, Volume 120, Issue 1, pp 93–98 | Cite as

Effect of (−)-DS 121 and (+)-UH 232 on cocaine self-administration in rats

  • A. Smith
  • D. C. S. Roberts
  • M. Piercey
Original Investigation


The novel dopamine autoreceptor antagonists (−)-DS 121 and (+)-UH 232 were tested for their ability to alter cocaine self-administration behavior in rats reinforced on a progressive ratio (PR) schedule. (−)-DS 121 (15 mg/kg) and (+)-UH 232 (30 mg/kg) produced significant decreases in breaking point. (−)-DS 121 produced variable results on rate of cocaine intake on an FR1 schedule, indicating that rate may on occasion be insensitive to changes in cocaine reinforcement. In animals previously trained to self-administer cocaine, (−)-DS 121 failed to maintain responding when substituted for cocaine. This profile suggests that (−)-DS 121 is a promising new candidate for the treatment of cocaine abuse.

Key words

(−)-DS 121 (+)-UH232 Cocaine Rats Self-administration 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Britton DR, Curzon P, Mackenzie RG, Kebabian JW, Williams JEG, Kerkman D (1991) Evidence for involvement of both D1 and D2 receptors in maintaining cocaine self-administration. Pharmacol Biochem Behav 39:911–915Google Scholar
  2. Corrigall WA, Coen KM (1991) Cocaine self-administration is increased by both D1 and D2 dopamine antagonists. Pharmacol Biochem Behav 39:799–802Google Scholar
  3. Dalton JCH, Vickers GJ, Roberts DCS (1986) Increased self-administration of cocaine following haloperidol: sex-dependent effects of the antiestrogen tamoxifen. Pharmacol Biochem Behav 25:497–501Google Scholar
  4. Dackis CA, Gold MS, Davies RK, Sweeney DR (1985) Bromocriptine treatment for cocaine abuse: The dopamine depletion hypothesis. Int J Psychiatry Med 15:125–135Google Scholar
  5. Dackis CA, Gold MS, Sweeney DR, Byron JP Jr, Climko R (1987) Single-dose bromocriptine reverses cocaine craving. Psychiatry Res 20:261–264Google Scholar
  6. De Wit H, Wise RA (1977) Blockade of cocaine reinforcement in rats with the dopamine receptor blocker pimozide, but not with nonadrenergic blockers phentolamine and phenoxybenzamine. Can J Psychiatry 31:195–203Google Scholar
  7. Depoortere RY, Li DH, Lane JD, Emmett-Oglesby MW (1993) Parameters of self-administration of cocaine in rats under a progressive-ratio schedule. Pharmacol Biochem Behav 45:539–548Google Scholar
  8. Drukarch B, Stoof JC (1990) D-2 dopamine autoreceptor selective drugs: do they really exist? Life Sci 47:361–376Google Scholar
  9. Ettenberg A, Pettit HO, Bloom FE, Koob GF (1982) Heroin and cocaine intravenous self-administration in rats: mediation by separate neural systems. Psychopharmacology 78:204–209Google Scholar
  10. Gawin FH, Kleber HD (1984) Cocaine abuse treatment. Open pilot trial with desipramine and lithium carbonate. Arch Gen Psychiatry 41:903–909Google Scholar
  11. Gawin FH, Riordan C, Kleber HD (1985) Methylphenidate treatment of cocaine abusers without attention deficit disorder: a negative report. Am J Drug Alcohol Abuse 11:193–197Google Scholar
  12. Gawin FH, Byck R, Kleber HD (1986) Desipramine augmentation of cocaine abstinence: initial results. Clin Neuropharmacol 9 [Suppl 4]:202–204Google Scholar
  13. Gawin FH, Kleber HD, Byck R, Rounsaville BJ et al. (1989a) Desipramine facilitation of initial cocaine abstinence. Arch Gen Psychiatry 46:117–121Google Scholar
  14. Gawin FH, Morgan C, Kosten TR, Kleber HD (1989b) Doubleblind evaluation of the effect of acute amantadine on cocaine craving. Psychopharmacology 97:402–403Google Scholar
  15. Giannini AJ, Folts DJ, Feather JN, Sullivan BS (1989) Bromocriptine and amantadine in cocaine detoxification. Psychiatry Res 29:11–16Google Scholar
