Abstract
Developing rats are far more sensitive than adults to the behavioral effects of haloperidol. The present results support the hypothesis that this change may reflect age-related changes in brain responses such as alterations in drug-receptor or drug-effector mechanisms. Dose-response studies of catalepsy and ptosis were conducted in male Sprague-Dawley rats aged 30, 56, or 100 days. Resulting dose-effect curves were approximately parallel and showed rightward shifts with highly significant progressive increases of ED50. Similar developmental decreases in drug sensitivity (3–6 ×) were found following systemic (PO or IP) administration of haloperidol or the phenothiazine neuroleptic perphenazine, which differ markedly in structure, potency, distribution, and metabolism. Age-related decreases in drug sensitivity (3–4 ×) were also found using intracerebroventricular (ICV) administration of both agents in an attempt to bypass potential “pharmacokinetic” influences. Since the age-dependent decrease in sensitivity to both neuroleptics was found during the rising phase of drug action (1st hour) and ranked: PO>IP>ICV, some change in absorption and distribution of both drugs may occur in addition to the apparently important maturational decrease in target-organ sensitivity indicated by the responses to direct ICV injection and by the similarity of results obtained with dissimilar agents.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Baldessarini RJ (1985) Chemotherapy in psychiatry: principles and practice. Harvard University Press, Cambridge, pp 14–92
Brakkee JH, Wiegant VM, Gispen WH (1979) A simple technique for rapid implantation of a permanent cannula into the rat brain ventricular system. Lab Anim Sci 29:78–81
Brus R, Krzeminski T, Pigula J (1983) Cataleptogenic effect of haloperidol, chlorpromazine, and morphine in developing rats. Pol J Pharmacol Pharm 35:377–382
Campbell A, Baldessarini RJ (1981a) Effects of maturation and aging on behavioral responses to haloperidol in the rat. Psychopharmacology 73:219–222
Campbell A, Baldessarini RJ (1981b) Tolerance to behavioral effects of haloperidol. Life Sci 29:1341–1346
Campbell A, Baldessarini RJ, Stoll A, Teicher MH, Maynard P (1984) Effect of age on behavioral responses and tissue levels of apomorphine in the rat. Neuropharmacology 23:725–730
Campbell A, Baldessarini RJ, Teicher MH, Neumeyer JL (1985) S(+)apomorphines: Selective inhibition of excitatory effects of dopamine injected into the limbic system of the rat. Neuropharmacology 21:391–399
Cheronis JC, Erinoff L, Heller A, Hoffmann PC (1979) Pharmacological analysis of the functional ontogeny of the nigrostriatal dopaminergic neurons. Brain Res 169:545–560
Coyle JT, Compochiaro P (1976) Ontogenesis of dopaminergic-cholinergic interaction in the rat striatum: A neurochemical study. J Neurochem 27:673–678
Coyle S, Napier TC, Breese GR (1985) Ontogeny of tolerance to haloperidol: Behavioral and biochemical measures. Dev Brain Res 23:27–38
DeLean A, Munson PG, Rodbard D (1978) Simultaneous analysis of families of sigmoid curves: Application to bioassay, radioligand assay, and physiological dose-response curves. Am J Physiol 4:E97-E102
Forrest IS, Carr CJ, Usdin E (eds) (1974) Phenothiazines and related compounds. Raven, New York, p 818
Kapetanovic IM, Sweeney DJ, Rapoport SI (1982) Age effects on haloperidol pharmacokinetics in male Fischer-344 rats. J Pharmacol Exp Ther 221:434–438
Keepers GA, Clappison VJ, Casey DE (1983) Initial anticholinergic prophylaxis for acute neuroleptic induced extrapyramidal syndromes. Arch Gen Psychiatry 40:1113–1117
Lewi PJ, Heykants JJ, Allewijn FT, Dony JG, Janssen PA (1970) Distribution and metabolism of neuroleptic drugs. Arzneimittelforschung 20:943–948
Meyer ME, Smith RL, Van Hartesveldt C (1984) Haloperidol differentially potentiates tonic immobility, the dorsal immobility response, and catalepsy in the developing rat. Dev Psychobiol 17:383–389
Murrin LC, Zeng W (1986) Postnatal ontogeny of dopamine D-2 receptors in rat striatum. Biochem Pharmacol 35:1159–1162
Murrin LC, Gibbens DL, Ferrer JR (1985) Ontogeny of dopamine, serotonin, and spirodecanone receptors in rat forebrain — an autoradiographic study. Dev Brain Res 23:91–109
O'Boyle KM, Waddington JL (1986) A reevaluation of changes in rat striatal D-2 dopamine receptors during development and aging. Neurobiol Aging 7:265–267
Pellegrino LJ, Cushman AJ (1967) A stereotaxic atlas of the rat brain. Meredith, New York, pp 10–25
Pizzolato G, Soncrant TT, Holloway HW, Rapoport SI (1985) Reduced metabolic response of the aged rat brain to haloperidol. J Neurosci 5:2831–2838
Stoll AL, Baldessarini RJ, Cohen BM, Finklestein SP (1984) Assay of plasma thioridazine and metabolites by high-performance liquid chromatography with amperometric detection. J Chromatogr Biomed Appl 307:457–463
Sunderland T, Cohen BM (1987) Blood to brain distribution of neuroleptics. Psychiatry Res 20:299–305
Teicher MH (1983) MED-65 ALLFIT, GRAFIT (Applesoft): Conversion of the iterative non-linear least-squares logistic dose-response analysis programs of P.J. Munson, A. DeLean, and D. Rodbard to the Apple II computer, with addition of a new graphics package. Biomedical Computing Technology Information Center, Vanderbilt University, Nashville, TN
Teicher MH, Baldessarini RJ (1987) Developmental pharmacodynamics. In: Popper C (ed) Developmental pharmacosciences of children and adolescents. Washington, APA Press, pp 45–80
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Campbell, A., Baldessarini, R.J. & Teicher, M.H. Decreasing sensitivity to neuroleptic agents in developing rats; evidence for a pharmacodynamic factor. Psychopharmacology 94, 46–51 (1988). https://doi.org/10.1007/BF00735879
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00735879