Women experience higher levels of craving and relapse during periods of drug abstinence, and take larger amounts of drug during bouts of relapse, as compared to men. Although this dfferential responding has been attributed to female's neuroendcrine functioning, the actual mechanim(s) underlying these sex differences are not well understood. Thus, the objective of the proposed research is to a) characterize sex differences in responseviness to cocaine, b) determine the role of estradiol (E2) and striatal membrane estrogen receptors (mERs) in cocaine reward, and c) in mediating cocaine-induced intracellular signaling within the nucleus accumbens (NAc). Our recent work demonstrates that females display higher levels of cocaine-primed reinstatement, as measured by conditioned place preference (CPP), than males. These data indicate that females form stronger associations between cocaine and the environment in which it was administered. We present data demonstrating sex differences in second messenger expression in NAc after reinstatement to cocaine-CPP, which can potentially explain differential behavioral responsivity previously observed. The proposed studies will complement and logically extend our previous work using behavioral, pharmacology, and molecular methods. First, we will examine our previous observations closer by subjecting intact male and cycling females to an extended CPP paradigm to examine sex and cycle differences in behavior and expression of three key molecular substrates important in forming drug reward associations in the NAc ? FosB, ERK and CREB. Second, we will complement these studies by directly manipulating E2 in gonadectomized (GDX) rats and subjecting them to the same CPP paradigm and biochemical measurements as above. Lastly, we will selectively block the mERs in NAc of GDX rats to determine sex specific roles of mERs in modulating the molecular events associated with sex differences in cocaine seeking behavior. Results from the proposed experiments will fill a large gap in our knowledge regarding interactions between E2 and brain reward circuitry associated with continual drug exposure. Clarification of the mechanisms by which E2 interacts with DA- mediated intracellular signaling to modulate the motivational salience of cocaine to influence drug-seeking behaviors may provide novel prevention and treatment strategies for women. Besides addressing a scientific issue of great importance, this proposal will also enrich student research experiences at the University of Texas, at Arlington. These studies will provide students from diverse backgrounds with meaningful and high quality early training opportunities in neurobiology, neuropharmacology and behavioral neuroscience, and increase their prospects for future careers in health-related sciences.

Public Health Relevance

The experiments proposed in this project represent a comprehensive effort to characterize the effects of estradiol on cocaine-induced changes in three of the key molecular substrates implicated in conditioned drug reward. Currently, an understanding of the molecular mechanisms that underlie estradiol-dependent changes in the neuronal excitability and synaptic efficacy which underlie drug-seeking behaviors is limited. In this project we will examine, via complementary approaches, interactions between estradiol and the behavioral and molecular responses to conditioned cocaine reward. We will also elucidate the role of striatal membrane bound estrogen receptors in mediating some of the molecular events that are associated with cocaine reward. Results from this work will provide some important clues regarding the mechanism(s) by which estrogen regulates key moleuclar substrates implicated in signaling the motivational salience of a drug stimulus.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
1R15DA040809-01A1
Application #
9171774
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Su, Shelley
Project Start
2016-06-15
Project End
2019-05-31
Budget Start
2016-06-15
Budget End
2019-05-31
Support Year
1
Fiscal Year
2016
Total Cost
$413,970
Indirect Cost
$113,980
Name
University of Texas Arlington
Department
Type
Organized Research Units
DUNS #
064234610
City
Arlington
State
TX
Country
United States
Zip Code
76019