  16. Gifford AN, Johnson KM (1993) A pharmacological analysis of the effects of (+)-AJ 76 and (+)-UH 232 at release regulating pre- and postsynaptic dopamine receptors. Eur J Pharmacol 237:169–175Google Scholar
  17. Gui-Hua C, Woolverton WL (1991) Antagonism of quinpirole by (+)-AJ 76: possible involvement of D3 receptors. Eur J Pharmacol 209:285–286Google Scholar
  18. Hubner CB, Moreton JE (1991) Effects of selective D1 and D2 dopamine antagonists on cocaine self-administration in the rat. Psychopharmacology 105:151–156Google Scholar
  19. Jaffe JH, Cascella NG, Kumor KM, Sherer MA (1989) Cocaine-induced cocaine craving. Psychopharmacology 97:59–64Google Scholar
  20. Khalsa HK, Shaner A, Anglin MD, Wang J (1991) Prevalence of substance abuse in a psychiatric evaluation unit. Drug Alcohol Depend 28:215–223Google Scholar
  21. Kling-Petersen T, Svensson K (1993) Effects of the preferential dopamine autoreceptor antagonist (+)-AJ 76 in the intracranial self-stimulation paradigm. Pharmacol Biochem Behav 43:495–501Google Scholar
  22. Kling-Petersen T, Ljung E, Svensson K (1994) The preferential dopamine autoreceptor antagonist (+)-UH 232 antagonizes the positive reinforcing effects of cocaine andd-amphetamine in the ICSS paradigm. Pharmacol Biochem Behav 49:345–351Google Scholar
  23. Koob GF, Le HT, Creese I (1987a) The D1 dopamine receptor antagonist SCH 23390 increases cocaine self-administration in the rat. Neurosci Lett 79:315–320Google Scholar
  24. Koob GF, Vaccarino FJ, Amalric M, Bloom FE (1987b) Positive reinforcing properties of drugs: search for neural substrates In: Engel J, Oreland L (eds) Brain reward systems and abuse. Raven Press, New York, pp 35–50Google Scholar
  25. Kosten TR, Schumann B, Wright D, Carney MK, Gawin FH (1987) A preliminary study of desipramine in the treatment of cocaine abuse in methadone maintenance patients. J Clin Psychiatry 48:442–444Google Scholar
  26. Loh EA, Roberts DCS (1990) Break-points on a progressive ratio schedule reinforced by intravenous cocaine increase following depletion of forebrain serotonin. Psychopharmacology 101:262–266Google Scholar
  27. McGregor A, Roberts DCS (1993) Dopaminergic antagonism within the nucleus accumbens or the amygdala produces differential effects on intravenous cocaine self-administration under fixed and progressive ratio schedules of reinforcement. Brain Res 624:245–252Google Scholar
  28. Meyer RE (1992) New pharmacotherapies for cocaine dependence...revisited. Arch Gen Psychiatry 49:900–904Google Scholar
  29. Piercey MF, Lum JT (1990) Electrophysiological effects of dopamine autoreceptor antagonists, (+)-AJ 76 and (+)-UH 232. Eur J Pharmacol 182:219–226Google Scholar
  30. Richardson NR, Piercey MF, Svensson K, Collins RJ, Myers JE, Roberts DCS (1993) Antagonism of cocaine self-administration by the preferential dopamine autoreceptor antagonist, (+)-AJ 76. Brain Res 619:15–21Google Scholar
  31. Richardson NR, Smith AM, Roberts DCS (1994) A single injection of either flupenthixol decanoate or haloperidol decanoate produces long-term changes in cocaine self-administration in rats. Drug Alcohol Depend 36:23–25Google Scholar
  32. Roberts DCS (1989) Breaking points on a progressive ratio schedule reinforced by intravenous apomorphine increase daily following 6-hydroxydopamine lesions of the nucleus accumbens. Pharmacol Biochem Behav 32:43–47Google Scholar
  33. Roberts DCS (1992) Neural substrates mediating cocaine reinforcement: the role of monoamine systems Lakoski JM, Galloway MP, White FJ (eds) In: Cocaine: pharmacology, physiology and clinical strategies. CRC Press, Boca Raton, pp 73–90Google Scholar
