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Stop Animal Exploitation NOW!
S. A. E. N.
"Exposing the truth to wipe out animal experimentation"

Government Grants Promoting Cruelty to Animals

University of Minnesota, Minneapolis, MN

MARILYN E. CARROLL - Primate Testing - 2007

Please email:  [email protected]  to protest the inhumane use of animals in this experiment. We would also love to know about your efforts with this cause: [email protected]

2007  Total Funding  = $1,146,724

 Senior Scientist Award (K05)

The award provides salary support for award periods of up to five years as a means 
of enhancing the individual recipient’s skills and dedication to his/her area of research.

2007 Funding amount:    $138,988

Abstract:
DESCRIPTION (provided by applicant): The objective of this K05 application is to obtain salary support for release time from teaching and administrative duties not directly related to research. This would increase time allocated to research from 40% before the K05 to 75-90. An overview of the candidate's 31-year background in drug abuse research is provided including a list of publications, presentations, a citation analysis, research funding, and mentorship of students, science advocacy, and educational activities.

Short-and-long-term research plans that will be implemented with released time are discussed. Specific activities planned to sustain outstanding research performance, blending of past and future goals, the likelihood of continuing successful contributions, and plans to obtain and provide instruction on the responsible conduct of science are also discussed. A progress report describes accomplishments made in the first 4 years of this K05 award 2002-2006.

The research plan consists of 2 continuing R01 projects that have been funded by NIDA for over 20 years, a new R01 (PI) that is under review, and a P20 application (Co-Pi) that is under review. The first grant is a nonhuman primate model to study sex, phase of menstrual cycle, and impulsivity as factors that affect the Vulnerability to drug abuse and to implement innovative behavioral and pharmacological treatments for drug abuse.

The overall hypothesis is that these vulnerability factors will predict reinforcing efficacy and treatment success. The second grant will examine behavioral and pharmacological interventions in rats selected for several vulnerable behaviors.

These factors will be compared during critical transition phases of addiction, acquisition, escalation, and reinstatement. The hypothesis is that a predisposition (individual differences) for excessive behavior directed toward novel and rewarding nondrug activities increases vulnerability to drug abuse and responsiveness to treatment.

The third proposed grant, to be conducted in adolescent rats, is focused on factors underlying drug abuse. The overall hypothesis is that adolescent animals are more impulsive and susceptible to hormonal influences on drug seeking behavior than adults.

The fourth proposed grant, a P20, would consist of an animal project that will parallel and inform two human projects involving cocaine abusers and college students varying in impulsive behavior. The basic theme is how, impulsivity is related to drug abuse, and MR imaging will be used in rats and monkeys to compare neurobiological and behavioral phenotypes. Species, gender, several drugs of abuse, routes of administration, and phases of addiction will be compared. The results will allow for identification of biological, behavioral, and environmental factors leading to recognition of individuals at risk for drug abuse, and the experimental interventions used with these models will inform prevention and treatment strategies for humans.

Public Health Relevance:
This Public Health Relevance is not available.

Thesaurus Terms:
drug abuse prevention, drug abuse therapy, substance abuse related behavior
biological model, cocaine, craving, drug administration route, gender difference, heroin, menstrual cycle, phencyclidine, reinforcer, self medication, sex behavior
Macaca mulatta, behavioral /social science research tag, laboratory rat

2007 Funding Amount:   $411,125  

Abstract:
DESCRIPTION (provided by applicant): 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.

Public Health Relevance:
This Public Health Relevance is not available.

Thesaurus Terms:
behavior therapy, disease /disorder proneness /risk, drug abuse chemotherapy, nonhuman therapy evaluation, substance abuse related behavior, substance abuse related disorder
analgesic, buprenorphine, cocaine, corticosterone, disease /disorder model, drug addiction antagonist, drug interaction, ethanol, gender difference, heroin, ketoconazole, menstrual cycle, methadone, muscle relaxant, oral administration, phencyclidine, psychological reinforcement, psychopharmacology, reinforcer, self medication, smoking
Macaca mulatta, behavioral /social science research tag

 2007 Funding Amount:     $326,186  

Abstract:
DESCRIPTION (provided by applicant): The overall objective of this research application is to focus on major vulnerability factors in drug abuse, including avidity for nondrug rewards, impulsive behavior, sex, and ovarian hormones, and determine how groups with differing vulnerability levels respond to treatment efforts.

Both behavioral (nondrug alternatives) and pharmacological (medication) treatments will be examined. A main goal is also to study treatment approaches as they are applied during several key phases of addiction such as acquisition of initial drug use, escalation from controlled to uncontrolled drug abuse, and reinstatement of drug seeking (relapse) after a period of abstinence.

These transition phases, and particularly reinstatement, are the greatest challenges to solving drug abuse problems. Much of the previous work has been conducted with cocaine (COC), and that work will be extended to new areas; however, new proposed studies will also be conducted with methamphetamine (METH), a drug that has become an enormous health concern and for which prevention and treatment models are urgently needed.

The following are the Specific Aims that correspond to 5 proposed experiments:

• Aim 1, to examine sex and hormonal influences in drug abuse vulnerability,
     a) during vulnerable phases of drug abuse, specifically, acquisition, escalation, and reinstatement, and to examine the contributions of estrogen and progesterone to vulnerability status,
     b) to examine estrogen receptor sensitivity by comparing the contribution of agonists at the alpha and beta estrogen receptor subtypes with the goal of identifying more selective treatment targets, and
     c) by investigating the role of endogenous increases in progesterone that occur during pregnancy. Self-administration of COC and METH will be compared before, during, and after pregnancy and weaning to determine whether elevated levels of drug self-administration decrease when progesterone is elevated.

