- Email: [email protected]
Remembering the gut-brain connection
TIPS - November
acid r e c e p t o r a n t a g o n i s t s failed to protect the i s c h a e m i c n e u r o n a l d a m a g e a n d a final i n t e r p r e t a t i o n of these results m u s t therefore a w a i t clarification. Focal i s c h a e m i a m o d e l s
Data f r o m a n i m a l m o d e l s of focal cerebral ischaemia, w h i c h m o r e closely m i m i c the s i t u a t i o n in h u m a n stroke w h e n b l o o d clots block the cerebral vasculature, also s h o w MK-801 to h a v e p r o n o u n c e d n e u r o p r o t e c t i v e effects. Thus, following a 6 h occlusion of the m i d d l e cerebral artery in the cat, MK-801 (5 m g kg -1 i n t r a v e n ous) g i v e n 3 0 m i n before the i s c h a e m i c insult, r e d u c e d b y m o r e t h a n 50% the v o l u m e of cortical tissue d a m a g e 16. F u r t h e r m o r e , in a similar m o d e l in the rat, TCP (1 m g kg -1 i.p.), the thienyl analogue of PCP w h i c h is also a n o n c o m p e t i t i v e N M D A receptor antagonist, significantly r e d u c e d the v o l u m e of infarction w h e n a d m i n i s t e r e d 30 m i n before the occlusion 17. In a m i c r o - e m b o l i multi-infarct m o d e l in the rabbit, in w h i c h plastic m i c r o s p h e r e s are injected into the carotid artery to lodge in small d i a m e t e r cerebral arteries c a u s i n g multiple ischaemic foci, MK-801 (0.5 m g kg -1 i.p.) was effective g i v e n 5 m i n after the e m b o l i z a t i o n TM. []
415
1987 [Vol. 8]
[]
Trends Neurosci. 10 (special issue) 8 Beneviste, H., Drejer, J., Schousboe, A. a n d Diemer, N. H. (1984) J. Neurochem.
ultimately results in the d e l a y e d neuronal degeneration. Recent e v i d e n c e s u g g e s t s that these delayed m e c h a n i s m s m a y o p e r a t e in h u m a n s following c a r d i o r e s p i r a tory arrest 22. If so, this m a y p r o v i d e an o p p o r t u n i t y for successful therapeutic i n t e r v e n t i o n , after the initial insult, w i t h an N M D A antagonist such as MK-801.
43, 1369-1374 9 Brierley, J. B. and Graham, D. I. (1984) in Greenfields Neuropathology (Adams, J.H., Corsellis, J. A. N. and Duchen, L.W., eds), pp. 125--205, Edward Arnold 10 Simon, R. P., Swan, J. H., Griffith, T. and Meldrum, B. S. (1984) Science 226, 850-852 11 Foster, A. C., Gill, R., Kemp, I. A. and Woodruff, G.N. (1987) Neurosci. Left. 76, 307-311 12 Foster, A. C., Gill, R., Iversen, L. L. and Woodruff, G. N. (1987) Br. J. Pharmacol. Proc. 90 (Suppl.), 9P 13 Gill, R., Foster, A.C., and Woodruff, G. N. J. Neurosci. (in press) 14 Gill, R., Foster, A.C. and Woodruff, G.N. (1987) Br. J. Pharmacol. Proc. 91 (Suppl.), 311P 15 Block, G. A. and Pulsinelli, W. A. (1987) J. Cereb. Blood Flow Metab. 7 (Suppl. 1), $149 16 Oyzurt, E., Graham, D. I., McCulloch, J. and Woodruff, G.N. (1987) ]. Cereb. Blood Flow Metab. 7 (Suppl. 1), $146 17 Duverger, D., Benavides, J., Cudennac,
J. A. KEMP, A. C. FOSTER, R. G I L L A N D G. N. WOODRUFF
Neuroscience Research Centre, Merck Sharp & Dohme Research Laboratories, Terlings Park, Harlow CM20 2QR, UK.
