Summary
A single injection of diazepam (10 mg/kg, s. c.), haloperidol (2 mg/kg, i. p.) or chlorpromazine (10 mg/kg, i. p.) decreased the ambulatory as well as sniffing behaviour of rats. These behavioural responses were further decreased when diazepam was administered concurrently with the neuroleptic. Acute haloperidol or chlorpromazine treatment increased striatal dopamine as well as cerebro-cortical norepinephrine turnover. In contrast, diazepam diminished the release of both of these catecholamines. When diazepam was administered together with haloperidol or chlorpromazine, a further decrease particularly in dopamine release was seen in striatum. This effect of diazepam on norepinephrine and dopamine turnover persisted even after 21 days of daily treatment. Similarly, the sedative effect of diazepam elicited in the form of depressed locomotor activity was also apparent after long-term administration of this benzodiazepine. However, chronic administration of neuroleptics enhanced the spontaneous locomotor activity and sniffing behaviour by about 25% Furthermore, repeated neuroleptic treatment decreased the synthesis and turnover of dopamine and norepinephrine. This was reflected in decreased tyrosine hydroxylase and homovanillic acid level in striatum as well as by low concentration of 3-methoxy-4-hydroxyphenylethylene glycol in the cerebral cortex. When diazepam was administered together with haloperidol or chlorpromazine for 21 days, behavioural activity remained elevated and was comparable to groups of rats receiving neuroleptics alone. The concommitant injection of diazepam and neuroleptics for 21 days elicited a synergistic effect on decreased synthesis and release of dopamine as well as norepinephrine. These data provide neurochemical evidence for potentiation of the neuroleptic effects by a benzodiazepine.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Al-Shabibi, U. M. H., Doggett, N. S.: On the central noradrenergic mechanism involved in haloperidol-induced catalepsy in the rat. J. Pharm. Pharmacol.30, 529–532 (1978).
Beckmann, H., Haas, S.: High dose of diazepam in schizophrenia. Psychopharmacology71, 79–82 (1980).
Bird, E. D., Spokes, E. G., Iverssen, L. L.: Brain norepinephrine and dopamine in schizophrenia. Science204, 93–94 (1979).
Blumberg, J. B., Vetulani, J., Stawarz, R. J., Sulser, F.: The noradrenergic cyclic AMP generating system in the limbic forebrain: pharmacological characterization and possible role in the mode of action of antipsychotics. Eur. J. Pharmacol.37, 357–366 (1976).
Broadhurst, P. L.: Experiments in psychogenetics. In: Experiments in personality (Eysenck, HJ., ed.), pp. 3–71. London: Routledge & Kegan Paul. 1960.
Burt, D. R., Creese, I., Pardo, J., Coyle, J. T., Snyder, S. H.: Dopamine receptor binding: influences of age, chronic drugs and specific lesions. Neurosci. Soc. Abstr.6, 775 (1976).
Carlsson, A.: Does dopamine play a role in schizophrenia? Psychol. Med.7, 583–597 (1977).
Carlsson, A.: Does dopamine have a role in schizophrenia? Biol. Psychiat.13, 3–21 (1978).
Carlsson, A., Persson, T., Roos, B. E., Walinder, J.: Potentiation of phenothiazines by α-methyltyrosine in treatment of chronic schizophrenia. J. Neural Transm.33, 83–90 (1972).
Corrodi, H., Fuxe, K., Lidbrink, P., Olson, L.: Minor tranquilizers, stress and central catecholamine neurons. Brain Res.29, 1–16 (1971).
Costa, E., Guidotti, A., Mao, C. C., Suria, A.: New concepts on the mechanism of action of benzodiazepines. Brain Res.29, 1–14 (1975).
Costall, B., Naylor, R. J.: The importance of the ascending dopaminergic systems to the extrapyramidal and mesolimbic brain areas for the cateleptic action of the neuroleptic and cholinergic agents. Neuropharmacology13, 353–364 (1974).
Crane, G. E.: Factors predisposing to drug-induced neurologic effects. In: Advances in Biochemical Psychopharmacology,Vol. 9 (Costa, E., Greengard, P., eds.), pp. 269–279. New York: Raven Press. 1974.
Dunstan, R., Jackson, D. M.: The demonstration of a change in adrenergic receptor sensitivity in the central nervous system of mice after withdrawal from long-term treatment with haloperidol. Psychopharmacology48, 131–141 (1977).
Farley, I. J., Price, K. S., McCullough, E., Deck, J. H. N., Hordynski, W., Hornykiewicz, O.: Norepinephrine in chronic paranoid schizophrenia: above normal levels in limbic forebrain. Science200, 456–458 (1978).
Feltz, P.:γ-Aminobutyric acid and a caudato-nigral inhibition. Can. J.Physiol. Pharmacol.49, 1113–1115 (1971).
Fuxe, K., Agneti, L. F., Bolme, P., Hokfelt, T., Lidbrink, P., Ljungdahl, A., Mignel, P. M., Ogren, S. O.: The possible involvement of GABA mechanisms in the action of benzodiazepines on central catecholamine neurons. In: Mechanisms of action of benzodiazepines (Costa, E., Greengard, P., eds.), pp. 45–62. New York: Raven Press. 1975.
Guz, I., Moraes, R., Sartoretto, J. N.: The therapeutic effects of lorazepam with psychotic patients treated with haloperidol-a double-blind study. Curr. Ther. Res.14, 761–774 (1972).
Hanlon, T. E., Ota, K. Y., Kurland, A. A.: Comparative effects of fluphenazine, fluphenazine-chlordiazepoxide and fluphenazine-imipramine. Dis. Nerv. Syst.37, 257–261 (1976).
