Individual differences in neurobehavior and drug abuse prevention

Transcription

1 Washington University School of Medicine Digital Presentations 2009: Translating Basic Science Findings to Guide Prevention Efforts 2009 Individual differences in neurobehavior and drug abuse prevention Michael T. Bardo University of Kentucky Follow this and additional works at: Part of the Medicine and Health Sciences Commons Recommended Citation Bardo, Michael T., "Individual differences in neurobehavior and drug abuse prevention" (2009). Presentations. Paper 1 Samuel B. Guze Symposium on Alcoholism. This Presentation is brought to you for free and open access by the 2009: Translating Basic Science Findings to Guide Prevention Efforts at Digital Commons@Becker. It has been accepted for inclusion in Presentations by an authorized administrator of Digital Commons@Becker. For more information, please contact engeszer@wustl.edu.

2 Individual Differences in Neurobehavior and Drug Abuse Prevention Michael T. Bardo, PhD Professor of Psychology and Director Center for Drug Abuse Research Translation (CDART)

3 Disclosure Statement Michael T. Bardo University of Kentucky The 9th Annual Guze Symposium on Alcoholism February 19, 2009 Source of research support: P50 DA05312, R01 DA12964 and R01 MH63705 Consulting relationships: None commercial Stock equity: Yaupon Therapeutics Speaker s Bureaus: None commercial

4 Outline 1. Overview 2. Preclinical Experiments with Rats 3. Controlled Experiments with Human Subjects 4. Translation to Drug Abuse Prevention

5 Center Mission Translate basic neurobehavioral research findings into small-scale efficacy trials to enhance the impact of anti-drug prevention messages.

6 Conceptual Framework Basic Research Prevention Research Mesolimbic Dopamine Reward System & Drug Reward Sensation Seeking Alternative Activities & Designing Public Service Announcements (PSAs)

7 Sensation Seeking Personality trait characterized by a need for novel, complex, ambiguous and emotionally intense stimuli and by a willingness to take risks to obtain such stimulation. (Zuckerman, 1988)

8 Sensation Seeking and % Drug Use In Last 30 Days Among Junior and Senior High School Students in Fayette County Drug Category Grade 6-8 Grade 6-8 Grade 9-12 Grade 9-12 Low SS High SS Low SS High SS (n=658) (n=565) (n=450) (n=420) Marijuana Cocaine Liquor Beer Stimulants Sedatives

9 Hypothesis High sensation seekers are biologically predisposed to be at risk for drug abuse.

10 Reward System Inhibition System Stress System NAcc VTA ACC OFC NAcc PVN Amyg Pit ACTH cortisol adrenal gland mpfc = medial prefrontal cortex VTA = ventral tegmental area OFC = orbitofrontal cortex Pit = pituitary gland ACTH = adrenocorticotropic hormone NAcc = nucleus accumbens ACC = anterior cingulate cortex PVN = paraventricular nucleus Amyg = amygdala

11 Outline 1. Overview 2. Preclinical Experiments with Rats 3. Controlled Experiments with Human Subjects 4. Translation to Drug Abuse Prevention

12 Sensation Seeking in Rats

13 Drug Self-Administration Method Male Sprague-Dawley rats, g. Food restriction to 85% normal body weight Shape to lever press for sucrose pellet Free feed for one week Implant jugular catheter One week recovery Initiate drug self-administration All procedures approved by University of Kentucky IACUC and conformed to NIH Guide (1996).

14 High Novelty Responders Self-Administer More Amphetamine Than Low Novelty Responders 250 Males Females Number of Responses HR Active Lever LR Active Lever HR Inactive Lever LR Inactive Lever Sessions Sessions

15 Enhanced Amphetamine Self-Administraiton in High Responders Involves the Central Nucleus of Amygdala NUMBER OF INFUSIONS NUMBER OF INFUSIONS A 30 HR Muscimol Vehicle * * S AMPHETAMINE DOSE (mg/kg/inf) B 30 LR Muscimol Vehicle S AMPHETAMINE DOSE (mg/kg/inf)

16 Amphetamine Infusions Novelty Seeking and Amphetamine Self- Administration are Linked Genetically Free-Choice Novelty vs. Amphetamine Self-Administration DSS WKY r=0.601 SHR p<0.05 WAG ACI 8 BUF LEW 6 4 WF FH BN 2 F344 0 BD Novelty Place Preference

17 Environmental Influence in Relation Between Novelty Seeking and Amphetamine Reward Enriched Condition (EC) Isolated Condition (IC) GET ENRICHED!!!

