This is a new application for a NIDA Program Project (P-01) entitled Cocaine and Polydrug Abuse: New Medication Strategies. Cocaine abuse remains one of the nation's most serious drug abuse problems, and as yet, there are no effective anti-cocaine medications. Cocaine is often abused in combination with heroin, and dual dependence on cocaine and opioids further complicates medication based treatment. Four inter- related clinical and pre-clinical research projects are proposed to develop novel medications for the treatment of cocaine abuse and polydrug abuse. These multi-disciplinary collaborative projects involve behavioral science, endocrinology, neurobiology and pharmacology. An innovative new preclinical model of speedball (cocaine+heroin) abuse will be used to evaluate novel medication strategies, and to test the hypothesis that medication combinations targeted at both the cocaine and the opioid components of the speedball will be more effective than treatment with either anti-cocaine or anti-opioid medications alone. Acute and chronic treatment with potential anti-cocaine medications (endocrine modulators, dopamine reuptake inhibitors; dopamine agonists and antagonists ) and anti-opioid medications (high and intermediate efficacy mu agonists and a new long-acting mu antagonist) will be evaluated. In addition to pharmacological approaches, we propose to evaluate novel biologic approaches to reduce cocaine abuse that are based on our recent discoveries of cocaine-neuroendocrine interactions. We hypothesize that the acute neuroendocrine effects of cocaine may contribute to its abuse- related effects and that analysis of cocaine-endocrine interactions will guide new strategies for medications development. The temporal covariance between cocaine stimulation of anterior pituitary, gonadal and adrenal hormones will be examined in both clinical and preclinical studies. The behavioral relevance of cocaine's acute endocrine effects will be evaluated both in clinical studies and preclinical studies of biologic approaches to cocaine abuse treatment. The pharmacological mechanisms underlying cocaine's acute endocrine effects will be evaluated with selective monoamine agonists and antagonists in preclinical studies. In addition, we propose to systematically examine changes in the acute endocrine profile of cocaine produced by (a) repeated cocaine dosing in a binge pattern, (b) the addition of heroin to cocaine to simulate milieu on the efficacy of medications for cocaine abuse treatment will e examined. These studies should clarify the ways in which cocaine abuse influences and is influenced by neuroendocrine factors. Advances in understanding the neurobiological determinants of the abuse-related effects of drugs should facilitate the development of more effective treatment medications.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Program Projects (P01)
Project #
5P01DA014528-05
Application #
7048554
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Acri, Jane
Project Start
2002-03-15
Project End
2009-02-28
Budget Start
2006-03-01
Budget End
2009-02-28
Support Year
5
Fiscal Year
2006
Total Cost
$1,183,074
Indirect Cost
Name
Mc Lean Hospital (Belmont, MA)
Department
Type
DUNS #
046514535
City
Belmont
State
MA
Country
United States
Zip Code
02478
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Mello, Nancy K; Knudson, Inge M; Kelly, Maureen et al. (2011) Effects of progesterone and testosterone on cocaine self-administration and cocaine discrimination by female rhesus monkeys. Neuropsychopharmacology 36:2187-99
Thomsen, Morgane; Caine, S Barak (2011) Psychomotor stimulant effects of cocaine in rats and 15 mouse strains. Exp Clin Psychopharmacol 19:321-41
Banks, Matthew L; Negus, S Stevens (2010) Effects of extended cocaine access and cocaine withdrawal on choice between cocaine and food in rhesus monkeys. Neuropsychopharmacology 35:493-504
Mello, Nancy K (2010) Hormones, nicotine, and cocaine: clinical studies. Horm Behav 58:57-71
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
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
Thomsen, Morgane; Hall, F Scott; Uhl, George R et al. (2009) Dramatically decreased cocaine self-administration in dopamine but not serotonin transporter knock-out mice. J Neurosci 29:1087-92
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
Goletiani, Nathalie V; Mendelson, Jack H; Sholar, Michelle B et al. (2009) Opioid and cocaine combined effect on cocaine-induced changes in HPA and HPG axes hormones in men. Pharmacol Biochem Behav 91:526-36

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