This is a competing continuation application to identify and evaluate potential treatment medications for cocaine abuse and dependence in preclinical studies. Cocaine abuse is a significant public health problem and the development of effective anti-cocaine medications is a high priority for NIDA. The proposed interdisciplinary studies will involve pharmacology, medicinal chemistry, and behavioral science. The overall goal is to provide an empirical basis for translation of novel medication approaches into clinical treatment. The novel medications proposed for study are based on our discoveries during the past project period, and on recent findings from clinical studies. Agonist medications that mimic cocaine's interactions with the mesolimbic dopamine system may also produce selective and sustained decreases in the abuse-related effects of cocaine. However, the challenge is to identify long acting agonists with minimal abuse liability or other adverse side effects. We have found that two classes of compounds, non-selective monoamine releasers and mixed action mu/kappa agonists, each effectively reduce cocaine self-administration. We hypothesize that systematic manipulation of the relative ratio of dopamine to serotonin activity and the relative ratio of mu to kappa opioid activity may produce optimal monoaminergic and mixed action mu/kappa medications. We propose to study the effects of monoamine releasers, monoamine reuptake inhibitors and a novel stimulant, modafinil, as well as mu/kappa mixtures on cocaine self-administration and discrimination. Complementary behavioral procedures are proposed to provide a comprehensive evaluation of the effects of novel medications on the abuse-related effects of cocaine. Complete cocaine dose-effect curves will be studied in each procedure. Drug discrimination procedures will be used to characterize the potency, time course and cocaine-like stimulus characteristics of novel compounds. Medications will be administered chronically to model clinical treatment paradigms, and to determine the stability of treatment medication effects, the duration of any adverse side effects, and to monitor medication withdrawal signs when treatment is discontinued. The relative selectivity of medication effects will be determined in a Second Order Schedule of cocaine- and food- maintained responding. A Progressive Ratio procedure will be used to compare those treatment drugs that selectively reduce cocaine self-administration to determine the extent to which they alter the reinforcing efficacy of cocaine. This research will suggest new medication-based approaches to treatment of this serious and pervasive addictive disorder.

Public Health Relevance

Cocaine abuse is a significant public health problem and the development of effective anti-cocaine medications is a high priority for NIDA. We propose interdisciplinary preclinical studies of two novel medication approaches to cocaine abuse treatment, based in part on our discoveries during the past project period. Medicinal chemist collaborators will synthesize mixed action mu/kappa medications and novel monoaminergic medications for this project. The effectiveness of these novel medications for reducing the abuse-related effects of cocaine will be evaluated in powerful drug self-administration and drug discrimination procedures that have excellent predictive validity for translation into clinical treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA002519-27
Application #
8261987
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Acri, Jane
Project Start
1979-12-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
27
Fiscal Year
2012
Total Cost
$386,521
Indirect Cost
$146,446
Name
Mclean Hospital
Department
Type
DUNS #
046514535
City
Belmont
State
MA
Country
United States
Zip Code
02478
Mello, Nancy K; Fivel, Peter A; Kohut, Stephen J et al. (2014) Effects of chronic varenicline treatment on nicotine, cocaine, and concurrent nicotine+cocaine self-administration. Neuropsychopharmacology 39:1222-31
Cordova, David; Huang, Shi; Lally, Meghan et al. (2014) Do parent-adolescent discrepancies in family functioning increase the risk of Hispanic adolescent HIV risk behaviors? Fam Process 53:348-63
Mello, Nancy K; Fivel, Peter A; Kohut, Stephen J (2013) Effects of chronic buspirone treatment on nicotine and concurrent nicotine+cocaine self-administration. Neuropsychopharmacology 38:1264-75
Mello, Nancy K; Fivel, Peter A; Kohut, Stephen J et al. (2013) Effects of chronic buspirone treatment on cocaine self-administration. Neuropsychopharmacology 38:455-67
Kohut, Stephen J; Fivel, Peter A; Mello, Nancy K (2013) Differential effects of acute and chronic treatment with the ?2-adrenergic agonist, lofexidine, on cocaine self-administration in rhesus monkeys. Drug Alcohol Depend 133:593-9
Kohut, Stephen J; Fivel, Peter A; Blough, Bruce E et al. (2013) Effects of methcathinone and 3-Cl-methcathinone (PAL-434) in cocaine discrimination or self-administration in rhesus monkeys. Int J Neuropsychopharmacol 16:1985-98
Fivel, Peter A (2011) Computer-controlled drug doses for IV drug self-administration. Exp Clin Psychopharmacol 19:131-3
Negus, S S; Baumann, M H; Rothman, R B et al. (2009) Selective suppression of cocaine- versus food-maintained responding by monoamine releasers in rhesus monkeys: benzylpiperazine, (+)phenmetrazine, and 4-benzylpiperidine. J Pharmacol Exp Ther 329:272-81
Negus, S Stevens; Rice, Kenner C (2009) Mechanisms of withdrawal-associated increases in heroin self-administration: pharmacologic modulation of heroin vs food choice in heroin-dependent rhesus monkeys. Neuropsychopharmacology 34:899-911
Negus, S S; Mello, N K; Kimmel, H L et al. (2009) Effects of the monoamine uptake inhibitors RTI-112 and RTI-113 on cocaine- and food-maintained responding in rhesus monkeys. Pharmacol Biochem Behav 91:333-8

Showing the most recent 10 out of 65 publications