In this competing renewal application currently in its 9th year of funding we propose to expand our findings of the last funding period to explore new dimensions of polydrug abuse using both electrophysiological and behavioral instruments. Seven specific experiments are planned to address the following: 1) Whether pretreatment with ethanol or marihuana alters the electrophysiological and behavioral components of cocaine-seeking behavior. 2) Whether the presentation of cocaine-related cues to cocaine-dependent subjects elicits changes in brain electrical activity and behavior that are similar to those observed during cocaine-seeking behavior. A related experiment will measure whether tobacco-related cues elicit conditioned responses in cocaine freebase smokers. 3) Whether tobacco-related cues elicit electrophysiological and behavioral responses in tobacco-dependent subjects that are similar to those observed in cocaine-dependent subjects who are exposed to cocaine-related cues. 4) Whether cocaine alone, ethanol alone or cocaine/ethanol combinations disrupt sleep architecture and continuity. A related study will evaluate chronic cocaine freebase smokers for primary sleep disorders. 5) Whether the acute effects of cocaine are different in heavy tobacco smokers as compared to non smokers. Whether pretreatment with a nicotine transdermal patch alters cocaine's acute effects and cocaine self-administration using a choice procedure. 6) Whether ethanol, cocaine or ethano/cocaine combinations increase aggressive behavior and whether estrogen or marihuana pretreatment attenuates the resultant aggressive behavior. 7) What are the neuroanatomical profiles of the alterations in EEG alpha activity and P3 event-related potentials (ERP) associated with drug-seeking behavioral and drug-related cue exposure? Both male and female healthy volunteers will serve as subjects; cocaine- dependent subjects will be recruited from our outpatient treatment program for the cocaine cue studies. The major dependent variables will be brain electrical activity, P3 ERPs, heart rate, skin temperature, subjective reports of intoxication, Addiction Research Inventory scales, visual analog scales, instrumental joystick responding, Point Subtraction Aggression Paradigm for aggressive behavior and reaction time performance. Frequent blood samples will be collected to quantify potential changes in pharmacokinetic parameters. These studies will expand the scope of our understanding of the dynamics of polydrug abuse by examining the factors that contribute to multiple drug use with tools that are sensitive to the subtle but reproducible changes in brain activity and behavior associated with drug reinforcement. Our observations that tobacco and cocaine share many common features helped to shape our current strategy of evaluating pharmacotherapies that is a departure from the currently popular theme of studying drugs that alter dopamine and/or serotonin systems. It is anticipated that information obtained in the present series of experiments will be useful in understanding the mechanism of polydrug abuse, identifying factors that support polydrug abuse and to designing completely new strategies for treating polydrug abuse and dependence.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA003994-14
Application #
6164343
Study Section
Special Emphasis Panel (SRCD (26))
Program Officer
Gordon, Harold
Project Start
1992-03-01
Project End
2002-02-28
Budget Start
2000-03-01
Budget End
2002-02-28
Support Year
14
Fiscal Year
2000
Total Cost
$455,201
Indirect Cost
Name
Mc Lean Hospital (Belmont, MA)
Department
Type
DUNS #
City
Belmont
State
MA
Country
United States
Zip Code
02478
Lukas, Scott E (2014) New perspectives on using brain imaging to study CNS stimulants. Neuropharmacology 87:104-14
Penetar, David M; Lindsey, Kimberly P; Peters, Erica N et al. (2012) Decreasing Nicotine Content Reduces Subjective and Physiological Effects of Smoking. Tob Use Insights 5:1-9
Lindsey, K P; Lukas, S E; MacLean, R R et al. (2009) Design and validation of an improved nonferrous smoking device for self-administration of smoked drugs with concurrent fMRI neuroimaging. Clin EEG Neurosci 40:21-30
Frederick, Blaise deB; Lindsey, Kimberly P; Nickerson, Lisa D et al. (2007) An MR-compatible device for delivering smoked marijuana during functional imaging. Pharmacol Biochem Behav 87:81-9
Lundahl, Leslie H; Lukas, Scott E (2007) Negative cocaine effect expectancies are associated with subjective response to cocaine challenge in recreational cocaine users. Addict Behav 32:1262-71
Cowan, Ronald L; Bolo, Nicolas R; Dietrich, Mary et al. (2007) Occipital cortical proton MRS at 4 Tesla in human moderate MDMA polydrug users. Psychiatry Res 155:179-88
Hopper, James W; Su, Zhaohui; Looby, Alison R et al. (2006) Incidence and patterns of polydrug use and craving for ecstasy in regular ecstasy users: an ecological momentary assessment study. Drug Alcohol Depend 85:221-35
Anderson, Carl M; Maas, Luis C; Frederick, Blaise deB et al. (2006) Cerebellar vermis involvement in cocaine-related behaviors. Neuropsychopharmacology 31:1318-26
Lowen, Steven B; Lukas, Scott E (2006) A low-cost, MR-compatible olfactometer. Behav Res Methods 38:307-13
Penetar, David M; Looby, Alison R; Su, Zhaohui et al. (2006) Benztropine pretreatment does not affect responses to acute cocaine administration in human volunteers. Hum Psychopharmacol 21:549-59

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