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 (vs. 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 vs. a large-delayed reward), and the Go/No-go task (inhibition of behavior durinc signaled nonreward vs. 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 4 proposed experiments: 1) To address the extent to which impulsivity is a major factor contributing to vulnerability to drug abuse in adolescents vs. 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 i.v. 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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA019942-05
Application #
8128724
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Lynch, Minda
Project Start
2007-09-30
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2012
Total Cost
$275,815
Indirect Cost
$81,775
Name
University of Minnesota Twin Cities
Department
Psychiatry
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Anker, Justin J; Baron, Thomas R; Zlebnik, Natalie E et al. (2012) Escalation of methamphetamine self-administration in adolescent and adult rats. Drug Alcohol Depend 124:149-53
Anker, Justin J; Carroll, Marilyn E (2011) Adolescent nicotine exposure sensitizes cue-induced reinstatement of cocaine seeking in rats bred for high and low saccharin intake. Drug Alcohol Depend 118:68-72
Anker, Justin J; Zlebnik, Natalie E; Navin, Sean F et al. (2011) Responding during signaled availability and nonavailability of iv cocaine and food in rats: age and sex differences. Psychopharmacology (Berl) 215:785-99
Gosnell, Blake A; Mitra, Anaya; Avant, Ross A et al. (2010) Operant responding for sucrose by rats bred for high or low saccharin consumption. Physiol Behav 99:529-33
Anker, Justin J; Zlebnik, Natalie E; Carroll, Marilyn E (2010) Differential effects of allopregnanolone on the escalation of cocaine self-administration and sucrose intake in female rats. Psychopharmacology (Berl) 212:419-29
Anker, Justin J; Carroll, Marilyn E (2010) Reinstatement of cocaine seeking induced by drugs, cues, and stress in adolescent and adult rats. Psychopharmacology (Berl) 208:211-22
Carroll, Marilyn E; Anker, Justin J (2010) Sex differences and ovarian hormones in animal models of drug dependence. Horm Behav 58:44-56
Anker, Justin J; Carroll, Marilyn E (2010) Sex differences in the effects of allopregnanolone on yohimbine-induced reinstatement of cocaine seeking in rats. Drug Alcohol Depend 107:264-7
Carroll, Marilyn E; Anker, Justin J; Perry, Jennifer L (2009) Modeling risk factors for nicotine and other drug abuse in the preclinical laboratory. Drug Alcohol Depend 104 Suppl 1:S70-8