This competing continuation application (R01 DA002519) is designed to identify and evaluate potential treatment medications for cocaine abuse and dependence. Cocaine abuse remains a significant public health problem that afflicts an estimated 5 million Americans and over 16 million persons worldwide. There is no uniformly effective FDA-approved medication for cocaine abuse treatment, and this continues to be a high priority area. On the basis of our discoveries during the past project period, we propose to examine some potential treatment medications approved by the FDA for another indication, as well as novel approaches that may suggest new directions for medications development. In translational studies, we reported that buspirone and modafinil significantly and selectively decreased cocaine self-administration by rhesus monkeys (See Preliminary Studies). We now propose to evaluate modifications of these clinically available medications that may be more effective than the parent compounds due to longer duration of action and an improved safety profile (lower potential for abuse or dependence). Buspirone's active metabolites (5-OH and 6-OH buspirone) have dopamine D3 and D4 receptor activity that may account for buspirone's reduction of cocaine self-administration. Armodafinil, the R- enantiomer of modafinil, is longer acting, effective at lower doses and likely to have low abuse potential. A second focus of our proposed research is to continue to examine how monoaminergic ligands modulate the abuse-related effects of cocaine. We hypothesize that novel combinations of norepinephrine + serotonin releasers and dopamine releasers + serotonin reuptake inhibitors may selectively reduce cocaine self-administration with minimal abuse liability and side effects. We discovered that acute administration of a 5-HT2C agonist and a 5-HT2A antagonist each significantly and selectively reduced cocaine self-administration by rhesus monkeys (see Preliminary Studies). We propose to study the effects of chronic treatment with these serotonergic compounds on the abuse-related effects of cocaine. We hypothesize that combining low doses of 5-HT2C and 5-HT2A compounds will have synergistic effects on cocaine self-administration and reinstatement in rhesus monkeys. Well-validated behavioral procedures (drug self-administration, drug-, cue-, and stress-induced reinstatement, and drug discrimination) will be used to evaluate candidate medications in a nonhuman primate model of cocaine addiction. The neurobiology, neurochemistry and neuroanatomy of rhesus monkeys is very similar to humans, and there is good correspondence between preclinical and clinical evaluations of medication effects on several aspects of cocaine addiction. These preclinical models of cocaine addiction are essential for guiding decisions about development of novel medications for clinical treatment. The overall goal of the proposed research is to discover more effective medications for the treatment of cocaine abuse.

Public Health Relevance

Cocaine addiction afflicts over 5 million Americans and remains a significant public health problem that increases risk for many potentially lethal medical disorders, and is commonly involved in emergency ward admissions. No consistently effective FDA approved medication is currently available for the treatment of cocaine abuse and dependence so we propose translational studies to evaluate medications that are FDA approved for another indication (buspirone, armodafinil), as well as innovative novel hybrid monoamine releasers/reuptake inhibitors, and serotonin agonists and antagonists for effectiveness in reducing the abuse- related effects of cocaine in an established nonhuman primate model of cocaine addiction.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01DA002519-28A1
Application #
8761300
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Acri, Jane
Project Start
Project End
Budget Start
Budget End
Support Year
28
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Mclean Hospital
Department
Type
DUNS #
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

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