  34. Roberts DCS, Richardson NR (1992) Self-administration of psychomotor stimulants using progressive ratio schedules of reinforcement In: Wu P, Boulton A, Baker GB (eds) Neuromethods: animal models of drug addiction, vol. 24. Humana Press, Clifton, N.J., pp 263–269Google Scholar
  35. Roberts DCS, Vickers GJ (1982) A typical neuroleptics increase self-administration of cocaine: a possible screening procedure for antipsychotic drugs. Soc. Neurosci Abstr 8:1Google Scholar
  36. Roberts DCS, Vickers GJ (1984) A typical neuroleptics increase self-administration of cocaine: an evaluation of a behavioral screen for antipsychotic drug activity. Psychopharmacology 82:135–139Google Scholar
  37. Roberts DCS, Bennett SAL, Vickers GJ (1989a) The estrous cycle affects cocaine self-administration on a progressive ratio schedule in rats. Psychopharmacology 98:408–411Google Scholar
  38. Roberts DCS, Loh EA, Vickers GJ (1989b) Self-administration of cocaine on a progressive ratio schedule in rats: dose-response relationship and effect of haloperidol pretreatment. Psychopharmacology 97:535–538Google Scholar
  39. Ruffolo RRJ (1982) Important concepts of receptor theory. J Auton Pharmacol 2:277–295Google Scholar
  40. Salloum IM, Moss HB, Daley DC (1991) Substance abuse and schizophrenia: impediments to optimal care. Am J Drug Alcohol Abuse 17:321–336Google Scholar
  41. Shaner A, Khalsa ME, Roberts L, Wilkins J, Anglin D, Hsieh S-C (1993) Unrecognized cocaine use among schizophrenic patients. Am J Psychiatry 150:758–762Google Scholar
  42. Svensson KA, Hjorth S, Clark D, Carlsson A, Wikström H, Andersson B, Sanchez D, Johansson AM, Arvidsson L-E, Hacksell U, Nilsson JLG (1986a) (+)-UH 232 and (+)-AJ 76: novel stereoselective dopamine receptor antagonists with preferential action on autoreceptors. J Neural Transm 65:1–27Google Scholar
  43. Svensson KA, Johansson AM, Magnusson T, Carlsson A (1986b) (+)-AJ 76 and (+)-UH 232: central stimulants acting as preferential dopamine autoreceptor antagonists. Naunyn-Schmiedebergs Arch Pharmacol 334:234–245Google Scholar
  44. Svensson KA, Waters N, Carlsson A (1993) (-)-DS 121, a novel dopamine D3- and autoreceptor preferring antagonist: effects on locomotor activity in the rat. Soc Neurosci Abstr 19:80Google Scholar
  45. Tennant FS, Sagherian AA (1987) Double-blind comparison of amantadine and bromocriptine for ambulatory withdrawal from cocaine dependence. Arch Int Med 147:109–112Google Scholar
  46. Waters N, Lagerkvist S, Löfberg L, Piercey M, Carlsson A (1993a) The dopamine D3 receptor and autoreceptor preferring antagonists (+)-AJ 76 and (+)-UH 232; a microdialysis study. Eur J Pharmacol 242:151–163Google Scholar
  47. Waters N, Sonesson C, Svensson KA (1993b) (−)-DS 121, a novel dopamine D3- and autoreceptor preferring antagonist: biochemical and electrophysiological effects. Soc Neurosci Abstr 19:80Google Scholar
  48. Wilson MC, Schuster CR (1972) The effects of chlorpromazine on psychomotor stimulant self-administration in the rhesus monkey. Psychopharmacology 26:115–126Google Scholar
  49. Woolverton WL, Johnson KM (1992) Neurobiology of cocaine abuse. Trends Pharmacol Sci 13:193–200Google Scholar
  50. Yokel RA, Wise RA (1975) Increased lever pressing for amphetamine after pimozide: implications for a dopamine theory of reward. Science 187:547–549Google Scholar
  51. Yokel RA, Wise RA (1976) Attenuation of intravenous amphetamine reinforcement by central dopamine blockade in rats. Psychopharmacology 48:311–318Google Scholar

Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • A. Smith
    • 1
  • D. C. S. Roberts
    • 1
  • M. Piercey
    • 2
  1. 1.Department of PsychologyCarleton UniversityOttawaCanada
  2. 2.CNS ResearchUpjohn Co.KalamazzoUSA

Personalised recommendations