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INVOLVEMENT OF CENTRAL SYSTEM IN DECREASE OF SERUM FATTY ACIDS AFTER INTRACEREBROVENTRICULAR ADMINISTRATION OF

Yoko UCHIDA and Teruko NOMOTO Department of Pharmacology, Tokyo Women's Medical College, 10 Kawada-cho, Shinjuku-ku, Tokyo 162, Japan

Accepted October 18, 1982

We reported that an injection of chlor Pharmaceutical Co. Ltd., (ACh) (CPZ) into the lateral ventricle chloride: Daiichiseiyaku Co. Ltd., carbamyl caused a transient decrease in serum FFA. (CAR) chloride: Sigma Chemical Co. The involvement of the central dopaminergic Ltd., sulfate: lwakiseiyaku Co. Ltd., mechanism in this decrease was considered methyl sulfate: Shionogi Phar (1). The dopaminergic-cholinergic an maceutical Co. Ltd.) were dissolved in saline, tagonistic relationship in the nigro-striatal and the solution was adjusted to a pH of system, indicated by metabolic (2-6), 6.8. All doses of used are given in the behavioral (6, 7) and microiontophoretical results as the amount of free base. Blood (8) evidence, is now well known. Therefore, samples for determination of FFA were in order to know the involvement of the obtained from the jugular vein of rats with a central cholinergic system in the control of disposable syringe. Serum FFA was deter peripheral lipid mobilization after intra mined colorimetrically according to the cerebroventricular (i.c.v.) injection of CPZ, method of Novak (9). we examined the effect of cholinergic agents As is described in the previous report (1), on the change in the serum FFA level after the i.c.v. Injection of CPZ produced a marked the i.c.v. injection of CPZ in rats. transient decrease in serum FFA with the two Male Wistar-lmamichi rats weighing 180 doses (200, 500 ug/kg) examined, whereas 280 g were kept in an air-conditioned room the same volume of vehicle (20 ul/kg) had (23±2°C, 55±5% humidity) lighted 14 hr a no effect. Serum FFA levels reached a day (06:00 to 20:00) and maintained on a rat minimum 30 min after injection of CPZ and standard diet and water ad libitum. For then returned to the initial level during the injections into the cerebral ventricles, a second hour. With a lower dose of 100 ug/kg stainless steel cannula was implanted into CPZ, only a slight decrease was observed, but the right lateral ventricle under sodium this was not statistically significant. Micro anesthesia (nembutal, 40 mg/ injection of either ACh alone at a dose of kg i.p.). After a 7-day post-operative recovery 20 ug/kg or carbachol at the same dose did period, drugs were injected through this not affect the serum concentration of FFA. cannula without any anesthesia. All i.c.v. The simultaneous administration of ACh and injections of drugs were made in the same CPZ at 100 ug/kg into the right lateral volume (20 ul/kg) over a period of 20 sec. ventricle accelerated the fall in the serum All the drugs (CPZ hydrochloride: Shionogi FFA level, whereas the simultaneous admin istration of ACh with two higher doses of ACh with 100 fig/kg CPZ was significantly CPZ (200 or 500 ,ag/kg) did not show any blocked by the prior i.c.v. injection of atropine, modification. On the other hand, the fall in indicating that muscarinic synaptic receptors the serum FFA level after CPZ at 100 or are involved in this effect. However, the 200 ug/kg i.c.v. was significantly accelerated potentiation by carbachol was hardly inhibited with the simultaneous injection of 20 ag/kg by preinjection of atropine, suggesting that carbachol. However, at a dose of 500 ug/kg the mechanisms of the potentiation by i.c.v. CPZ, the significant modification carbachol may be different from that by ACh. following the simultaneous injection of After the i.c.v. injection of 5 ag/kg carbachol was not observed. The potentiation neostigmine, the tendency of the opposite by carbachol of CPZ was more pronounced response in the potentiation of CPZ action by and long-lasting than that of ACh (Fig. 1). these two cholinergic agents (ACh, car Further, in an attempt to examine the effect bachol) was observed, even though it was of an agent and anticholi not significant. These results after preinjection nesterase, 50 Jag/kg atropine or 5 ,ag/kg of atropine or neostigmine suggest that neostigmine was injected intracerebroven carbachol produced the potentiation of CPZ triculary 10 min prior to the injection of CPZ, action as well as ACh; but the details of the ACh and carbachol. As shown in Fig. 2, the mechanisms of the action by this is potentiation by simultaneous injection of probably different from ACh, i.e., the possible

Fig. 1. Effect of simultaneous injection of ACh (20 pg/kg i.c.v.) or carbachol (20 ,ug/kg i.c.v.) alone with CPZ (100, 200, 500 gg/kg) on the decrease in serum FFA. Numbers in parentheses represent the numbers of animals employed. The vertical lines indicate the S.E. of the mean. P values were calculated by the Student's t-test. *P<0.05, **P<0.01 as compared to CPZ alone. involvement of the muscarinic cholinergic nigro-striatal dopamine neurons exert an receptors in the potentiation by ACh of CPZ excitatory (10, 11) or inhibitory (2, 12) effect action was revealed, but presumably not in on cholinergic interneurons in the striatum. the potentiation by carbachol. Furthermore, several reports have shown that On the other hand, it has been already dopamine or dopamine-mimetic drugs inhibits demonstrated that there is an antagonistic the cholinergic cells in the caudate nucleus, relationship between the dopaminergic and reducing ACh turnover or release, and cholinergic system in the striatum (2-8), resulting in an increase in ACh content in this although it remains still controversial whether area. The opposite effect is produced by