References
1 Clineschmidt, B. V., Martin, G. E. and Bunting, P. R. (1982) Drug. Dev. Res. 2, 123-134 2 Wong, E. H. F., Kemp, J. A., Priesfley, T., Knight, A. R., Woodruff, G. N. and Iversen, L. L. (1986) Proc. Natl Acad. Sci. USA 83, 7104-7108 3 Kemp, J. A., Foster, A. C. and Wong, E. H. F. (1987) Trends Neurosci. 10, 294298 4 Lodge, D., Aram, J.A., Church, J., Davies, S.N., Martin, D., O'Shaughnessy, C.T. and Zeman, S. (1987) in Neurology and Neurobiology, Vol. 24
A., MacKenzie,
(Excitatory Amino Acid Transmission)
(Hicks, T. P., Lodge, D. and McLennan, H., eds), pp. 83-90, Alan R. Liss 5 Nowak, L., Bregestovski, P., Ascher, P., Herbet, A. and Prochiantz, A. (1984) Nature 307, 462-465 6 MacDermott, A. B., Mayer, M. L., Westbrook, G. L., Smith, S. I and Barker, J. L. (1986) Nature 321, 519-522 7 Cotman, C. W. and Iversen, L. L. (1987)
E.T.,
Scatton, B.,
Seylaz, J. and Verrecchia, C. (1987) }. Cereb. Blood Flow Metab. 7 (Suppl. 1), $144 18 Kochlar, A., Zivin, J., Lyden, P. and Mozzarella, V. (1987) Neurology 37 (Suppl. 1), 184 19 Choi, D. W., Peters, S. and Yokoyama, M. (1986) Soc. Neurosci. Abstr. 12, 381 20 Rothman, S. M. and Olney, J. W. (1987) Trends Neurosci. 10, 299--302 21 Foster, A. C., Gill, R. and Woodruff, G. N. Soc. Neurosci. Abstr. (in press) 22 Petito, C. K., Feldmann, E., Pulsinetti, W. A. and Plum, F. (1987) Neurology 37, 1281-1286
[]
Overall these f i n d i n g s p r o v i d e strong s u p p o r t for the h y p o t h e s i s that N M D A receptors play a central role in the d e v e l o p m e n t of i s c h a e m i a - i n d u c e d n e u r o n a l degeneration. Recent i n - v i t r o studies u s i n g n e u r o n a l cultures h a v e s h o w n that selective N M D A antagonists greatly reduce the d e g r e e of n e u r o n a l loss w h e n g i v e n foll o w i n g a brief e x p o s u r e to Lg l u t a m a t e 19 (and see Ref. 20). This has b e e n followed b y the d e m o n stration in v i v o that systemically administered MK-801 protects against the loss of n e u r o n a l m a r k e r e n z y m e s w h e n g i v e n several h o u r s after a single intrastriatal injection of N M D A or quinolinic acid 21. T o g e t h e r w i t h the e v i d e n c e that MK-801 protects against cell d e a t h u p to 2 4 h after the i s c h a e m i c episode, these results indicate that the initial p e r i o d of excessive s t i m u l a t i o n of N M D A receptors leads to a s u b s e q u e n t s u s t a i n e d activation of these receptors w h i c h
Remembering the gut-brain connection C h o l e s c y s t o k i n i n (CCK) is an intestinal h o r m o n e i n v o l v e d in the control of p a n c r e a t i c secretion a n d bile ejection w h i c h a p p e a r s to be an i m p o r t a n t satiety signal f r o m the p e r i p h e r y to the b r a i n 1. In the late 1970s i m m u n o c y t o chemical e v i d e n c e of the p r e s e n c e of CCK-like p e p t i d e s in the b r a i n 2 w a s shortly followed b y the isolation of t w o C C K o c t a p e p t i d e s w i t h biological activity f r o m sheep b r a i n 3. C C K - c o n t a i n i n g n e u r o n s h a v e since b e e n d e m o n strated in the neocortex, h i p p o c a m p u s , striatum, h y p o t h a l a m u s a n d a m y g d a l o i d c o m p l e x 4. D i v e r s e pharmacological and biochemical studies suggest that CCK m a y act as a n e u r o t r a n s m i t t e r or n e u r o m o d u l a t o r s-7, a n d it is k n o w n to h a v e an excitatory effect u p o n m i d b r a i n a n d prefrontal d o p a m i n ergic n e u r o n s ~. Behavioral studies h a v e s h o w n that C C K a n t a g o n i z e s the catalepsy a n d the analgesia
