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Amphetamine, cocaine, and dizocilpine enhance performance on a lever-release, conditioned avoidance response task in rats


A lever-release version of the conditioned avoidance response (CAR) task was used to assess the behavioral effects of several psychomotor stimulants in rats. The indirect dopamine agonists,d-amphetamine (0.1 and 0.25 mg/kg) and cocaine (7.5 and 15 mg/kg), enhanced performance on this task. Both drugs incre ased percent avoidance responses and decreased avoidance latency. A higher dose of amphetamine (0.5 mg/kg) also decreased avoidance latency but failed to improve percent avoidance. Similar effects were seen at low (0.01 and 0.025 mg/kg) and high (0.05 mg/kg) doses of dizocilpine (MK-801), a stimulant that acts as a noncompetitive antagonist ofN-methyl-d-aspartate (NMDA) glutamate receptors. When combined with haloperidol (0.1 mg/kg), a dopamine antagonist, amphetamine (0.25 mg/kg) and dizocilpine (0.025 mg/kg) had differential effects on the lever-release CAR task. Thus, amphetamine-haloperidol was significantly better than haloperidol alone on percent avoidance but not on avoidance latency, whereas dizocilpine-haloperidol had the opposite effect: significantly better than haloperidol alone on avoidance latency but not on percent avoidance. Taken together, these results provide further support for dopaminergic mechanisms in CAR performance but suggest an opposing glutamatergic influence.

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  1. Amalric M, Koob GF (1987) Depletion of dopamine in the caudate nucleus accumbens impairs reaction-time performance in rats. J Neurosci 7:2129–2134

  2. Arnt J (1982) Pharmacological specificity of conditioned avoidance response inhibition in rats: inhibition by neuroleptics and correlation to dopamine receptor blockade. Acta Pharmacol Toxicol 51:321–329

  3. Bauer RH, Fuster JM (1978) Effects ofd-amphetamine and prefrontal cortical cooling on delayed matching-to-sample behavior. Pharmacol Biochem Behav 8:243–249

  4. Beninger RJ (1983) The role of dopamine in locomotor activity and learning. Brain Res Rev 6:173–196

  5. Carlsson A, (1978) Antipsychotic drugs, neurotransmitters, and schizophrenia. Am J Psychiatry 135:164–173

  6. Carlsson M, Carlsson A (1989) The NMDA antagonist MK-801 causes marked locomotor stimulation in monoamine-depleted mice. J Neural Transm 75:221–226

  7. Carlsson M, Carlsson A (1990) Interactions between glutaminergic and monoaminergic systems within the basal ganglia — implications for schizophrenia and Parkinson's disease. Tr Neurosci 13:272–276

  8. Cook L, Davidson AB (1978) Behavioral pharmacology: animal models involving aversive control of behavior. In: Lipton MA, Di Mascio A, Killam KF (eds) Psychopharmacology: a generation of progress. Raven Press, New York, pp 563–567

  9. Criswell HE, Johnson KB, Mueller RA, Breese GR (1993) Evidence for involvement of brain dopamine iiiiand other mechanisms in the behavioral action of theN-methyl-d-aspartic acid antagonist MK-801 in control and 6-hydroxydopamine-lesioned rats. J Pharmacol Exp Ther 265:1001–1010

  10. Davis M (1985) Cocaine: excitatory effects on sensorimotor reactivity measured with acoustic startle. Psychopharmacology 87:31–36

  11. Dews PB (1958) Studies on behavior. IV. Stimulant actions of methamphetamine. J Pharmacol Exp Ther 122:137–147

  12. Di Chiara G, Morelli M (1993) Dopamine-acetylcholine-glutamate interactions in the striatum. In: Narabayashi H, Nagatsu T, Yanagisawa N, Mizuno Y (eds) Advances in neurology, vol. 60. Raven Press, New York, pp 102–106

  13. Dunnett SB, Robbins TW (1992) The functional role of mesotelencephalic dopamine systems. Biol Rev 67:491–518

  14. Ellenbroek BA (1993) Treatment of schizophrenia-a clinical and preclinical evaluation of neuroleptic drugs. Pharmacol Ther 57:1–78

  15. Fowler C, Ford KE, Gramling SE, Nail GL (1984) Acute and subchronic effects of neuroleptics on quantitative measures of discriminative motor control in rats. Psychopharmacology 84:373–386

  16. Greenamyre JT (1993) Glutamate-dopamine interactions in the basal ganglia — relationship to Parkinson's disease. J Neural Transm 91:255–269

