dynamic response to an IV cocaine infusion with fmri From Breiter et al. (1997) Neuron 19: 591.
From Breiter et al. (1997) Neuron 19: 591. Addictive substances activate the human salience (wanting) pathway From Breiter et al. (1997) Neuron 19: 591.
Addictive substances activate the human salience (wanting) pathway KEY: AC and PC = ant, post cingulate; Cau = caudate; Put = putamen; Thal = thalamus; Hip = hippocampus; Pahip = parahippocampus; BF = basal forebrain; VT = ventral tegmentum; NAc = nucleus accumbens; Amy = amygdala. From Breiter et al. (1997) Neuron 19: 591.
Framework for Addiction Genetic Loading Physiologic Tolerance and Withdrawal Impaired Cognition and Control Risk and Protective Factors Choice Drug Use Neurobiological Changes Environment Medical Drug-related Morbidity Hijacked Salience Detection Psychosocial Substance Use Disorder
Multiple neural systems are now implicated in addiction INHIBITORY CONTROL HABIT FORMATION REWARD SALIENCE MOTIVATION DRIVE MEMORY/ LEARNING From NIDA slide set (www.nida.gov) From NIDA slide set www.nida.gov
Imaging studies show frontal cortex changes in cocaine addicts PET scans done in control subjects and chronic cocaine users. A chronic decrease in the density of Dopamine (D2) receptors (a) correlates with a decrease in regional brain metabolism in the orbitofrontal cortex (b). Suggests structural change / damage to key cortical structures involved in motivation and inhibitor control. From Volkow and Li (2004) Nat Rev Neurosci 5: 963.
The IRISA syndrome (Impaired Response Inhibition and Salience Attribution) Prefrontal cortex functions that may be damaged by addiction: Motivation and task persistence Behavioral control Emotional regulation Self-awareness and insight Flexible attention and memory
The IRISA syndrome (Impaired Response Inhibition and Salience Attribution) From Goldstein and Volkow (2011) Nat Rev Neurosci 12: 652.
A grand unified theory of addiction: roles of three brain circuits From: Koob and Volkow (2010) Neuropsychopharmacol Rev 35: 217.
Framework for recovery Genetic Loading Physiologic Tolerance and Withdrawal Impaired Cognition and Control Risk and Protective Factors Choice Drug Use Neurobiological Changes Environment Medical Drug-related Morbidity Hijacked Salience Detection Psychosocial Substance Use Disorder
Framework for recovery Detoxification Opioid Maintenance Therapy (Agonist, Partial agonist, Antagonist) Choice Physiologic Tolerance and Withdrawal Drug Use Impaired Cognition and Control Neurobiological Changes Individual and group therapy: MET, CBT and DBT Contingency management Neurotransmitter antagonists Anti-epileptic drugs Cocaine / Nicotine vaccines? Transcription factor or epigenetic manipulations? Hijacked Salience Detection
Framework for recovery Genetic Loading Wraparound care: Social support Therapeutic communities Self-help Risk and Protective Factors Choice Drug Use Prevention Strategies Strategies for Reduction of Negative Consequences Environment Medical Drug-related Morbidity Substance Use Disorder Psychosocial Primary Medical and Psychiatric Care
From: Volkow et al. (2001) J Neurosci 21: 9414. From: Volkow and Li (2004) Nat Rev Neurosci 5: 963. THANK YOU! Questions?