i n d u c e d b y O - e n d o r p h i n 9"1°, a n d that it d i m i n i s h e s l o c o m o t o r activity a n d the n u m b e r of r e a r i n g s in an o p e n - f i e l d a p p a r a t u s , an effect that can b e b l o c k e d b y its r e c e p t o r a n t a g o n i s t p r o g l u m i d e (a glutaramic acid derivative) 11. Recently, Flood and his colleagues 12 s h o w e d that the p o s t training a d m i n i s t r a t i o n of f o o d to previously food-deprived animals e n h a n c e s retrieval in a T - m a z e a v o i d a n c e task, a n d that this effect is s h a r e d b y the i n t r a p e r i t o n e a l injection of CCK o c t a p e p t i d e (0.05-1.0 ~tg kg-1). T h e y r e a s o n e d that the e n d o g e n o u s CCK released b y f e e d i n g could be r e s p o n s i b l e for the effect of f e e d i n g u p o n retrieval: the d o s e r a n g e of injected CCK w a s c o m p a t i b l e w i t h k n o w n circulating levels of C C K in r o d e n t s in the a b s o r t i v e p e r i o d , and a dose-response experiment revealed a n i n v e r t e d U - s h a p e d curve, as is typical for the influence 1987, ElsevierPublications, Cambridge 0165- 6147/87/$02.00
416
TIPS - November
on m e m o r y of post-training active drugs 13 (doses below 0.05 or above 1.0 ~g kg -1 were ineffective). Subdiaphragmatic vagotomy abolishes both the suppression of food intake 12 and the reduction of locomotor activity14caused by i.p. CCK. Flood and his group found that vagotomy also abolishes the effect of CCK on memory, without altering acquisition 12. These data show clearly that both feeding and peripherally administered CCK enhance memo r y in mice, and suggest that at least part of the effect of feeding may be due to peripheral CCK release. An additional experiment in which vagotomized animals were trained and then allowed to feed immediately after would be a crucial test of this hypothesis. The data of Flood e t al. add to several other recent suggestions that CCK may be involved in m e m o r y regulation: CCK may facilitate inhibitory avoidance and this may be antagonized by CCK antiserum~S; the CCK receptor antagonist proglumide may induce experimental amnesia in rats~6; and the amnesia induced by electroconvulsive shock may be prevented b y the intracerebroventricular administration of the CCK
octapeptide 16. Thus, it seems possible that CCK may pertain to the seemingly ever-increasing list of endogenous substances that influence m em ory processes 13. Its role could be related to the signaling of satiety, and could be triggered by the ingestion of food; it would, therefore, have the peculiarity of being a message that the periphery sends to the brain in order both to stop eating and to start making memories 12. The presence of CCK in neurons of systems possibly involved in m em ory modulation (hippocampus, striatum, amygdala, etc.)4, however, and its effectiveness on memory processes w hen centrally administered is also suggest a role for central CCK in memory processes. The interaction between this new putative m em ory modulator and the m any others that are now know n (~-endorphin, acetylcholine, noradrenaline, peripheral adrenocorticotropic hormone and adrenaline, vasopressin, etc.; see Ref. 13) may be an interesting subject of research. CARLOS A. NETTO AND IVAN
IZQUIERDO
Centro de Memoria, Departamento de Bioquimica, Instituto de Biociencias, UFRGS (centro), 90049 Porto Alegre, RS, Brazil.
