The main objective of this research is to develop nonhuman primate models (rhesus monkeys) of critical aspects of addiction that will yield useful information for the prevention and treatment of drug abuse. The proposed experiments are designed to evaluate vulnerability factors in drug abuse, such as sex and phase of the menstrual cycle (hormonal status), that are related to the development and persistence of drug abuse. Nonhuman primate models of oral drug self-administration such as phencyclidine (PCP) and methamphetamine (METH) and smoked drugs such as cocaine (COC), heroin (HER), and METH will be used, and behavioral and pharmacological interventions will be applied as treatment models in males and females and in females during different phases of the menstrual cycle. Sensitive behavioral economic measures of demand for drug will be used to assess drug self-administration behavior providing an estimate of the reinforcing strength of the drugs under various conditions. The proposed experiments will also use rhesus monkeys and drug self-administration by drinking and smoking to study the relationship between drug- reinforced behavior and impulsivity for a food reward as a function of sex. Growing literature suggests that impulsivity is a behavioral phenotype that predicts drug self-administration, and drug abuse alters impulsive behavior, increasing or decreasing it, depending on the type of drug. The proposed research will extend the study of impulsivity and drug abuse to self-administered drugs. The monkeys are also an ideal model to prospectively study responsiveness to novel behavioral and pharmacological treatments for drug abuse with respect to their success in the context of sex and hormonal factors. These nonhuman primate oral models of drug abuse do not exist in many laboratories, yet they are valuable because results with monkeys are very close to those found in human laboratory and clinical settings. The following are the Specific Aims:
Aim 1 - To examine the effects of sex and menstrual cycle phase on the reinforcing strength of orally-delivered PCP and METH, and a nondrug control substance, saccharin, as well as smoked COC, HER, and METH.
Aim 2 - To study the influence of sex and hormonal status on the effectiveness of behavioral (nondrug alternatives) and pharmacological (progesterone) treatments and their combination. It is essential to understand the relationship between vulnerability factors and responsiveness to treatment in order to optimize prevention and treatment of drug abuse in humans.
Aim 3 - To investigate the effects of self-administered drugs on impulsive behavior maintained by nondrug reinforcers (e.g., food, saccharin). Initial work with rats indicates a relationship between drug abuse and impulsive choice of a small, immediate versus large, delayed reward. The proposed work will further our understanding of addiction-prone vulnerability factors and treatment for drug abuse.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
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Lynch, Minda
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University of Minnesota Twin Cities
Schools of Medicine
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Carroll, Marilyn E; Lynch, Wendy J (2016) How to study sex differences in addiction using animal models. Addict Biol 21:1007-29
Carroll, Marilyn E; Kohl, Emily A; Johnson, Krista M et al. (2013) Increased impulsive choice for saccharin during PCP withdrawal in female monkeys: influence of menstrual cycle phase. Psychopharmacology (Berl) 227:413-24
Brand, Theresa; Anderson, George M (2011) The measurement of platelet-poor plasma serotonin: a systematic review of prior reports and recommendations for improved analysis. Clin Chem 57:1376-86
Carroll, Marilyn E; Anker, Justin J (2010) Sex differences and ovarian hormones in animal models of drug dependence. Horm Behav 58:44-56
Carroll, Marilyn E; Mach, Jami L; La Nasa, Rachel M et al. (2009) Impulsivity as a behavioral measure of withdrawal of orally delivered PCP and nondrug rewards in male and female monkeys. Psychopharmacology (Berl) 207:85-98
Newman, Jennifer L; Perry, Jennifer L; Carroll, Marilyn E (2008) Effects of altering reinforcer magnitude and reinforcement schedule on phencyclidine (PCP) self-administration in monkeys using an adjusting delay task. Pharmacol Biochem Behav 90:778-86
Newman, Jennifer L; Perry, Jennifer L; Carroll, Marilyn E (2007) Social stimuli enhance phencyclidine (PCP) self-administration in rhesus monkeys. Pharmacol Biochem Behav 87:280-8
Perry, Jennifer L; Normile, Lisa M; Morgan, Andrew D et al. (2006) Sex differences in physical dependence on orally self-administered phencyclidine (PCP) in rhesus monkeys (Macaca mulatta). Exp Clin Psychopharmacol 14:68-78
Newman, Jennifer L; Carroll, Marilyn E (2006) Reinforcing effects of smoked methamphetamine in rhesus monkeys. Psychopharmacology (Berl) 188:193-200
Newman, Jennifer L; Thorne, Joseph J; Batulis, David K et al. (2006) Effects of menstrual cycle phase on the reinforcing effects of phencyclidine (PCP) in rhesus monkeys. Pharmacol Biochem Behav 85:584-91

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