Abstract
The present study examined the effects of two novel dopamine D3 receptor compounds, NGB 2904 [N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-9H-fluorene-2-carboxamide], an antagonist, and CJB 090 [N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-4-(pyridin-2-yl)benzamide], a partial agonist, in two models of cocaine abuse in rhesus monkeys. To establish a dose range and time course of effects, both compounds were shown to block quinpirole-induced yawning when administered i.m. 15, 30, or 120 min before quinpirole. Next, rhesus monkeys were trained to discriminate i.m. injections of saline (0.5 ml) and cocaine (0.3 mg/kg). Neither D3 compound (0.03–3.0 mg/kg; n = 3) substituted for cocaine in any monkey. When given in combination with cocaine, CJB 090 but not NGB 2904 attenuated the discriminative stimulus effects of cocaine, shifting the cocaine dose-response curve to the right. In a separate group of monkeys, responding was maintained under a second-order schedule of either food (1.0-g pellets; n = 3) or cocaine (0.1 mg/kg/injection; n = 4) presentation. When responding was stable, a dose of NGB 2904 (1.0–5.6 mg/kg i.v.) or CJB 090 (0.3–3.0 mg/kg i.v.) was administered for 5 consecutive days, immediately before the session. CJB 090, but not NGB 2904, decreased cocaine- and food-maintained responding. These data indicate that compounds with relatively high affinity and selectivity for the D3 receptor can attenuate the discriminative and reinforcing stimulus effects of cocaine while not producing cocaine-like effects. The present findings support the continued examination of D3 compounds as pharmacological tools for better understanding the role of this receptor subtype in cocaine addiction and as potential lead compounds for novel therapeutic agents.
Footnotes
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This study was supported by the National Institute on Drug Abuse (Grants DA 12460 to M.A.N. and DA 016279 to B.A.R.) and by the NIDA Intramural Research Program (to A.H.N.). Experiments were performed in accordance with the U.S. National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the Animal Care and Use Committee of Wake Forest University. Wake Forest University is fully accredited by the Association for the Assessment and Accreditation of Laboratory Animal Care International. Environmental enrichment was provided as outlined in the Animal Care and Use Committee of Wake Forest University Nonhuman Primate Environmental Enrichment Plan.
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J.L.M. and R.C. contributed equally to this work.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.113571.
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ABBREVIATIONS: DA, dopamine; hD2L, human D2L receptor; hD3, human D3 receptor; CJB 090, N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-4-(pyridin-2-yl)benzamide; NGB 2904, N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-9H-fluorene-3-carboxamide; ANOVA, analysis of variance; TO, time-out; FR, fixed ratio; S, saline; FI, fixed interval; SB277011-A, N-[4-[2-(6-cyano-3,4-dihydro-1H-isoquinolin-2-cyclohexyl]quinoline-4-carboxamide; BP 897, N-(4-(4-2-methoxyphenyl)piperazin-1-yl)butyl-2-naphthamide HCl; PNU 99194-A, 5,6-dimethoxy-N,N-dipropyl-2,3-dihydro-1H-inden-2-amine HCl.
- Received September 7, 2006.
- Accepted January 19, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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