1 9 8 7 [ V o l . 8]
References
1 Morley, J. E. and Levine, A. S. (1985) Annu. Rev. Pharmacol. Toxicol. 25, 127146 2 Dockray,G. J. (1976)Nature 264,568-570 3 Dockray, G. J., Gregory, R. A. and Hutchison, J. B. (1978) Nature 274, 711713 4 Vanderhaeghen, J. J., Lotstra, F., De Mey, J. and Gilles, C. (1980) Proc. Natl Acad. Sci. USA 7, 1190-1194 5 Saito, A., Sankaran, H., Goldfine, I. D. and Williams, J. A. (1980) Science 208,
1155-1156 6 Rehfeld, J. F. (1980) Trends Neurosci. 3, 65-67 7 Emson, P. C., Lee, C. M. and Rehfeld, J. F. (1980) Life Sci. 26, 2157-2163 8 Chiodo, L. A. and Bunney, B. S. (1983) Science 219, 1449-1451 9 Itoh, S. and Katsuura, G. (1981) Eur. J. Pharmacol. 74, 381-384 10 Itoh, S., Katsuura, G. and Maeda, Y. (1982) Eur. J. Pharmacol. 80, 421-425 11 Katsuura,G., Hsiao,S. and Itoh, S. (1984) Peptides 5, 529--534 12 Smith, G. P., Jerome, C., Cushin, B. J., Eterno, R. and Simansky, K.J. (1981) Science 313, 1036-1037 13 Gold, P. E. and Zornetzer, S. F. (1983) Behav. Neural Biol. 38, 151-189 14 Crawley, J. N., Hays, S. E. and Paul, S.M. (1981) Eur. J. Pharmacol. 73, 379380 15 Fekete,M. A., Lengyel,A., Negados, B., Penke, B., Zarandy, M., Toth, G. K. and Telegdy, G. (1984) Eur. J. Pharmacol. 98, 79-91 16 Katsuura, G. and Itoh, S. (1986)Peptides 7, 105-110
This and that: on books and belle donne, antimony and anti-caffeine IT SEEMS T O b e s a d l y t r u e t h a t x e r o x i n g has l argel y r e p l a c e d r e a d i n g . D u r i n g his s t u d e n t d a y s , Joe D a r v o n ' s x e r o x i n g bills w e r e a m a j o r i t e m of e x p e n d i t u r e i n hi s l a b o r a t o r y , y e t w h e n hi s a d v i s o r g a v e h i m a t w o - p a g e d article to r e a d , t h r e e w e e k s later it w a s still u n r e a d . H e c l a i m e d h e w a s t oo b u s y . To m y m i n d , for a s c h o l a r to claim h e is too b u s y to r e a d is as l u d i c r o u s as for s o m e o n e to claim h e is t o o b u s y to b r e a t h e . S o m e say it is b e t t e r to w r i t e t he l i t e r a t u r e t h a n to r e a d it, b u t it is o n l y b y r e a d i n g t h a t o n e l earns to w ri t e. In t h e w o r d s of S a m u e l J o h n s o n , ' h e o n l y can r a t i o n a l l y p r e s u m e t h a t h e u n d e r s t a n d s a s u b j e c t w h o has r e a d a n d c o m p a r e d t h e w r i t e r s t h a t h a v e h i t h e r t o d i s c u s s e d i t . . . In like m a n n e r , h e o n l y ha s a r i g h t to s u p p o s e t h a t h e can e x p r e s s his t h o u g h t s , w h a t e v e r t h e y are, w i t h p e r s p i c u i t y or el egance, w h o h a s c a r e f u l l y p e r u s e d t he b e s t a u t h o r s . . . ' A s t o r y is to ld of a c h a i r m a n of a pharmacology department a s k i n g a class of m e d i c a l students how many had even o p e n e d a G o o d m a n a n d Gilman. Not one student raised a h a n d . D e s p i t e this cul t ur a l atavism, this textbook had a major influence on the
t e a c h i n g of p h a r m a c o l o g y . I a m t h e f o r t u n a t e p o s s e s s o r of c o p i e s of all e d i t i o n s (Fig. 1), r a n g i n g f r o m t h e first, p u b l i s h e d i n 1941 at a cost of $5.95, to t h e s e v e n t h , p u b l i s h e d i n 1985 at $65.75 (a still n o t u n r e a s o n a b l e p r i c e of 3.6 c e n t s a pa ge ) 1. It is i n s t r u c t i v e to
1987, Elsevier Publications, Cambridge 0165- 6147/87/$02.00
