During the period 01 Oct 04 to 30 Sept 05, major progress was made on this research project. We found that blockade of brain dopamine D3 receptors by the D3 receptor antagonist SB277011A significantly attenuates stress-triggered relapse to cocaine-seeking behavior in laboratory rats who had been pharmacologically detoxified and behaviorally extinguished from their prior intravenous cocaine-taking habits. By microinjecting the D3 receptor antagonist directly into the brain, we found that one brain site of anti-relapse action is the nucleus accumbens. We further found that blockade of brain dopamine D3 receptors by the D3 receptor antagonists SB277011A, NGB2904, or BP897 significantly attenuates relapse to cocaine-seeking behavior in laboratory rats triggered by exposure to environmental cues previously associated with the intravenous cocaine-taking habit. We further determined that the anti-relapse actions of SB277011A and NGB2904 were likely due to their D3 receptor antagonist properties, but that the anti-relapse action of BP897 was likely due to D2 receptor antagonist properties. We further determined that the D3 receptor antagonist SB277011A blocks alcohol consumption in both genetically alcohol-preferring and alcohol-nonpreferring laboratory rats. We further determined that the D3 receptor antagonist SB277011A significantly attenuates cocaine-induced reward in laboratory rats by two different preclinical procedures--progressive-ratio reinforcement and variable-cost/variable-payoff reinforcement. We further determined that the D3 receptor antagonists SB277011A, NGB2904, or BP897 significantly attenuate nicotine-induced enhancement of brain reward. All of these findings suggest that dopamine D3 receptor antagonists may have anti-addiction, anti-craving, and anti-relapse efficacy in human drug addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Intramural Research (Z01)
Project #
1Z01DA000473-01
Application #
7149328
Study Section
(BNRB)
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2005
Total Cost
Indirect Cost
Name
National Institute on Drug Abuse
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Xi, Zheng-Xiong; Yang, Zheng; Li, Shi-Jiang et al. (2007) Levo-tetrahydropalmatine inhibits cocaine's rewarding effects: experiments with self-administration and brain-stimulation reward in rats. Neuropharmacology 53:771-82
Heidbreder, Christian A; Andreoli, Michela; Marcon, Cristina et al. (2007) Evidence for the role of dopamine D3 receptors in oral operant alcohol self-administration and reinstatement of alcohol-seeking behavior in mice. Addict Biol 12:35-50
Xi, Zheng-Xiong; Gardner, Eliot L (2007) Pharmacological actions of NGB 2904, a selective dopamine D3 receptor antagonist, in animal models of drug addiction. CNS Drug Rev 13:240-59
Pak, Arlene C; Ashby Jr, Charles R; Heidbreder, Christian A et al. (2006) The selective dopamine D3 receptor antagonist SB-277011A reduces nicotine-enhanced brain reward and nicotine-paired environmental cue functions. Int J Neuropsychopharmacol 9:585-602
Xi, Zheng-Xiong; Newman, Amy Hauck; Gilbert, Jeremy G et al. (2006) The novel dopamine D3 receptor antagonist NGB 2904 inhibits cocaine's rewarding effects and cocaine-induced reinstatement of drug-seeking behavior in rats. Neuropsychopharmacology 31:1393-405
Gilbert, Jeremy G; Newman, Amy Hauck; Gardner, Eliot L et al. (2005) Acute administration of SB-277011A, NGB 2904, or BP 897 inhibits cocaine cue-induced reinstatement of drug-seeking behavior in rats: role of dopamine D3 receptors. Synapse 57:17-28
Xi, Zheng-Xiong; Gilbert, Jeremy G; Pak, Arlene C et al. (2005) Selective dopamine D3 receptor antagonism by SB-277011A attenuates cocaine reinforcement as assessed by progressive-ratio and variable-cost-variable-payoff fixed-ratio cocaine self-administration in rats. Eur J Neurosci 21:3427-38
O'Brien, Charles P; Gardner, Eliot L (2005) Critical assessment of how to study addiction and its treatment: human and non-human animal models. Pharmacol Ther 108:18-58
Heidbreder, Christian A; Gardner, Eliot L; Xi, Zheng-Xiong et al. (2005) The role of central dopamine D3 receptors in drug addiction: a review of pharmacological evidence. Brain Res Brain Res Rev 49:77-105
Thanos, Panayotis K; Katana, John M; Ashby Jr, Charles R et al. (2005) The selective dopamine D3 receptor antagonist SB-277011-A attenuates ethanol consumption in ethanol preferring (P) and non-preferring (NP) rats. Pharmacol Biochem Behav 81:190-7

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