  17. Harty TP, Davis M (1985) Cocaine: effects on acoustic startle and startle elicited electrically from the cochlear nucleus. Psychopharmacology 87:396–399

  18. Heise GA, Boff E (1962) Continuous avoidance as a base-line for measureing behavioral effects of drugs. Psychopharmacologia 3:264–282

  19. Hienz RD, Lukas SE, Brady JV (1985) Effects ofd-methamphetamine and auditory and visual reaction times and detection thresholds in the baboon. Psychopharmacology 85:476–482

  20. Hienz RD, Spear DJ, Brady JV, Bowers DA (1993) Effects of cocaine on sensory motor function in baboons. Pharmacol Biochem Behav 45:399–408

  21. Janak PH, Maritinez Jr JL (1992) Cocaine and amphetamine facilitate retention of jump-up responding in rats. Pharmacol Biochem Behav 41:837–840

  22. Kemp JA, Foster AC, Wong EHF (1987) Non-competitive antagonists of excitatory amino acid receptors. Trends Neurosci 10:294–298

  23. Koelega HS (1993) Stimulant drugs and vigilance performance: a review. Psychopharmacology 111:1–16

  24. Kuribara H (1993) Ceruletide, a cholecystokinin-like decapeptide, differentially reduces the stimulant effect of MK-801 and ketamine: evaluation by discrete shuttle avoidance in mice. Eur J Pharmacol 231:7–11

  25. Kuribara H, Tadokoro S (1981) Correlation between antiavoidance activities of antipsychotic drugs in rats and daily clinical doses. Pharmacol Biochem Behav 14:181–192

  26. Laduron PM (1989) Dopamine receptors and neuroleptic drugs. In: Boulton AB, Baker GB, Juorio AV (eds) Neuromethods, vol. 12: drugs as tools in neurotransmitter research. Humana Press, Clifton, N.J. pp 261–298

  27. Lillrank SM, O'Connor WT, Saransaari P, Ungerstedt U (1994) In vivo effects of local and systemic phencyclidine on the extracellular levels of catecholamines and transmitter amino acids in the dorsolateral striatum of anaesthetized rats. Acta Physiol Scand 150:109–115

  28. MacPhail RC, Gollub LR (1975) Separating the effects of response rate and reinforcement frequency in the rate-dependent effects of amphetamine and scopolamine on the schedule-controlled performance of rats and pigeons. J Pharmacol Exp Ther 194:332–342

  29. Marrow L, Overton P, Clark D (1992) Amelioration of some neuroleptic-induced deficits by the NMDA antagonist MK-801 in a conditioned reaction time task. Behav Pharmacol 3:57–64

  30. Mayfield RD, Randall PK, Spirduso WW, Wilcox RE (1993a) Selective D1 and D2 dopamine receptor antagonists produce differential effects on reaction time in the rat. Pharmacol Biochem Behav 46:759–768

  31. Mayfield RD, Randall PK, Spirduso WW, Wilcox RE (1993b) Apomorphine and amphetamine produce differential effects on the speed and success of reaction time responding in the rats. Pharmacol Biochem Behav 46:769–775

  32. McCulloough LD, Salamone JD (1992) Increases in extracellular dopamine levels and locomotor activity after direct infusion of phenyclidine into the nucleus accumbens. Brain Res 577:1–9

  33. Miller DW, Abercrombie ED (1993) MK-801 induced stimulation of striatal dopamine release: analysis of possible mechanisms. Soc Neurosci Abstr 19:1175

  34. Mondadori C, Weiskrantz L (1993) NMDA receptor blockers facilitate and impair learning via different mechanisms. Behav Neural Biol 60:205–210

  35. Olney JW, Price MT, Labruyer J, Shahid Salles K, Frierdich G, Mueller M, Silverman E (1987) Anti-Parkinsonian agents are phencyclidine agonists andN-methyl aspartate antagonists. Eur J Pharmacol 142:319–320

  36. Pierce RC, Rebec GV (1993) Intraneostriatal administration of glutamate antagonists increases behavioral activation and decreases neostriatal ascorbate via non-dopaminergic mechanisms. J Neurosci 13:4272–4280

  37. Rebec GV, Bashore TR (1984) Critical issues in assessing the behavioral effects of amphetamine. Neurosci Biobehav Rev 8:153–159

  38. Salamone JD (1988) Dopaminergic involvement in activational aspects of motivation: effects of haloperidol on schedule-induced activity, feeding and foraging in rats. Psychobiology 16:196–206