browse the various editions, a n d to p o n d e r t h e c h a n g e s in o u r d i s c i p l i n e . O n e of t h e m o s t d r a m a t i c is t he r a p i d e v o l u t i o n of h e a v y m e t a l s f r o m t h e r a p e u tic a g e n t s to toxins. The first edition describes mercury as being a metal extensively employed in medicine. Mercuric salts were used as antiseptics, antisyphilitics, diuretics and cathartics. It is pointed out, however, that mercury has but one pharmacological action, that of being a general protoplasmic poison. "The manifestations of this basic action vary greatly'. It is now common knowledge that the actions of metals and metalloids such as mercury and arsenic have a common basis in the complexing of biological sulfhydryl groups. This action of arsenic was discovered in the 1920s, but publication was delayed until 1945 for security
acid r e c e p t o r a n t a g o n i s t s failed to protect the i s c h a e m i c n e u r o n a l d a m a g e a n d a final i n t e r p r e t a t i o n of these results m u s t therefore a w a i t clarification. Focal i s c h a e m i a m o d e l s
Data f r o m a n i m a l m o d e l s of focal cerebral ischaemia, w h i c h m o r e closely m i m i c the s i t u a t i o n in h u m a n stroke w h e n b l o o d clots block the cerebral vasculature, also s h o w MK-801 to h a v e p r o n o u n c e d n e u r o p r o t e c t i v e effects. Thus, following a 6 h occlusion of the m i d d l e cerebral artery in the cat, MK-801 (5 m g kg -1 i n t r a v e n ous) g i v e n 3 0 m i n before the i s c h a e m i c insult, r e d u c e d b y m o r e t h a n 50% the v o l u m e of cortical tissue d a m a g e 16. F u r t h e r m o r e , in a similar m o d e l in the rat, TCP (1 m g kg -1 i.p.), the thienyl analogue of PCP w h i c h is also a n o n c o m p e t i t i v e N M D A receptor antagonist, significantly r e d u c e d the v o l u m e of infarction w h e n a d m i n i s t e r e d 30 m i n before the occlusion 17. In a m i c r o - e m b o l i multi-infarct m o d e l in the rabbit, in w h i c h plastic m i c r o s p h e r e s are injected into the carotid artery to lodge in small d i a m e t e r cerebral arteries c a u s i n g multiple ischaemic foci, MK-801 (0.5 m g kg -1 i.p.) was effective g i v e n 5 m i n after the e m b o l i z a t i o n TM. []
415
1987 [Vol. 8]
[]
Trends Neurosci. 10 (special issue) 8 Beneviste, H., Drejer, J., Schousboe, A. a n d Diemer, N. H. (1984) J. Neurochem.
ultimately results in the d e l a y e d neuronal degeneration. Recent e v i d e n c e s u g g e s t s that these delayed m e c h a n i s m s m a y o p e r a t e in h u m a n s following c a r d i o r e s p i r a tory arrest 22. If so, this m a y p r o v i d e an o p p o r t u n i t y for successful therapeutic i n t e r v e n t i o n , after the initial insult, w i t h an N M D A antagonist such as MK-801.
43, 1369-1374 9 Brierley, J. B. and Graham, D. I. (1984) in Greenfields Neuropathology (Adams, J.H., Corsellis, J. A. N. and Duchen, L.W., eds), pp. 125--205, Edward Arnold 10 Simon, R. P., Swan, J. H., Griffith, T. and Meldrum, B. S. (1984) Science 226, 850-852 11 Foster, A. C., Gill, R., Kemp, I. A. and Woodruff, G.N. (1987) Neurosci. Left. 76, 307-311 12 Foster, A. C., Gill, R., Iversen, L. L. and Woodruff, G. N. (1987) Br. J. Pharmacol. Proc. 90 (Suppl.), 9P 13 Gill, R., Foster, A.C., and Woodruff, G. N. J. Neurosci. (in press) 14 Gill, R., Foster, A.C. and Woodruff, G.N. (1987) Br. J. Pharmacol. Proc. 91 (Suppl.), 311P 15 Block, G. A. and Pulsinelli, W. A. (1987) J. Cereb. Blood Flow Metab. 7 (Suppl. 1), $149 16 Oyzurt, E., Graham, D. I., McCulloch, J. and Woodruff, G.N. (1987) ]. Cereb. Blood Flow Metab. 7 (Suppl. 1), $146 17 Duverger, D., Benavides, J., Cudennac,
J. A. KEMP, A. C. FOSTER, R. G I L L A N D G. N. WOODRUFF
Neuroscience Research Centre, Merck Sharp & Dohme Research Laboratories, Terlings Park, Harlow CM20 2QR, UK.