Fig. 2. Effect of preinjection of atropine (50,ug/kg i.c.v.) or neostigmine (5 jig/kg i.c.v.) on the acceler ation of the decrease in serum FFA after the simultaneous injection of ACh (20 fig/kg i.c.v.) or carbachol (20 pg/kg i.c.v.) with CPZ (100 pg/kg i.c.v.). Atropine or neostigmine was injected 10 min. prior to the injection of CPZ, ACh and carbachol. Values show the mean standard error at 30 min after administration of CPZ, ACh and carbachol. Figures at the foot of each of the columns represent the numbers of animals employed. P values were calculated by the Student's t-test. *P<0 .05, **P<0.01. dopamine antagonists or dopamine-depleting by apomorphine, piribedil and D-amphetamine. agents (2, 4, 13, 14). Brain Res. 84, 221-226 (1975) 5) Ladinsky, H., Consolo, S., Bianchi, B., Ghezzi, In this experiment herein, the effect of D. and Samanin, R.: Link between dopaminergic CPZ on the decrease in serum FFA was and cholinergic neurons in the striatum as potentiated by the cholinergic agents such evidenced by pharmacological, biochemical, as ACh and carbachol. On the contrary, this and lesion studies. In Interactions Between Putative Neurotransmitters in the Brain, Edited effect was blocked by dopamine and apo by Garattini, S., Pujol, J.F. and Samanin, R., morphine as described in our previous report p. 3-21, Raven Press, New York (1978) (1). Now, a possible cholinergic involvement 6) James, T.A. and Massey, S.: Evidence for a in the control of peripheral lipid mobilization possible dopaminergic link in the action of acetylcholine in the rat substantia nigra. Neuro induced by CPZ is also suggested. It is pharmacology 17, 687-690 (1978) therefore possible to say that the central 7) Neill, D.B.: Frontal-striatal control of behavioral dopaminergic-cholinergic system is involved inhibition in the rat. Brain Res. 105, 89-103 in the peripheral lipid mobilization induced (1976) 8) Aghajanian, G.K. and Bunney, B.S.: Dopami by CPZ. nergic and non-dopaminergic neurons of the Acknowledgement: We thank Prof. substantia nigra: differential responses to Tonoue, Department of Physiology II, Azabu putative transmitters. Neuropsychopharmac ology, Edited by Boissier, J.R., Hippius, H. and University, for comments on the manuscript. Pichot, P., p. 444-452, Excerpta Medica , This work was supported in part by grant Amsterdam (1974) 567037 from the Ministry of Education, 9) Novak, M.: Colorimetric ultramicro method for Science and Culture, Japan. the determination of free fatty acids. J. Lipid Res. 6, 431-433 (1965) 10) Kitai, S.T., Sugimori, M. and Kocsis, J.D.: References Exitatory nature of dopamine in the nigro 1) Uchida, Y. and Nomoto, T.: Effect of intra caudate pathway. Exp. Brain Res. 24, 351-363 cerebroventricular administration of chlor (1976) promazine on the serum level of free fatty acids 11) Butcher, S.H., Butcher, L.L. and Cho, A.K.: in rats. Japan. J. Pharmacol. 32, 709-718 Modulation of neostriatal acetylcholine in the (1982) rat by dopamine and 5-hydroxytryptamine 2) McGeer, P.L., Grewaal, D.S. and McGeer, afferents. Life Sci. 18, 733-744 (1976) E.G.: Influence of noncholinergic drugs on rat 12) McLennan, H. and York, D.H.: The action of striatal acetylcholine levels. Brain Res. 80, 211 dopamine on neurones of the caudate nucleus. 217 (1974) - J. Physiol. 189, 393-402 (1967) 3) Guyenet, P.G., Agid, Y., Javoy, F., Beaujouan, 13) Stadler, H., Lloyd, K.G., Gadea-Ciria, M. and J.C., Rossier, J. and Glowinski, J.: Effects of Bartholini, G.: Enhanced striatal acetylcholine dopaminergic receptor and antagonists release by chlorpromaizine and its reversal by on the activity of the neo-striatal cholinergic apomorphine. Brain Res. 55, 476-480 (1973) system. Brain Res. 84, 227-244 (1975) 14) Cheney, D.L., Zsilla, G. and Costa, E.: Acetyl 4) Ladinsky, H., Consolo, S., Bianchi, S., Samanin, choline turnover rate in n. accumbens, n. R. and Ghezzi, D.: Cholinergic-dopaminergic caudatus, globus pallidus and substantia nigra: interaction in the striatum: The effect of 6 Actions of cataleptogenic and noncatalepo hydroxydopamine or treatment on the- tgenic antipsychotics. Adv. Biochem. Psycho increased striatal acetylcholine levels induced pharmacol. 16, 179-186 (1977)