| 2009 — 2010 |
Dominguez, Juan M |
R21Activity Code Description:
To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
A Role For the Medial Preoptic Area in Regulating Gender-Sensitive Differences In @ University of Texas, Austin
DESCRIPTION (provided by applicant): Men and women respond differently to cocaine. Although epidemiological data show that more men than women abuse cocaine, there is preclinical and clinical evidence indicating that females are more vulnerable to its psychostimulant effects. Evidence also indicates that estrogen is at least partly responsible for this difference in sensitivity. Most studies point to the striatum and nucleus accumbens (NAcc) as brain areas on which estrogen acts to produce this gender difference. However, one area that has received little attention as potentially important for mediating this effect is the medial preoptic area (MPOA). The MPOA is sexually dimorphic, it is involved in regulating naturally rewarding behaviors, and it is one of the most sensitive regions to estrogen activity. These attributes make the MPOA a likely candidate in which estrogen might act to mediate gender-sensitive differences in response to cocaine. However, little is known about its role in this effect. The goals of these studies is: (1) to determine whether cocaine-induced activation of the medial preoptic nucleus (MPN) is sexually dimorphic, and whether it is mediated by estrogen;(2) to determine whether estrogen works via the MPOA to mediate cocaine-induced DA activity in the NAcc;(3) to determine whether estrogen acts via the MPOA to mediate cocaine-induced conditioned place preference, as a measure of cocaine's rewarding effects. Using neuroanatomical, neurochemical, and behavioral assays, the proposed work will examine whether estrogen enhances female1s response to cocaine via the MPOA. The planned experiments will also contribute to a more complete understanding of how hypothalamic mechanisms, especially one that is highly sensitive to gonadal signals, may affect response to cocaine use. Finally, the proposed studies will help us better understand the neuroendocrine regulation of gender-sensitive differences in response to cocaine, by exploring a possible new mechanism mediating this effect. Such an understanding may be beneficial when designing treatments for addiction, when gender-sensitive differences are especially important. PUBLIC HEALTH RELAVANCE The proposed studies will help us better understand the neuroendocrine regulation of gender-sensitive differences in response to cocaine, by exploring a possible new mechanism mediating this effect. Such an understanding may be beneficial when designing treatments for addiction, when gender-sensitive differences are especially important.
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| 2012 — 2016 |
Dominguez, Juan M |
R01Activity Code Description:
To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
A Role For the Preoptic Area in Modulating Cocaine Reward @ University of Texas, Austin
DESCRIPTION (provided by applicant): Most studies point to the mesocorticolimbic dopamine (DA) system as the necessary neurobiological endpoint when describing cocaine's rewarding properties; however, this system does not operate in isolation, and input from other structures may play a significant role in cocaine reward. One area that has received little attention as a potential modulator of cocaine-induced activity is the medial preoptic area of the hypothalamus (MPOA). The MPOA is involved in the regulation of two naturally rewarding behaviors (maternal and sexual behaviors), is sexually dimorphic, and interacts with areas in the mesocorticolimbic system. As such, the MPOA is a logical candidate for a neuroanatomical locus modulating cocaine-induced activity, yet surprisingly little is known about the role of this structure in the context of drug abuse. Here, we focus on preclinical animal models of cocaine reward, hypothesizing that the MPOA modulates cocaine-induced activity in the mesocorticolimbic system and resulting behavioral expression of reward, including sex differences. The proposed studies will answer the following questions: (1) Does the MPOA modulate cocaine-induced neuronal and dopamine activity in the mesocorticolimbic system? (2) Does the MPOA modulate cocaine reward? (3) Do cells in the MPOA containing gonadal-hormone receptors interact with the mesocorticolimbic system? (4) Do gonadal hormones act via the MPOA to modulate cocaine-induced neuronal and dopamine activity in the mesocorticolimbic system? (5) Do gonadal hormones act via the MPOA to modulate cocaine reward? Using neuroanatomical, neurochemical, and behavioral assays, the proposed work will examine whether the MPOA may serve as an extension of the reward pathway in modulating cocaine-induced activity. The findings from these studies will yield a greater understanding of the neurochemical and neuroendocrine substrates regulating cocaine reward. A greater understanding of the neurochemical and neuroendocrine regulation of cocaine reward will facilitate the development of treatment for drug addiction, when hormonal factors may be especially important. PUBLIC HEALTH RELEVANCE: According to the National Survey on Drug Use and Health (NSDUH), in 2009 there were 1.6 million current cocaine users aged 12 or older, comprising 0.7 percent of the nation's population. This is a dangerous epidemic because cocaine use can produce addiction and other adverse health consequences. As evidence of the addictive consequences of cocaine use, according to the NSDUH, nearly 1.1 million Americans met the DSM-IV criteria for dependence or abuse of cocaine in 2009. Additional data also indicate that 448,481 of the total 1,449,154 visits to emergency rooms for drug abuse involved cocaine, highlighting the adverse health consequences of cocaine use. Studies presented in this proposal will examine a region of the brain that has received little attention as a potential modulator of cocaine activity. This brain region is important for the integration of endocrine stimulation into the nervous system. Since gonadal hormones modulate rewarding and gender-sensitive responses to cocaine, the preclinical findings generated upon completion of the planned experiments will help us better understand the neurochemical, neuroendocrine, and gender-relevant substrates regulating cocaine abuse. The successful completion of the proposed aims will facilitate the development of prevention and treatment strategies for addiction, especially if these strategies involve an endocrine component. Furthermore, because pharmacological and behavioral treatments affect men and women differently, then a better understanding of how hormones impact cocaine-induced brain activity, while developing future treatment, should optimize the effectiveness of those treatment strategies.
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