References
1 Clineschmidt, B. V., Martin, G. E. and Bunting, P. R. (1982) Drug. Dev. Res. 2, 123-134 2 Wong, E. H. F., Kemp, J. A., Priesfley, T., Knight, A. R., Woodruff, G. N. and Iversen, L. L. (1986) Proc. Natl Acad. Sci. USA 83, 7104-7108 3 Kemp, J. A., Foster, A. C. and Wong, E. H. F. (1987) Trends Neurosci. 10, 294298 4 Lodge, D., Aram, J.A., Church, J., Davies, S.N., Martin, D., O'Shaughnessy, C.T. and Zeman, S. (1987) in Neurology and Neurobiology, Vol. 24
A., MacKenzie,
(Excitatory Amino Acid Transmission)
(Hicks, T. P., Lodge, D. and McLennan, H., eds), pp. 83-90, Alan R. Liss 5 Nowak, L., Bregestovski, P., Ascher, P., Herbet, A. and Prochiantz, A. (1984) Nature 307, 462-465 6 MacDermott, A. B., Mayer, M. L., Westbrook, G. L., Smith, S. I and Barker, J. L. (1986) Nature 321, 519-522 7 Cotman, C. W. and Iversen, L. L. (1987)
E.T.,
Scatton, B.,
Seylaz, J. and Verrecchia, C. (1987) }. Cereb. Blood Flow Metab. 7 (Suppl. 1), $144 18 Kochlar, A., Zivin, J., Lyden, P. and Mozzarella, V. (1987) Neurology 37 (Suppl. 1), 184 19 Choi, D. W., Peters, S. and Yokoyama, M. (1986) Soc. Neurosci. Abstr. 12, 381 20 Rothman, S. M. and Olney, J. W. (1987) Trends Neurosci. 10, 299--302 21 Foster, A. C., Gill, R. and Woodruff, G. N. Soc. Neurosci. Abstr. (in press) 22 Petito, C. K., Feldmann, E., Pulsinetti, W. A. and Plum, F. (1987) Neurology 37, 1281-1286
[]
Overall these f i n d i n g s p r o v i d e strong s u p p o r t for the h y p o t h e s i s that N M D A receptors play a central role in the d e v e l o p m e n t of i s c h a e m i a - i n d u c e d n e u r o n a l degeneration. Recent i n - v i t r o studies u s i n g n e u r o n a l cultures h a v e s h o w n that selective N M D A antagonists greatly reduce the d e g r e e of n e u r o n a l loss w h e n g i v e n foll o w i n g a brief e x p o s u r e to Lg l u t a m a t e 19 (and see Ref. 20). This has b e e n followed b y the d e m o n stration in v i v o that systemically administered MK-801 protects against the loss of n e u r o n a l m a r k e r e n z y m e s w h e n g i v e n several h o u r s after a single intrastriatal injection of N M D A or quinolinic acid 21. T o g e t h e r w i t h the e v i d e n c e that MK-801 protects against cell d e a t h u p to 2 4 h after the i s c h a e m i c episode, these results indicate that the initial p e r i o d of excessive s t i m u l a t i o n of N M D A receptors leads to a s u b s e q u e n t s u s t a i n e d activation of these receptors w h i c h
Remembering the gut-brain connection C h o l e s c y s t o k i n i n (CCK) is an intestinal h o r m o n e i n v o l v e d in the control of p a n c r e a t i c secretion a n d bile ejection w h i c h a p p e a r s to be an i m p o r t a n t satiety signal f r o m the p e r i p h e r y to the b r a i n 1. In the late 1970s i m m u n o c y t o chemical e v i d e n c e of the p r e s e n c e of CCK-like p e p t i d e s in the b r a i n 2 w a s shortly followed b y the isolation of t w o C C K o c t a p e p t i d e s w i t h biological activity f r o m sheep b r a i n 3. C C K - c o n t a i n i n g n e u r o n s h a v e since b e e n d e m o n strated in the neocortex, h i p p o c a m p u s , striatum, h y p o t h a l a m u s a n d a m y g d a l o i d c o m p l e x 4. D i v e r s e pharmacological and biochemical studies suggest that CCK m a y act as a n e u r o t r a n s m i t t e r or n e u r o m o d u l a t o r s-7, a n d it is k n o w n to h a v e an excitatory effect u p o n m i d b r a i n a n d prefrontal d o p a m i n ergic n e u r o n s ~. Behavioral studies h a v e s h o w n that C C K a n t a g o n i z e s the catalepsy a n d the analgesia
