Methamphetamine (MA) and related stimulant abuse remains a major public health concern globally. MA addiction is a highly complicated neuropathological disorder that recruits multiple brain regions and neurotransmitter systems. Despite decades of research, no effective pharmacotherapy has yet been developed for treating MA addiction. Imidazoline I2 receptors may represent a novel target for developing pharmacotherapy of drug addiction. Accumulating evidence indicates that I2 receptor agonists can modulate the dopaminergic system and behavioral studies have demonstrated the attenuation of the addiction-related effects of opioids by the endogenous imidazoline receptor ligand agmatine. However, little is known of whether pharmacologically selective I2 receptor ligands modulate the addiction-related effects of drugs of abuse. We recently observed that a selective I2 receptor agonist, 2-BFI, markedly attenuates MA induced behavioral sensitization and conditioned place preference. The objective of the present application is to evaluate the proof-of-concept that the I2 receptor is a novel drug target for the treatment of MA addiction. Guided by exciting preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) examine the effect of an I2 receptor agonist, 2-BFI, and an antagonist, tracizoline, on the development and reinstatement of MA-induced conditioned place preference (Aim 1);2) examine the interaction between I2 receptor ligands and MA in animals discriminating MA or the I2 receptor agonist, 2-BFI, using a drug discrimination procedure (Aim 2). Collectively, the proposed studies systematically evaluate the effects of I2 receptor ligands on the addiction- related (e.g., rewarding and discriminative stimulus) effects of MA. These data will provide valuable information regarding the potential therapeutic value of I2 receptor agonists for the treatment of addiction to MA and related stimulants. In addition, data obtained in the proposed investigation may contribute to the identification of further novel I2 receptor based pharmacotherapies for addiction to MA.

Public Health Relevance

Methamphetamine abuse and addiction remains a significant public health challenge and effective pharmacotherapy is lacking. This application explores the potential therapeutic value of imidazoline I2 receptor agonists for methamphetamine addiction. The proposed research is relevant to the part of NIH's mission that may identify novel pharmacotherapies to help combat methamphetamine addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DA033426-01A1
Application #
8581533
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Hillery, Paul
Project Start
2013-06-01
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$259,071
Indirect Cost
$95,185
Name
State University of New York at Buffalo
Department
Pharmacology
Type
Schools of Medicine
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260
Siemian, Justin N; Shang, Li; Seaman Jr, Robert W et al. (2018) Effects of imidazoline I2 receptor agonists on reserpine-induced hyperalgesia and depressive-like behavior in rats. Behav Pharmacol :
Li, Jun-Xu (2017) Imidazoline I2 receptors: An update. Pharmacol Ther 178:48-56
Thorn, David A; Qiu, Yanyan; Jia, Shushan et al. (2016) Antinociceptive effects of imidazoline I2 receptor agonists in the formalin test in rats. Behav Pharmacol 27:377-83
Thorn, David A; Zhang, Yanan; Li, Jun-Xu (2016) Effects of the imidazoline I2 receptor agonist 2-BFI on the development of tolerance to and behavioural/physical dependence on morphine in rats. Br J Pharmacol 173:1363-72
Thorn, David A; Li, Jiuzhou; Qiu, Yanyan et al. (2016) Agmatine attenuates the discriminative stimulus and hyperthermic effects of methamphetamine in male rats. Behav Pharmacol 27:542-8
Liu, Jian-Feng; Thorn, David A; Zhang, Yanan et al. (2016) Effects of Trace Amine-associated Receptor 1 Agonists on the Expression, Reconsolidation, and Extinction of Cocaine Reward Memory. Int J Neuropsychopharmacol 19:
Grandy, David K; Miller, Gregory M; Li, Jun-Xu (2016) ""TAARgeting Addiction""--The Alamo Bears Witness to Another Revolution: An Overview of the Plenary Symposium of the 2015 Behavior, Biology and Chemistry Conference. Drug Alcohol Depend 159:9-16
Siemian, Justin N; Li, Jiuzhou; Zhang, Yanan et al. (2016) Interactions between imidazoline I2 receptor ligands and acetaminophen in adult male rats: antinociception and schedule-controlled responding. Psychopharmacology (Berl) 233:873-82
Qiu, Yanyan; Zhang, Yanan; Li, Jun-Xu (2015) Discriminative stimulus effects of the imidazoline I2 receptor ligands BU224 and phenyzoline in rats. Eur J Pharmacol 749:133-41
Jing, Li; Li, Jun-Xu (2015) Trace amine-associated receptor 1: A promising target for the treatment of psychostimulant addiction. Eur J Pharmacol 761:345-52

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