During the present reporting period, no further laboratory work was conducted on this project due to budgetary limitations. However, a backlog of laboratory findings on this project were brought forward to the publication stage during this reporting period. First, we reported that the novel selective dopamine D3 receptor antagonist YQA14 inhibits intravenous cocaine self-administration under fixed-ratio reinforcement in laboratory rats, and also significantly attenuates intravenous cocaine self-administration under progressive-ratio reinforcement in laboratory rats - revealing a significant decrease in incentive motivation to self-administer cocaine. At the same time, YQA14 does not alter self-administration of the natural rewarding substance sucrose. This is in line with our previous findings with our two lead proof-of-concept compounds SB277011A and NGB2904 that selective dopamine D3 receptor antagonism blocks drug reward but not natural biologically essential rewards such as food, water, or sex. Also, we reported that YQA14 does not alter cocaine-enhanced locomotion at doses that significantly inhibit cocaine self-administration, showing that YQA14's anti-cocaine effect is not merely due to nonspecific inhibition of motoric ability. In addition, we found that YQA14 dose-dependently inhibits intravenous cocaine self-administration (under both fixed-ratio and progressive-ratio reinforcement conditions) in wild-type mice but not in dopamine D3 receptor gene-deleted mice. This shows that the anti-addiction effects of YQA14 are indeed mediated via the dopamine D3 receptor in the brain. Thus, YQA14 now joins SB277011A and NGB2904 as an extremely promising anti-addiction medication, adding yet more weight to our previous findings that selective dopamine D3 receptor antagonists appear to have anti-addiction, anti-craving, and anti-relapse efficacy that may well translate to clinical efficacy in human drug addiction. Second, using two new additional animal behavioral models, we reported that our lead proof-of-concept compound SB277011A reverses conditioned place aversion produced by naloxone-precipitated opiate withdrawal in rats - suggesting efficacy of selective dopamine D3 receptor antagonists for treating opiate withdrawal dysphoria. Third, we reported that SB277011A very robustly inhibits incubation of cocaine craving in laboratory rats, with locus of action in the brain being the nucleus accumbens and central amygdala (as determined by discrete focal intracerebral microinjections of SB277011A) - suggesting potential efficacy of selective dopamine D3 antagonists for treating time-dependent incubation of psychostimulant craving in human addicts. Such findings significantly broaden the range of pathognomonic symptoms of drug addiction against which selective dopamine D3 antagonists show efficacy - a very important development in this research field. Fourth, we reported that mice lacking D3 receptors (D3 knockout mice) show increased vulnerability to cocaine, an effect that we attribute to neural compensatory mechanisms. Fifth, we reported that D3 receptor blockade induced by the novel D3 receptor antagonist YQA14 (see above) significantly attenuates cocaine-induced conditioned place preference in mice. Sixth, we reported that our primary proof-of-concept selective D3 receptor antagonist SB277011A significantly attenuates morphine-triggered reactivation of the expression of cocaine-induced conditioned place preference in laboratory rats. We consider this last finding to be exceptionally important, as it is the first report - in the entire world literature - suggesting that selective dopamine D3 receptor blockade may have clinical efficacy against the cross-triggering of relapse phenomenon (in which other addictive drugs than the one primarily used by the addicted patient have the ability to trigger relapse to drug-seeking of the primary addictive drug) that is so common and pathognomonic in addiction.

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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
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
Ashby Jr, Charles R; Rice, Onarae V; Heidbreder, Christian A et al. (2015) The selective dopamine D₃ 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
Rice, Onarae V; Schonhar, Charles A; Gaál, J et al. (2015) The selective dopamine D₃ receptor antagonist SB-277011-A significantly decreases binge-like consumption of ethanol in C57BL/J6 mice. Synapse 69:295-8
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
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
Rice, Onarae V; Heidbreder, Christian A; Gardner, Eliot L et al. (2013) The selective D₃ receptor antagonist SB-277011A attenuates morphine-triggered reactivation of expression of cocaine-induced conditioned place preference. Synapse 67:469-75
Song, Rui; Zhang, Hai-Ying; Peng, Xiao-Qing et al. (2013) Dopamine D(3) receptor deletion or blockade attenuates cocaine-induced conditioned place preference in mice. Neuropharmacology 72:82-7
Song, Rui; Zhang, Hai-Ying; Li, Xia et al. (2012) Increased vulnerability to cocaine in mice lacking dopamine D3 receptors. Proc Natl Acad Sci U S A 109:17675-80

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