i n d u c e d b y O - e n d o r p h i n 9"1°, a n d that it d i m i n i s h e s l o c o m o t o r activity a n d the n u m b e r of r e a r i n g s in an o p e n - f i e l d a p p a r a t u s , an effect that can b e b l o c k e d b y its r e c e p t o r a n t a g o n i s t p r o g l u m i d e (a glutaramic acid derivative) 11. Recently, Flood and his colleagues 12 s h o w e d that the p o s t training a d m i n i s t r a t i o n of f o o d to previously food-deprived animals e n h a n c e s retrieval in a T - m a z e a v o i d a n c e task, a n d that this effect is s h a r e d b y the i n t r a p e r i t o n e a l injection of CCK o c t a p e p t i d e (0.05-1.0 ~tg kg-1). T h e y r e a s o n e d that the e n d o g e n o u s CCK released b y f e e d i n g could be r e s p o n s i b l e for the effect of f e e d i n g u p o n retrieval: the d o s e r a n g e of injected CCK w a s c o m p a t i b l e w i t h k n o w n circulating levels of C C K in r o d e n t s in the a b s o r t i v e p e r i o d , and a dose-response experiment revealed a n i n v e r t e d U - s h a p e d curve, as is typical for the influence 1987, ElsevierPublications, Cambridge 0165- 6147/87/$02.00
416
TIPS - November
on m e m o r y of post-training active drugs 13 (doses below 0.05 or above 1.0 ~g kg -1 were ineffective). Subdiaphragmatic vagotomy abolishes both the suppression of food intake 12 and the reduction of locomotor activity14caused by i.p. CCK. Flood and his group found that vagotomy also abolishes the effect of CCK on memory, without altering acquisition 12. These data show clearly that both feeding and peripherally administered CCK enhance memo r y in mice, and suggest that at least part of the effect of feeding may be due to peripheral CCK release. An additional experiment in which vagotomized animals were trained and then allowed to feed immediately after would be a crucial test of this hypothesis. The data of Flood e t al. add to several other recent suggestions that CCK may be involved in m e m o r y regulation: CCK may facilitate inhibitory avoidance and this may be antagonized by CCK antiserum~S; the CCK receptor antagonist proglumide may induce experimental amnesia in rats~6; and the amnesia induced by electroconvulsive shock may be prevented b y the intracerebroventricular administration of the CCK
octapeptide 16. Thus, it seems possible that CCK may pertain to the seemingly ever-increasing list of endogenous substances that influence m em ory processes 13. Its role could be related to the signaling of satiety, and could be triggered by the ingestion of food; it would, therefore, have the peculiarity of being a message that the periphery sends to the brain in order both to stop eating and to start making memories 12. The presence of CCK in neurons of systems possibly involved in m em ory modulation (hippocampus, striatum, amygdala, etc.)4, however, and its effectiveness on memory processes w hen centrally administered is also suggest a role for central CCK in memory processes. The interaction between this new putative m em ory modulator and the m any others that are now know n (~-endorphin, acetylcholine, noradrenaline, peripheral adrenocorticotropic hormone and adrenaline, vasopressin, etc.; see Ref. 13) may be an interesting subject of research. CARLOS A. NETTO AND IVAN
IZQUIERDO
Centro de Memoria, Departamento de Bioquimica, Instituto de Biociencias, UFRGS (centro), 90049 Porto Alegre, RS, Brazil.
