, Volume 53, Issue 3, pp 283–288 | Cite as

Blockade of intracranial self-stimulation by antipsychotic drugs: Failure to correlate with central alpha-noradrenergic blockade

  • Peter Zarevics
  • Edwin Weidley
  • Paulette Setler


The involvement of central alpha-noradrenergic receptors in intracranial self-stimulation (ICSS) was studied. Dose-response curves were established for the blockade of ICSS by the antipsychotic drugs chlorpromazine, thioridazine, clozapine, and pimozide and the alpha-antagonist phenoxybenzamine. Antagonism of the facilitation, produced by the central alpha-agonist clonidine, of flexor withdrawal reflexes in the reserpinized spinal rat was used to assess the central alpha-blocking potency of the same drugs, and dose-response curves were established. No correlation was found between central alpha-blockade, as reflected by the ED50 for blockade of clonidine-facilated spinal reflexes, and the ED50 for blockade of ICSS. Pimozide blocked ICSS at doses virtually devoid of central alpha-blocking activity, while phenoxybenzamine was a potent alpha-antagonist and a weak blocker of ICSS. The lack of correlation between central alpha-blockade and decreased ICSS suggests that alpha-receptors are not critically involved in self-stimulation behavior.

Key words

Alpha-receptors Intracranial selfstimulation Antipsychotic drugs Phenoxybenzamine Clonidine Spinal reflexes 