• Aim 2, to study the effects of behavioral interventions for reducing the escalation and reinstatement of COC and METH abuse in vulnerable groups. Behavioral interventions will be examined as a function of individual differences in vulnerability, such as male versus female, and those rated as high versus low on impulsivity, wheel-running, and sucrose intake.

• Aim 3, to explore the use of medications at vulnerable phases of drug abuse in vulnerable phenotypes. Medications to be tested will be baclofen, a gamma aminobutyric acid B (GABAB) agonist that blocks many aspects of drug abuse, and progesterone which has been shown to reduce drug-seeking behavior and the positive subjective effects of drugs in females and males, animals and humans. We currently have no viable treatments for COC, METH, or several other forms of stimulant abuse. The proposed research will show how enhanced drug-seeking behavior in vulnerable phenotypes can be reduced at the most critical, vulnerable phases of drug abuse through behavioral and pharmacological interventions.

Public Health Relevance:
This Public Health Relevance is not available.

Thesaurus Terms:
cocaine, drug abuse chemotherapy, drug addiction, drug addiction antagonist, heroin, nonhuman therapy evaluation
compulsive behavior, endocrine gland /system, estradiol, gender difference, hormone regulation /control mechanism, muscle relaxant, psychopharmacology, reinforcer, relapse /recurrence, self medication
laboratory rat, ovariectomy

 2007 Funding Amount:   $270,425

Abstract:
DESCRIPTION (provided by applicant): The overall objective of this project is to use innovative animal models to study individual differences that have emerged as key vulnerability factors in drug abuse (impulsivity, adolescence, sex, hormonal status, and avidity for nondrug rewards).

The main question to be addressed is whether impulsivity, a defining characteristic of adolescence, is related to the enhanced vulnerability to drug abuse that is seen more in adolescence (versus adulthood), and whether impulsivity is related to the increase in gonadal hormones that occurs during this critical phase of development.

Behavioral models of impulsivity; such as, delay discounting (choosing a small-immediate versus a large-delayed reward), and the Go/No-go task (inhibition of behavior during signaled nonreward versus reward periods) will be used. Other behaviors will be compared to the results of the impulsivity tests to determine whether they covary with impulsive behavior and have predictive value; such as, extinction and reinstatement (Ext/Reinst) of drug-seeking behavior (relapse). Finally, impulsivity measures will be related to various indices of novelty-seeking behavior for drug (e.g., cocaine, heroin) and nondrug (e.g., wheel-running, and sucrose intake) rewards.

The following are specific aims that correspond with the four proposed experiments:
   1) to address the extent to which impulsivity is a major factor contributing to vulnerability to drug abuse in adolescents versus adults. Male and female adolescent and adult rats will be compared within and between groups on two measures of impulsivity, delay-discounting (DD) and the Go/No- go tasks for food or IV cocaine.
   2) To investigate the question of whether impulsive adolescents become impulsive adults using the DD and Go/No-go procedures for cocaine and food rewards. Low (Lol) and high (Hil) impulsive male and female groups will also be compared on Ext/Reinst of cocaine-seeking behavior.
   3) To determine whether it is an increase in circulating gonadal hormones or innate developmental/ organizational differences that account for the sex differences in impulsivity and/or drug abuse in adolescents and adults using the DD or Go/No-go procedure, 5 groups will be compared:
      a) ovariectomized females (OVX),
      b) OVX with estrogen replacement (OVX + E),
      c) castrated males (CAST),
      d) sham-operated females (SHAM) and
      e) SHAM males.
   4) To examine the relationship between impulsivity and factors that covary with impulsivity in predicting drug abuse.

Rats will be selected for Hil and Lol (DD and Go/No-go) and tested on the other measure as well as for behavior maintained by other rewards. Other groups will be selected as high and low for behaviors reinforced by drug (cocaine, heroin) and nondrug (wheel-running, sucrose) rewards and tested on measures of impulsivity for a bidirectional comparison of impulsivity and avidity for drugs or nondrug rewards. The study of impulsivity in drug-seeking behavior will increase our understanding of the etiology, prevention, and treatment of drug abuse.

Public Health Relevance:
This Public Health Relevance is not available.

Thesaurus Terms:

There are no thesaurus terms on file for this project.

Please email:  [email protected]  to protest the inhumane use of animals in this experiment. We would also love to know about your efforts with this cause: [email protected]

Also See:
MARILYN E. CARROLL - Primate Testing - 2006
MARILYN E. CARROLL - Primate Testing - 2005

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Rats, mice, birds, amphibians and other animals have been excluded from coverage by the Animal Welfare Act. Therefore research facility reports do not include these animals. As a result of this situation, a blank report, or one with few animals listed, does not mean that a facility has not performed experiments on non-reportable animals. A blank form does mean that the facility in question has not used covered animals (primates, dogs, cats, rabbits, guinea pigs, hamsters, pigs, sheep, goats, etc.). Rats and mice alone are believed to comprise over 90% of the animals used in experimentation. Therefore the majority of animals used at research facilities are not even counted.