  39. Salamone JD (1992) Complex motor and sensorimotor functions of striatal and accumbens dopamine — involvement in instrumental behavior processes. Psychopharmacology 107:160–174

  40. Sanger DJ (1986) The effect of clozapine on shuttle-box avoidance responding in rats: comparison with haloperidol and chlorodiazapoxide. Pharmacol Biochem Behav 23:231–236

  41. Schmidt WJ, Bubser M (1989) Anticataleptic effects of theN-methyl-d-aspartate antagonist MK-801 in rats. Pharmacol Biochem Behav 32:621–623

  42. Schwartz J-C, Giros B, Martres M-P, Sokoloff P (1992) The dopamine receptor family: molecular biology and pharmacology. Semin Neurosci 4:99–108

  43. Seeman P (1980) Brain dopamine receptors. Pharmacol Rev 32:229–313

  44. Snell LD, Yi SJ, Johnson KM (1988) Comparison of the effects of MK-801 and phencyclidine on catecholamine uptake and NMDA-induced norepinephrine release. Eur J Pharmacol 145:223–226

  45. Spirduso WW, Gilliam P, Wilcox RE (1984) Reactive capacity: a sensitive behavioral marker of movement initiation and nigrostriatal dopamine function. Psychopharmacology 83:205–209

  46. Spirduso WW, Gilliam PE, Schallert T, Upchurch M, Vaughn DM, Wilcox RE (1985) Reactive capacity: a sensitive behavioral marker of movement initiation and nigrostriatal dopamine function. Brain Res 335:45–54

  47. Starr MS, Starr BS (1993) Glutamate-dopamine interactions in the production of pilocarpine motor seizures in the mouse. J Neural Transm 6:109–117

  48. Sunahara RK, Seeman P, Vantol HHM, Niznik HB (1993) Dopamine receptors and antipsychotic drug response. Br J Psychiatry 163:31–38

  49. Tschanz JT and Rebec GV (1988) Atypical antipsychotic drugs block selective components of amphetamine-induced stereotypy. Pharmacol Biochem Behav 31:519–522

  50. Waddington JL, O'Boyle KM (1989) Drugs acting on brain dopamine receptors: a conceptual re-evaluation five years after the first selective D-1 antagonist. Pharmac Ther 43:1–52

  51. Weiss B, Laties VG (1962) Enhancement of human performance by caffeine and the amphetamines. Pharmacol Rev 14:1–36

  52. White IM, Rebec GV (1993) Responses of rat striatal neurons during performance of a lever-release version of the conditioned avoidance response task. Brain Res 616:71–82

  53. White IM, Rebec GV (1994) Performance on a lever-release, conditioned avoidance response task involves both D1 and D2 dopamine receptors. Eur J Pharmacol 253:167–169

  54. White IM, Ciancone MT, Haracz JH, Rebec GV (1992) A lever-release version of the conditioned avoidance response paradigm: effects of haloperidol, clozapine, sulpiride and BMY-14802. Pharmacol Biochem Behav 41:29–35

  55. White IM, Miller DP, White W, Gretchen LD, Rebec GV, Steinmetz JE (1994) Neuronal activity in rabbit neostriatum during classical eyelid conditioning. Exp Brain Res 99:179–190

  56. Wilcox RE, Spirduso WW (1988) Apomorphine doses impair the reaction time of fast reacting but not slow reacting rats. Psychopharmacology 95:276–279

  57. Wilcox RE, Mudie E, Mayfield D, Young RK (1988) Movement initiation characteristics in young adult rats in relation to the high- and low-affinity agonist states of the striatal D2 dopamine receptor. Brain Res 443:190–198

  58. Yeh SY, Haertzen CA (1991) Cocaine-induced locomotor activity in rats. Pharmacol Biochem Behav 39:723–727

  59. Zhang J, Chiodo LA, Freeman AS (1992) Electrophysiological effects of MK-801 on rat nigrostriatal and mesoaccumbal dopaminergic neurons. Brain Res 590:153–163

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Correspondence to G. V. Rebec.

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White, I.M., Christensen, J.R., Flory, G.S. et al. Amphetamine, cocaine, and dizocilpine enhance performance on a lever-release, conditioned avoidance response task in rats. Psychopharmacology 118, 324–331 (1995). https://doi.org/10.1007/BF02245962

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Key words

  • Amphetamine
  • Cocaine
  • Conditioned avoidance response task
  • Dizocilpine
  • Haloperidol