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  1. Andén, N. E.: Changes in the impulse flow of central monoamine nerves by drugs affecting monoamine receptors. Acta Pharmacol. Toxicol. [Suppl.] (Kbh.) 25, 4, 1–5 (1967)Google Scholar
  2. Andén, N. E., Corrodi, H., Fuxe, K., Hökfelt, T.: Increased impulse flow in bulbospinal noradrenaline neurons produced by catecholamine receptor blocking agents. Eur. J. Pharmacol 2, 59–64 (1967)Google Scholar
  3. Andén, N. E., Corrodi, H., Fuxe, K., Hökfelt, T., Rydin, C., Svensson, T.: Evidence for a central noradrenaline receptor stimulation by clonidine. Life Sci. 9, 513–523 (1970a)Google Scholar
  4. Andén, N. E., Butcher, S. G., Corrodi, H., Fuxe, K., Ungerstedt, U.: Receptor activity and turnover of dopamine and noradrenaline after neuroleptics. Eur. J. Pharmacol. 11, 303–315 (1970b)Google Scholar
  5. Andén, N. E., Strömbom, V.: Adrenergic receptor blocking agents: effects on central noradrenaline and dopamine receptors and on motor activity. Psychopharmacologia (Berl.) 38, 91–103 (1974)Google Scholar
  6. Arbuthnott, G. W., Crow, T. J., Fuxe, K., Olson, L., Ungerstedt, U.: Depletion of catecholamines in vivo induced by electrical stimulation of central monoamine pathways. Brain Res. 24, 471–483 (1970)Google Scholar
  7. Black, W. C., Cooper, B. R.: Reduction of electrically-rewarded behavior by interference with monoamine synthesis. Physiol. Behav. 5, 1405–1409 (1970)Google Scholar
  8. Breese, G. R., Howard, J. L., Leahy, J. P.: Effect of 6-hydroxydopamine on electrical self-stimulation of the brain. Br. J. Pharmacol. 43, 255–257 (1971)Google Scholar
  9. Clavier, R. M., Routtenberg, A.: Ascending monoamine-containing fiber pathways related to intracranial self-stimulation: histochemical fluorescence study. Brain Res. 72, 25–40 (1974)Google Scholar
  10. Cooper, B. R., Cott, J. M., Breese, G. R.: Effects of catecholaminedepleting drugs and amphetamine on self-stimulation of brain following various 6-hydroxydopamine treatments. Psychopharmacologia (Berl.) 37, 235–248 (1974)Google Scholar
  11. Crow, T. J.: Catecholamine-containing neurones and electrical self-stimulation: 1. A review of some data. Psychol. Med. 2, 414–421 (1972)Google Scholar
  12. Finney, D. J.: Statistical method in biological assay. New York: Hafner Publishing Co. 1952Google Scholar
  13. Fouriezos, G., Wise, R. A.: Pimozide-induced extinction of intracranial self-stimulation: response patterns rule out motor or performance deficits. Brain Res. 103, 377–380 (1976)Google Scholar
  14. German, C. G., Bowden, D. M.: Catecholamine systems as the neural substrate for intracranial self-stimulation: a hypothesis. Brain Res. 73, 381–419 (1974)Google Scholar
  15. Gibson, S., McGeer, E. G., McGeer, P. L.: Effect of selective inhibitors of tyrosine and tryptophan hydroxylases on self-stimulation in the rat. Exp. Neurol. 27, 283–290 (1970)Google Scholar
  16. Hastings, L., Stutz, R. M.: The effects of alpha-and beta-adrenergic antagonists on the self-stimulation phenomenon. Life Sci. 13, 1253–1259 (1973)Google Scholar
  17. Hunt, G. E., Atrens, D. M., Chesher, G. B. Becker, F. T.: α-Noradrenergic modulation of hypothalamic self-stimulation: studies employing clonidine, l-phenylephrine and α-methyl-p-tyrosine. Eur. J. Pharmacol. 37, 105–111 (1976)Google Scholar
  18. Kamei, C., Masuda, Y., Shimizu, M.: Effects of psychotropic drugs on hypothalamic self-stimulation behavior in rats. Jpn. J. Pharmacol. 24, 613–619 (1974)Google Scholar
  19. König, J. F. R., Klippel, R. A.: The rat brain: a stereotaxic atlas of the forebrain and lower parts of the brain stem. Baltimore: Williams and Wilkins 1963Google Scholar
  20. Liebman, J. M., Butcher, L. L.: Effects on self-stimulation behavior of drugs influencing dopaminergic neurotransmission mechanisms. Naunyn Schmiedebergs Arch. Pharmacol 277, 305–318 (1973)Google Scholar
  21. Lippa, A. S., Antelman, S. M., Fisher, A.E., Canfield, D. R.: Neurochemical mediation of reward: significant role for dopamine? Pharmacol. Biochem. Behav. 1, 23–28 (1973)Google Scholar
  22. Olds, M. E.: Comparative effects of amphetamine, scopolamine chlordiazepoxide, and diphenylhydantoin on operant and extinction behavior with brain stimulation and food reward. Neuropharmacology 9, 519–532 (1970)Google Scholar
  23. Olds, M. E., Yuwiler, A.: Effect of brain stimulation in positive and negative reinforcing regions in the rat on content of catecholamines in hypothalamus and brain. Brain Res. 36, 385–398 (1972)Google Scholar
  24. Phillips, A. E., Fibiger, H. C.: Dopaminergic and noradrenergic substrates of positive reinforcement: differential effects of d-and l-amphetamine. Science 179, 575–577 (1973)Google Scholar
  25. Phillips, A. G., Brooke, S. M., Fibiger, H. C.: Effects of amphetamine isomers and neuroleptics on self-stimulation from the nucleus accumbens and dorsal noradrenergic bundle. Brain Res. 85, 13–22 (1975)Google Scholar
  26. Phillips, A. G., Carter, D. A., Fibiger, H. C.: Dopaminergic substrates of intracranial self-stimulation in the caudate putamen. Brain Res. 104, 221–232 (1976)Google Scholar
  27. Poschel, B. P. H., Ninteman, F. W.: Norepinephrine: a possible excitatory neurohormone of the reward system. Life Sci., 2, 782–788 (1963)Google Scholar
  28. Ritter, S., Stein, L.: Self-stimulation of noradrenergic cell group (A6) in locus coeruleus of rats. J. Comp. Physiol. Psychol. 85, 443–452 (1973)Google Scholar
  29. Rolls, E. T., Kelly, P. H., Shaw, S. G.: Noradrenaline, dopamine, and brain-stimulation reward. Pharmacol. Biochem. Behav. 2, 735–740 (1974)Google Scholar
  30. Stawarz, R. J., Hill, H., Robinson, S. E., Setler, P., Dingell, J. V., Sulser, F.: On the significance of the increase in homovanillic acid (HVA) caused by antipsychotic drugs in corpus striatum and limbic forebrain. Psychopharmacologia (Berl.) 43, 125–130 (1975)Google Scholar
  31. Stein, L.: Self-stimulation of the brain and the central stimulant action of amphetamine. Fed. Proc. 23, 836–850 (1964)Google Scholar
  32. Stein, L.: Chemistry of reward and punishment. In: Psychopharmacology, a review of progress: 1957–1967, D. H. Efron, ed., pp. 105–123. Washington: U.S. Government Printing Office 1968Google Scholar
  33. Stinus, L., Thierry, A. M.: Self-stimulation and catecholamines. II. Blockade of self-stimulation by treatment with alpha-methylparatyrosine and the reinstatement by catecholamine precursor administration. Brain Res. 64, 189–198 (1973)Google Scholar
  34. Stinus, L., Thierry, A. M., Blanc, G., Glowinski, J., Cardo, B.: Self-stimulation and catecholamines. III. Effect of imposed or self-stimulation in the area ventralis tegmenti on catecholamine utilization in the rat brain. Brain Res. 64, 199–210 (1973)Google Scholar
  35. St. Laurent, J., Roizen, M. F., Miliaressis, E., Jacobowitz, D. M.: The effects of self-stimulation on the catecholamine concentration of discrete areas of the rat brain. Brain Res. 99, 194–200 (1975)Google Scholar
  36. Ungerstedt, U.: Striatal dopamine release after amphetamine or nerve degeneration revealed by rotational behavior. Acta Physiol. Scand. [Suppl. 367] 82, 49–68 (1971)Google Scholar
  37. Wauquier, A., Niemegeers, C. J. E.: Intracranial self-stimulation in rats as a function of various stimulus parameters. II. Influence of haloperidol, pimozide and pipamperone on medial forebrain bundle stimulation with monopolar electrodes. Psychopharmacologia (Berl.) 27, 191–202 (1972)Google Scholar
  38. Wise, C. D., Berger, B. D., Stein, L.: Evidence of α-noradrenergic reward receptors and serotonergic punishment receptors in the rat brain. Biol. Psychol. 6, 3–21 (1973)Google Scholar

Copyright information

© Springer-Verlag 1977

Authors and Affiliations

  • Peter Zarevics
    • 1
  • Edwin Weidley
    • 1
  • Paulette Setler
    • 1
  1. 1.Smith Kline & French LaboratoriesPhiladelphiaU.S.A.

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