In this K01, the scientific project seeks to examine potential neurobiological changes that may contribute to alcohol use disorders as a result of prolonged early-life stress. Rats socially isolated in adolescence exhibit increases in anxiety-lik behaviors and multiple measures of ethanol self-administration in adulthood relative to group-housed rats, making them a well-tested model for propensity to alcohol use disorders. Thus, Aim 1 will test the hypothesis that socially isolated rats have lower basal dopamine levels compared to group-housed rats, studying the role of the dynorphin/kappa opioid (KOR) system in differential alcohol-induced dopamine response.
Aim 2 will examine the locus of increased sensitivity of the KOR system. Optogenetically isolated dopamine terminals will be selectively stimulated and dopamine release will be measured using voltammetry before and after application of the KOR agonist U50,488. Whole-cell patch-clamp electrophysiology will be used to study the sensitivity of KORs on Glu terminals in the NAc shell.
Aim 3 will test the KOR system as a potential therapeutic target for alcoholism. The supersensitivity of KORs is expected to predominantly increase appetitive measures in socially isolated rats. Together, these aims will explore the underlying mechanisms involved in the development of alcoholism in individuals exposed to chronic early-life stress. If successful, this work could confer a better understanding of the neurobiological changes linking prolonged adolescent stress and increases in behavioral risk factors of alcoholism, thus leading to KOR-targeted intervention and preventive therapies. Under the guidance of outstanding mentors in alcohol research, the candidate will further develop her knowledge base in addiction biology, dopamine, glutamate, and kappa opioid receptor signaling, and synaptic physiology while adding invaluable research skills such as optogenetics, voltammetry, patch clamp electrophysiology, and operant self-administration to her toolkit during this K01 award period. The completion of these proposed experiments and the formal and hands-on educational opportunities provided in a Mentored Career Development Award will allow the Candidate to complete her technical skill set and gain experience in peer-reviewed publications and other aspects of career development. This project will provide the training needed at a critical time in the Candidate's development, to ensure a smooth transition to independence as a successful investigator in alcohol research.
The proposed studies will use a rodent model of adolescent social isolation that results in enduring behavioral changes such as increased anxiety- and depression-like behavior and increased consumption of alcohol in adulthood compared to the rats that are housed in groups. Identifying the neurobiological changes involved in the development of increased vulnerability to alcoholism may aid in the development of therapies to treat relapse and potentially prevent the development of alcoholism. The current proposed studies also examine neurological systems involved in modulating stress and anxiety as potential therapeutic targets to prevent or treat alcoholism.
|Siciliano, Cody A; Karkhanis, Anushree N; Holleran, Katherine M et al. (2018) Cross-Species Alterations in Synaptic Dopamine Regulation After Chronic Alcohol Exposure. Handb Exp Pharmacol :|
|Karkhanis, Anushree; Holleran, Katherine M; Jones, Sara R (2017) Dynorphin/Kappa Opioid Receptor Signaling in Preclinical Models of Alcohol, Drug, and Food Addiction. Int Rev Neurobiol 136:53-88|
|Karkhanis, Anushree N; Rose, Jamie H; Weiner, Jeffrey L et al. (2016) Early-Life Social Isolation Stress Increases Kappa Opioid Receptor Responsiveness and Downregulates the Dopamine System. Neuropsychopharmacology 41:2263-74|
|Rose, Jamie H; Karkhanis, Anushree N; Steiniger-Brach, Björn et al. (2016) Distinct Effects of Nalmefene on Dopamine Uptake Rates and Kappa Opioid Receptor Activity in the Nucleus Accumbens Following Chronic Intermittent Ethanol Exposure. Int J Mol Sci 17:|
|Karkhanis, Anushree N; Beveridge, Thomas J R; Blough, Bruce E et al. (2016) The individual and combined effects of phenmetrazine and mgluR2/3 agonist LY379268 on the motivation to self-administer cocaine. Drug Alcohol Depend 166:51-60|
|Karkhanis, Anushree N; Huggins, Kimberly N; Rose, Jamie H et al. (2016) Switch from excitatory to inhibitory actions of ethanol on dopamine levels after chronic exposure: Role of kappa opioid receptors. Neuropharmacology 110:190-197|