Jus, A., Pineau, R., Lachance, R., Pelchat, G., Jus, K., Pires, P., Villeneuve, A.: Epidemiology of tardive dyskinesia, Part II. Dis. Nerv. Syst.37, 257–261 (1976).
Kellner, R., Wilson, R. M., Muldawer, M. D.: Anxiety in schizophrenia: the responses to chlordiazepoxide in an intensive design study. Arch. Gen. Psychiat.32, 1246–1254 (1975).
Lake, C. R., Sternberg, D. E., van Kämmen, D. P., Ballenger, J. C., Ziegler, M. G., Post, R. M., Kopin, I. J., Bunney, W. E.: Schizophrenia: elevated cerebrospinal fluid norepinephrine. Science207, 331–333 (1980).
Lerner, P., Nose, P., Gordon, E. K., Lovenberg, W.: Effect of long-term treatment on rat striatal dopamine synthesis and turnover. Science197, 181–183 (1977).
Lingjaerde, O., Engstrand, E., Ellingsen, P., Stylo, D. A., Robak, O. H.: Antipsychotic effect of diazepam when given in addition to neuroleptics in chronic psychotic patients: a double-blind clinical trial. Curr. Ther. Res.26, 505–514 (1979).
List, S. J., Seeman, P.: Dopamine agonists reverse the elevated3H-neuroleptic binding in neuroleptic-pretreated rats. Life Sci.24, 1447–1452 (1979).
Maickel, R. B., Cox, R. H. Jr., Saillant, J., Miller, P. R.: A method for the determination of serotonin and norepinephrine in discrete areas of rat brain. Int. J. Neuropharmacol.7, 275–281 (1968).
Meek, J. L.: Fluorometric estimation of 4-hydroxy-3-methoxyphenylethylene glycol sulfate in brain. Brit.J. Pharmacol.45, 435–441 (1972).
Muller, P., Seeman, P.: Brain neurotransmitter receptors after long-term haloperidol: dopamine, acetylcholine, serotonin,α-noradrenergic and naloxone receptors. Life Sci.21, 1751–1758 (1977).
Murphy, G. F., Robinson, D., Sharman, D. F.: The effect of tropolone on the formation of 3, 4-dihydroxyphenylacetic acid in the brains of the mouse. Brit. J. Pharmacol.36, 107–115 (1969).
Nagy, J. I., Lee, T., Seeman, P., Fibiger, H. C.: Direct evidence for pre-synaptic and post-synaptic dopamine receptors in brain. Nature274, 278–281 (1978).
Nair, N. P. V.: Personal Communication (1980).
Peroutka, S. J., U'Prichard, D. C., Greenberg, D. A., Snyder, S. H.: Neuroleptic drug interactions with norepinephrine alpha receptor binding sites in rat brain. Neuropharmacology16, 549–556 (1977).
Rastogi, R. B., Agarwal, R. A., Lapierre, Y. D., Singhal, R. L.: Effects of acute diazepam and clobazam on spontaneous locomotor activity and central amine metabolism in rats. Eur. J. Pharmacol.43, 91–98 (1977).
Rastogi, R. B., Lapierre, Y. D., Singhal, R. L.: Evidence for the role of brain norepinephrine and dopamine in “rebound” phenomenon seen during withdrawal after repeated exposure to benzodiazepines. J. Psychiat. Res.13, 65–75 (1976).
Roberts, E.: Disinhibition as an organizing principle in the nervous system-the role of the GABA system. Application to neuroleptic and psychiatric disorders. In: GABA in nervous system function (Roberts, E., Chase, T. N., Tower, D. B., eds.), pp. 515–539. New York: Raven Press. 1976.
Sedvall, G., Fyro, B., Nayback, H., Wiesel, F. A.: Actions of dopaminergic antagonists in the striatum. In: Advances in neurology, Vol. 9 (Calne, D., Chase, T. N., Barbeau, A., eds.), pp. 131–140. New York: Raven Press. 1975.
Spano, P. F., Neff, N. H.: Procedure for simultaneous determination of dopamine, 3-methoxy-4-hydroxyphenylacetic acid and 3,4-dihydroxyphenylacetic acid in brain. Anal. Biochem.42, 113–118 (1971).
Stein, L., Wise, C. D., Belluzzi, J. D.: Effects of benzodiazepines on central serotonergic mechanisms. In: Mechanism of action of benzodiazepines: Advances in biochemical psychopharmacology (Costa, E., Greengard, P., eds.), pp. 29–44. New York: Raven Press. 1975.
Takahashi, R., Aprison, M. H.: Acetylcholine content of discrete areas of the brain obtained by a near-freezing method. J. Neurochem.11, 887–898 (1964).
Tissari, A. H., Casu, M., Gessa, G. L.: Chronic haloperidol: tolerance to the stimulating effect on striatal tyrosine hydroxylase. Life Sci.24, 411–416 (1979).
van Kammen, D. P.:γ-Aminobutyric acid (GABA) and the dopamine hypothesis of schizophrenia. Amer. J. Psychiat.134, 138–143 (1977).
Zivkovic, B., Guidotti, A., Costa, E.: Effect of thioridazine, clozapine and other antipsychotics on the kinetic state of tyrosine hydroxylase and on the turnover rate of dopamine in striatum and nucleus accumbens. J. Pharmacol. Exp. Ther.194, 37–46 (1975).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Singhal, R.L., Rastogi, R.B. & Lapierre, Y.D. Diazepam potentiates the effect of neuroleptics on behavioural activity as well as dopamine and norepinephrine turnover: Do benzodiazepines have antipsychotic potency?. J. Neural Transmission 56, 127–138 (1983). https://doi.org/10.1007/BF01243272
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF01243272