1. c2004 Alcohol Medical Scholars Program1 Craving Karen Drexler, M.D. Emory University School of Medicine

2. c2004 Alcohol Medical Scholars Program2 Overview What is craving? Why is it so compelling? What are the neural mechanisms that drive craving? How does knowing neurobiology inform my clinical practice?

3. c2004 Alcohol Medical Scholars Program3 Features Intense desire Many components 3 types –Withdrawal-induced –Drug-induced –Cue-induced Compels drug-seeking in dependent individuals

4. c2004 Alcohol Medical Scholars Program4 DSM-IV Dependence 3 or more of the following: Tolerance Withdrawal Larger amounts than intended Persistent efforts to cut down or control A great deal of time spent getting the substance, taking it, or recovering Important activities given up Continued use despite psychological or physical problem exacerbated by use

5. c2004 Alcohol Medical Scholars Program5 Non-problematic use Liking Wanting Abuse Craving Dep Desire Corresponds With Drug Use

6. c2004 Alcohol Medical Scholars Program6 Overview What is craving? Why is it so compelling?

7. c2004 Alcohol Medical Scholars Program7 Why is Craving So Compelling? Correlates with other measures of substance dependence Better understanding may lead to better treatment

8. c2004 Alcohol Medical Scholars Program8 Overview What is craving? Why is it so compelling? What are the neural mechanisms that drive craving?

9. c2004 Alcohol Medical Scholars Program9 Neural Mechanisms FeatureNeural substrate Sensitization of motivation Mesocorticolimbic dopamine pathway Inhibition of behaviorPrefrontal cortex (PFC)- lateral Associative learningAmygdala (medial temporal lobe)

10. c2004 Alcohol Medical Scholars Program10 Mesocorticolimbic Pathway Ventral tegmental area Nucleus accumbens Anterior cingulate Subcallosal cortex

11. c2004 Alcohol Medical Scholars Program11 Prefrontal - Limbic Inhibition Nucleus accumbens Lateral Orbitofrontal cortex Dorsolateral PFC

12. c2004 Alcohol Medical Scholars Program12 Amygdala – Limbic Connections Nucleus accumbens Amygdala Medial PFC

13. c2004 Alcohol Medical Scholars Program13 Neural Mechanisms FeatureNeural substrate Sensitization of motivation Mesocorticolimbic dopamine pathway Inhibition of behaviorPrefrontal cortex (PFC)- lateral Associative learningAmygdala

14. c2004 Alcohol Medical Scholars Program14 Neuroimaging in Humans Confirm these hypotheses Two types of provocation –Drug-induced –Cue-induced

15. c2004 Alcohol Medical Scholars Program15 Drug-induced Craving High Craving

16. c2004 Alcohol Medical Scholars Program16 Drug-induced Craving StructurePossible function Mesocorticolimbic pathway (NAcc, SCC, medial OFC) Reward / Motivation +/- Amygdala Memory / Learning

17. c2004 Alcohol Medical Scholars Program17 Cue-induced Craving Widely distributed cortical activations –Temporal lobe (Amygdala) –Frontal cortex (DLPFC, OFC) Less often mesolimbic pathway

18. c2004 Alcohol Medical Scholars Program18 Cue-induced Craving StructurePossible function Prefrontal cortexExecutive function Lateral OFCInhibition / planning AmygdalaAssociative learning Mesocorticolimbic pathway Reward / motivation

19. c2004 Alcohol Medical Scholars Program19 Garavan et al, 2000 Cue-induced Craving Associated  in BOLD fMRI Dorsolateral Prefrontal Medial Prefrontal Ant Cingulate Post Cingulate

20. c2004 Alcohol Medical Scholars Program20 Amygdala Activation to Ethanol Cues Before and After Treatment Before treatmentAfter treatment Schneider et al, 2001 Amygdala

21. c2004 Alcohol Medical Scholars Program21 LeftRight -34 mm -19 mm -9 mm +34 mm +19 mm +9 mm insula anterior cingulate amygdala subcallosal cortex nucleus accumbens area Neural Correlates of Cocaine Cue-induced Craving

22. c2004 Alcohol Medical Scholars Program22 Drug-induced vs Cue-induced Craving Drug-inducedCue-induced Mesocorticolimbic pathway (+/-) AmygdalaAmygdala Prefrontal cortex

23. c2004 Alcohol Medical Scholars Program23 Overview What is craving? Why is it so compelling? What are the neural mechanisms associated with craving? How does this affect my clinical practice?

24. c2004 Alcohol Medical Scholars Program24 Implications for Treatment Appreciation that substance dependence is a brain disease Cognitive behavioral therapy Medications

25. c2004 Alcohol Medical Scholars Program25 Craving Summary Intense desire that compels use in dependent individuals Associated neural circuits involved in: –Reward –Cognitive control –Learning Treatment targeting craving may improve outcome