18 IC Rats Respond More for Novel Visual Stimulus No Novelty EC active IC active EC inactive IC inactive Novelty No Novelty Responses Session

19 IC Rats Self-Administer More Amphetamine on PR Schedule Mean Amphetamine Infusions mg/kg/infusion EC SC IC 0.1 mg/kg/infusion EC SC IC Treatment

20 IC Rats have Greater Amphetamine-induced Increase in Plasma Corticosterone 15 min 60 min 180 min

21 DOPAC content (ng/mg tissue) IC Rats have Increased Basal Tissue DOPAC Levels in mpfc, but not in Striatum or Nucleus Accumbens EC IC * mpfc 0.0 STR Brain region NAC

22 V max (pmol/min/mg) DA Clearance (DA Peak Amplitude/55 min) IC Rats have Increased Uptake of Dopamine in mpfc In vitro synaptosomes In vivo voltammetry * EC IC EC IC mpfc 10 0 STR Brain region NAC * mpfc

23 DAT Immunoreactivity (10 3 arbitrary units) IC Rats have Increased Cell Surface Expressed DAT Protein in mpfc 30 EC IC * 0 Total (I) Intracellular (II) Surface (III) I II III EC IC EC IC EC IC 75 kda DAT 34 kda Syntaxin 1A 92 kda 34 kda Calnexin PP2A-A

24 IC Rats have Increased DAT Function in Prefrontal Cortex Compared to EC Rats DOPAC DOPAC DOPAC DOPAC DOPAC DOPAC DA DA DA DA DA DA DA DA DA DA DA DA DA DA EC IC

25 Summary from Preclinical Experiment in Rats Relationship between novelty seeking and amphetamine self-administration is determined by both genetic and environmental factors. High novelty seekers are more sensitive to the reinforcing effect of amphetamine. High novelty seekers have a deficit in inhibitory control. High novelty seekers have overactive stress axis, which may involve alterations in amygdala and prefrontal cortex.

26 Outline 1. Overview 2. Preclinical Experiments with Rats 3. Controlled Experiments with Human Subjects 4. Translation to Drug Abuse Prevention

27 High Sensation Seekers Like Amphetamine More than Low Sensation Seekers Low Sensation-Seekers High Sensation-Seekers Amphet amine (mg/ 70 kg) Hour Post Dose

28 Number of Responses High Sensation Seekers Self-Administer Amphetamine More than Low Sensation Seekers High Sensation Seekers Low Sensation Seekers Break Point PLB 1 mg 2 mg d-amphetamine Dose Per Capsule

29 Hypothesis If high sensation stimuli and drugs of abuse activate common brain systems then brain reactivity to high sensation stimuli will be greater in high sensation seekers than in low sensation seekers. Novelty Detection Emotional Arousal

30 Explore responses to emotional content During brain imaging session, view a series of pictures Low arousal, positive valence High arousal, positive valence Low arousal, negative valence Press a button each time a picture appears High arousal, negative valence

31 High Sensation Seekers Low Sensation Seekers Right Insula: Autonomic arousal, cravings

32 High Sensation Seekers Low Sensation Seekers Left ACC: Emotional regulation, cognitive control

33 Summary of Controlled Experiments with Human Subjects Abuse liability of d-amphetamine is greater in high sensation seekers. With emotionally arousing images: High sensation seekers engage arousal region (insula) quickly, followed by emotional regulation region (anterior cingulate cortex). Low sensation seekers engage primarily emotional regulation region only (anterior cingulate cortex).

34 Outline 1. Overview 2. Preclinical Experiments with Rats 3. Controlled Experiments with Human Subjects 4. Translation to Drug Abuse Prevention

35 Communication Connection Sensation seeking and message sensation value

36 Message Sensation Value High Sensation-Seekers tend to prefer the following message characteristics: Novel, creative, or unusual Intense (strong sound and visual effects) Emotionally strong Physically Arousing (exciting, stimulating) Fast-paced Graphic or explicit Absence of preaching Unconventional

37 2-City Anti-Marijuana Campaign Study: Message Content Targeted HSS PSAs focused on scientifically-documented negative consequences of marijuana use that HSS teens saw as important (in focus group research) Damaged relationships with family and friends Decreased academic and sports performance Loss of part-time jobs Impaired memory and judgments Reduced motivation Depression Lung damage

38 Michael

39 Downer

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42 Safer Sex Mass Media Campaign Targeting Young Adults

43 My Story 2

44 Translation

45 Preliminary Study: Brain Response to Anti- Drug and Safe Sex PSA s HSS>LSS in temporal poles HSS<LSS in hippocampus High SS Low SS (a) (c) (e) (b) (d) (f)

46 Summary from Translational Field-Based Experiments Marijuana use can be significantly reduced among adolescents Condom use can be increased among young adults Preliminary results suggest that high sensation value anti-drug and safe sex PSAs produce greater frontal pole activation and less hippocampal activation among high sensation seekers

47 Acknowledgements R. Lewis Donohew Philip Palmgreen Nancy Harrington Linda Dwoskin Rick Zimmerman Catherine Martin Richard Milich Mark Fillmore Jane Joseph Yang Jiang Richard Kryscio George Rebec (Indiana Univ) Jun Zhu Dustin Stairs Thomas Kelly Elizabeth Lorch Rick Hoyle Derek Lane Pamela Cupp Seth Noar Richard Clayton William Stoops Richard Charnigo Donald Lynam (Purdue Univ) Andrew Meyer Emily Denehy Thomas Green Mary Cain Supported by USPHS grants P50 DA05312, R01 DA12964 and R01 MH63705