During the period 01 Oct 09 to 30 Sept 10, significant progress was made on this research project. We found that blockade of brain dopamine D3 receptors by the novel preferential dopamine D3 receptor antagonist S33138 emulates the putative anti-addiction, anti-craving, and anti-relapse efects that we have previously seen with our lead proof-of-concept dopamine D3 receptor antagonist SB277011A. Specifically, we found that S33138 attenuates intravenous cocaine self-administration, attenuates relapse to cocaine-seeking behavior (using the reinstatement animal model) triggered by cocaine, and significantly attenuates drug-enhanced brain reward (as assessed by electrical brain-stimulation reward electrophysiological techniques) produced by cocaine. These effects were seen at low to moderate doses of S33138. At high doses, dopamine D2 antogonist-like effects were observed. These findings add further weight to our previous suggestions that selective dopamine D3 receptor antagonists may be useful in the treatment of drug addiction. With regard to the effects observed with high doses of S33138, we found them to be similar to those that we previously observed with the putative selective D3 antagonist BP897 - and we conclude that the effects of both S33138 and BP897 are likely attributable to a combination of D3 and D2 receptor antagonism. During the reporting period, we also studied the selective dopamine D3 receptor antagonist PG01037. We found that PG01037 shares a very similar profile of action in animal models of addiction as our lead compound SB277011A - PG01037 does not alter intravenous methamphetamine self-administration when the cocaine is available under low-effort high-payoff conditions, PG01037 significantly lowers the progressive-ratio breakpoint for intravenous methamphetamine self-administration under progressive-ratio reinforcement conditions (reflecting decreased incentive motivation to self-administer methamphetamine), PG01037 significantly inhibits methamphetamine-associated cue-triggered relapse to drug-seeking behavior in animals behaviorally extinguished and pharmacologically weaned from methamphetamine, and PG01037 significantly inhibits methamphetamine-enhanced brain stimulation reward. These findings suggest that dopamine D3 receptor antagonists may have anti-addiction, anti-craving, and anti-relapse efficacy in human drug addiction, and that the D3 antagonist PG01037 appears to possess the same anti-addiction profile observed with our lead proof-of-concept compounds SB277011A and NGB2904.

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Rice, Onarae V; Ashby Jr, Charles R; Dixon, Clark et al. (2018) Selective dopamine D3 receptor antagonism significantly attenuates stress-induced immobility in a rat model of post-traumatic stress disorder. Synapse 72:e22035
Zhan, Jia; Jordan, Chloe J; Bi, Guo-Hua et al. (2018) Genetic deletion of the dopamine D3 receptor increases vulnerability to heroin in mice. Neuropharmacology 141:11-20
You, Zhi-Bing; Gao, Jun-Tao; Bi, Guo-Hua et al. (2017) The novel dopamine D3 receptor antagonists/partial agonists CAB2-015 and BAK4-54 inhibit oxycodone-taking and oxycodone-seeking behavior in rats. Neuropharmacology 126:190-199
Sushchyk, Sarah; Xi, Zheng-Xiong; Wang, Jia Bei (2016) Combination of Levo-Tetrahydropalmatine and Low Dose Naltrexone: A Promising Treatment for Prevention of Cocaine Relapse. J Pharmacol Exp Ther 357:248-57
Fraser, Kurt M; Haight, Joshua L; Gardner, Eliot L et al. (2016) Examining the role of dopamine D2 and D3 receptors in Pavlovian conditioned approach behaviors. Behav Brain Res 305:87-99
Kumar, Vivek; Bonifazi, Alessandro; Ellenberger, Michael P et al. (2016) Highly Selective Dopamine D3 Receptor (D3R) Antagonists and Partial Agonists Based on Eticlopride and the D3R Crystal Structure: New Leads for Opioid Dependence Treatment. J Med Chem 59:7634-50
Ashby Jr, Charles R; Rice, Onarae V; Heidbreder, Christian A et al. (2015) The selective dopamine D? receptor antagonist SB-277011A attenuates drug- or food-deprivation reactivation of expression of conditioned place preference for cocaine in male Sprague-Dawley rats. Synapse 69:336-44
Ashby Jr, Charles R; Rice, Onarae V; Heidbreder, Christian A et al. (2015) The selective dopamine D3 receptor antagonist SB-277011A significantly accelerates extinction to environmental cues associated with cocaine-induced place preference in male Sprague-Dawley rats. Synapse 69:512-4
Rice, Onarae V; Schonhar, Charles A; Gaál, J et al. (2015) The selective dopamine D? receptor antagonist SB-277011-A significantly decreases binge-like consumption of ethanol in C57BL/J6 mice. Synapse 69:295-8
Song, Rui; Bi, Guo-Hua; Zhang, Hai-Ying et al. (2014) Blockade of D3 receptors by YQA14 inhibits cocaine's rewarding effects and relapse to drug-seeking behavior in rats. Neuropharmacology 77:398-405

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