1. Drug Addiction Part II Karen Revere Kian Eftekhari Will Hiesinger

2. Clinical Case Patient from last week continues to smoke crack cocaine First he smokes only at parties Then it becomes a daily habit Gets caught stealing money from friends Drops out of college

3. Clinical Case His parents make him go to rehab, which he does for 6 weeks Patient is doing well, but one day he meets up with friends from college, and smokes crack because he thinks “one time won’t hurt” He begins using crack daily again After a fight one night, he’s taken to the ER

4. Clinical Exam in ER Hypertension, Tachycardia Nystagmus (abnormal eye movement) Mild ataxia (unsteady, clumsy limb motion) Finger-to-nose dysmetria Postural tremor Unsteady gait

5. Ataxia Poor tandem gait from gait ataxia

6. Appendicular Ataxia Intention tremor Dysdiadochokinesia Dysmetria on HTS testing Dysmetria in UEs

7. Cocaine increases synaptic dopamine (DA) levels by blocking the dopamine transporter (DAT) REVIEW: Neurobiology of Cocaine Euphoria Courtesy of Charles A. Dackis, MD Pre-Synaptic Neuron Post-Synaptic Neuron Dopamine Receptor Dopamine Re-uptake Transporter Dopamine

8. DSM IV: Substance Dependence Maladaptive pattern of drug use –Withdrawal –Tolerance –More use than intended (loss of control) –Unsuccessful efforts to quit –Significant time spent in procurement –Functional impairment –Continued use in the face of adverse effects Courtesy of Charles A. Dackis, MD

9. Cocaine Euphoria Positive Reinforcement Activated Reward Pathways  DA Cocaine Craving Negative Reinforcement  DA Cocaine Administration Drug-Seeking Behavior Failed Impulse Suppression Multiple Risks/Hazards Reward Dysregulation Cocaine Withdrawal  DA Cocaine Cues Limbic Activation  DA Loss of Control Denial / Poor Decision-Making Reduced Gray Matter Density Stress - + Dynamic Cycle of Cocaine Addiction Dynamic Cycle of Cocaine Addiction Cocaine Courtesy of Charles A. Dackis, MD

10. Brain Pleasure Centers Addictive drugs initially stimulate and later disrupt natural pleasure centers in the brain Courtesy of Charles A. Dackis, MD EXECUTIVE FUNCTION -Decision-making -Weighing of risks vs. benefits -Assigning emotional value to stimuli -Suppressing emotional impulses -Goal-directed behaviors -social "control" (the ability to suppress urges that, if not suppressed, could lead to socially unacceptable or illegal outcomes). Responsible for the rewards of drug use, sex, feeding and drinking.

11. Cocaine Withdrawal Symptoms ________________________________________________________________________________________ Hypersomnia (Lots of sleep) Depression Hyperphagia (Lots of eating) Slow moving and thinking Poor concentration Anergia (Lack of energy; inactivity) Craving? Courtesy of Charles A. Dackis, MD

12. Elements of the drug environment (people, places, and things) that are associated with cocaine have the remarkable ability to stimulate intense craving. Patients feel intense craving when they encounter these stimuli, which often leads directly to relapse. The only treatment that is currently available for cue reactivity is cue avoidance - an objective that is often difficult to attain. Cue-Induced Cocaine Craving Courtesy of Charles A. Dackis, MD

13. Amygdala Cocaine Video Anterior Cingulate 1.5 0.5 1.0 2.0 2.5 Childress, et al. AJP, 1999 Brain Changes During Cocaine Craving Courtesy of Charles A. Dackis, MD

14. Neuroimaging Studies of Cue Craving Robust limbic activation (PET & fMRI) - many studies Amygdala – plays a primary role in the formation and storage of memories associated with emotional events and is also important in classical conditioning. Anterior cingulate – Plays a role in rational cognitive functions, such as reward anticipation, error detection, decision-making, empathy and emotion. Craving intensity correlates with limbic activation Same regions activated by sexually explicit videos (Cocaine hijacks sex reward circuits) Courtesy of Charles A. Dackis, MD