1 9 8 7 [ V o l . 8]
References
1 Morley, J. E. and Levine, A. S. (1985) Annu. Rev. Pharmacol. Toxicol. 25, 127146 2 Dockray,G. J. (1976)Nature 264,568-570 3 Dockray, G. J., Gregory, R. A. and Hutchison, J. B. (1978) Nature 274, 711713 4 Vanderhaeghen, J. J., Lotstra, F., De Mey, J. and Gilles, C. (1980) Proc. Natl Acad. Sci. USA 7, 1190-1194 5 Saito, A., Sankaran, H., Goldfine, I. D. and Williams, J. A. (1980) Science 208,
1155-1156 6 Rehfeld, J. F. (1980) Trends Neurosci. 3, 65-67 7 Emson, P. C., Lee, C. M. and Rehfeld, J. F. (1980) Life Sci. 26, 2157-2163 8 Chiodo, L. A. and Bunney, B. S. (1983) Science 219, 1449-1451 9 Itoh, S. and Katsuura, G. (1981) Eur. J. Pharmacol. 74, 381-384 10 Itoh, S., Katsuura, G. and Maeda, Y. (1982) Eur. J. Pharmacol. 80, 421-425 11 Katsuura,G., Hsiao,S. and Itoh, S. (1984) Peptides 5, 529--534 12 Smith, G. P., Jerome, C., Cushin, B. J., Eterno, R. and Simansky, K.J. (1981) Science 313, 1036-1037 13 Gold, P. E. and Zornetzer, S. F. (1983) Behav. Neural Biol. 38, 151-189 14 Crawley, J. N., Hays, S. E. and Paul, S.M. (1981) Eur. J. Pharmacol. 73, 379380 15 Fekete,M. A., Lengyel,A., Negados, B., Penke, B., Zarandy, M., Toth, G. K. and Telegdy, G. (1984) Eur. J. Pharmacol. 98, 79-91 16 Katsuura, G. and Itoh, S. (1986)Peptides 7, 105-110
This and that: on books and belle donne, antimony and anti-caffeine IT SEEMS T O b e s a d l y t r u e t h a t x e r o x i n g has l argel y r e p l a c e d r e a d i n g . D u r i n g his s t u d e n t d a y s , Joe D a r v o n ' s x e r o x i n g bills w e r e a m a j o r i t e m of e x p e n d i t u r e i n hi s l a b o r a t o r y , y e t w h e n hi s a d v i s o r g a v e h i m a t w o - p a g e d article to r e a d , t h r e e w e e k s later it w a s still u n r e a d . H e c l a i m e d h e w a s t oo b u s y . To m y m i n d , for a s c h o l a r to claim h e is too b u s y to r e a d is as l u d i c r o u s as for s o m e o n e to claim h e is t o o b u s y to b r e a t h e . S o m e say it is b e t t e r to w r i t e t he l i t e r a t u r e t h a n to r e a d it, b u t it is o n l y b y r e a d i n g t h a t o n e l earns to w ri t e. In t h e w o r d s of S a m u e l J o h n s o n , ' h e o n l y can r a t i o n a l l y p r e s u m e t h a t h e u n d e r s t a n d s a s u b j e c t w h o has r e a d a n d c o m p a r e d t h e w r i t e r s t h a t h a v e h i t h e r t o d i s c u s s e d i t . . . In like m a n n e r , h e o n l y ha s a r i g h t to s u p p o s e t h a t h e can e x p r e s s his t h o u g h t s , w h a t e v e r t h e y are, w i t h p e r s p i c u i t y or el egance, w h o h a s c a r e f u l l y p e r u s e d t he b e s t a u t h o r s . . . ' A s t o r y is to ld of a c h a i r m a n of a pharmacology department a s k i n g a class of m e d i c a l students how many had even o p e n e d a G o o d m a n a n d Gilman. Not one student raised a h a n d . D e s p i t e this cul t ur a l atavism, this textbook had a major influence on the
t e a c h i n g of p h a r m a c o l o g y . I a m t h e f o r t u n a t e p o s s e s s o r of c o p i e s of all e d i t i o n s (Fig. 1), r a n g i n g f r o m t h e first, p u b l i s h e d i n 1941 at a cost of $5.95, to t h e s e v e n t h , p u b l i s h e d i n 1985 at $65.75 (a still n o t u n r e a s o n a b l e p r i c e of 3.6 c e n t s a pa ge ) 1. It is i n s t r u c t i v e to
1987, Elsevier Publications, Cambridge 0165- 6147/87/$02.00
browse the various editions, a n d to p o n d e r t h e c h a n g e s in o u r d i s c i p l i n e . O n e of t h e m o s t d r a m a t i c is t he r a p i d e v o l u t i o n of h e a v y m e t a l s f r o m t h e r a p e u tic a g e n t s to toxins. The first edition describes mercury as being a metal extensively employed in medicine. Mercuric salts were used as antiseptics, antisyphilitics, diuretics and cathartics. It is pointed out, however, that mercury has but one pharmacological action, that of being a general protoplasmic poison. "The manifestations of this basic action vary greatly'. It is now common knowledge that the actions of metals and metalloids such as mercury and arsenic have a common basis in the complexing of biological sulfhydryl groups. This action of arsenic was discovered in the 1920s, but publication was delayed until 1945 for security