On leaving drunks alone

TIPS -May

2987 Wol. Sj

161

On leaving drunks akme Everybody knows that the environment influences the effect of ethanol. A man who gets drunk alone, at home, may simply slowly collapse into bed; in a bar, he may either become excessively social, or enter into a brawl; in the job, he may be fired; in the presence of a permissive partner, he may go and drink another bottle; in the presenee of a nagging partner, he may react violently, or withdraw into self-pity; in the middk of a bout of self-pity, he might attempt (seldom commit) suicide; etc. The local culture may be a major influence, depending on how it Some views drunkenness. societies look more benevolently upon intoxicated persons than other@, depending on a variety of circumstances; in some countries or ethnic groups, drinking to the point of drunkenness is believed to be the normal way of drinkingL3; others believe it to be a sin, or a disgrace’, or merely unbusinesslike, or ungentlemanly. Whatever the influence of the environment, or of society, heavy drinkers prefer to be left alone when they know they are getting in bad shape; perhaps through fear that any interaction with others could be unpredictable and therefore potentially dangerous. In spite of the long search for animal models of alcoholism, this problem has been very little studied in laboratory animals. It has been known for some time that the post-training administration of ethauol in mice4, rats, or humans5 may facilitate memory. Others have found no effect, even after injecting very large doses of the substance’j. Colbern and her group’ have recently examined this problem from the point of view of the interaction between the environment and the effect of ethanol. In the course of their own avoidance conditioning studies, they had observed that mice intoxicated with ethanol to the point of ataxia were treated roughly, often severely bitten, by their saline-treated cagemates. Elliot and Sbordone’ had indeed shown, in rats, that the ataxic movements elicited by alcohol or

other. drugs bring about ‘pathologic’ biting attacks from undrugged opponents. In the case of the drunken mice taken back to their home cage, the situation is made worse by the fact that ethand itself suppresses their own intraspecific attack behaviors. So much for peace, tolerance, and understanding among rodents, particularly towards drunks. Colbem et al. wondered whether the reaction of cagemates to the mice given post-training ethanol could have anything to do with the memory facilitating influence of this substance. They trained Swiss Webster mice, housed six or ten per cage, in a standard step-through inhibitory avoidance task and assigned the animals to four groups: one treated with 3 g kg-’ ethanol, i.p. and placed after training in a novel cage, illone, for 90 min; another, treated with saline and also placed in a novel cage, alone; a third group, treated with the same dose of ethanol and taken back to the home cage; z treated with saline and back to its home cage, Ethanol enhanced retention test latencies, measured 24 h after training, only in the animals that were returned to their home cage a&r training. It had no effect in the animals left alone in the novel cage. Being housed six or ten to a cage had no influence on the results. Whatever the interpretation (the novel cage after training introduced a factor of stress, and a possible release of glucocorticoids, adrenocorticotrophic hormone, epinephrine, vasopressin, etc., as Colbem rt al. suggest; or being harrassed by their cagemates may add to and reinforce the aversive-

ness of the task, as might be a simpler explanation), these results are important in more than one way. First, they show that the interaction of a drug with the environment may be an important factor in determining its effects on memory. Second, they show, for the first time in animaIs, that the interaction with the environment may infhuence etbano! effects. Third, they suggest that leaving drunks alone, or at least not harassing them, may be a good thing to do. NAN rZQuIEaD0 Departamento de &JUFRGSIcmtd, 9Ml49Pow &Fe, Rs, Brasil.

Centro

de Menmria,

qihicn,

@ 1967, Elsevier PubliwHnno. Cambridge M65 - 6147fWiSD2.W

TPS - May 2987 IVol. 81

162

References 1 Makeia, K. (1986) Ann. N.Y. Acad. Sri. 472.2132 2 Miller, W. R. (1986) Ann. N.Y. Acad. Sci. 472,110-129 3 Hubbard, R. L.,Schlenger, W. E.,Ra&al, j_ V., Bray,R. M.. Craddock, S. G., Cava-

naugh, E. R. and Ginzbura H. M. (1986) Ann. N.Y. Acad. SIX’.472,60-74 4 Alkana, R. L. and Parker, E. S. (1979) Psychopharmacology66,117-119 5 Parker, E. S., Bimbaum, I. M., Weingartner, H.; Hartley, J. T., Stillan, R. C. and Wyatt, R. J. (1980) Psychopharmacology 69,219-222

ESarmacology of the isoquinoline sulfonamide protein kinase C inhibitors Since the initial identification of protein kinase C (Ref. l), biopharmacological approaches have been used to elucidate the physiologica! &es of this enzyme. Related activators include proteases, Ca2+, phospholipids, diacylglycerols, phorbolesters, and SC-9 and SC-10 (Ref. 2). These compounds, in particuiar the phorbol esters, have frequently been used as tools to elucidate the physiological role of protein kipase C in the pathways of intracellular signal transduction. However, it is difficult to prove the physiological significance of the enzyme without also suppressing the enzyme activity using inhibitors. To elucidate the physiological role of protein phosphorylation, protein kinase C inhibitors must meet definite criteria: (1) direct binding to protein kinase; (2) strict specificity for the protein kinase; and (3) cell membrane permeability. A number of natural or synthesized modulators of protein kinase C have been prepared (Table I), but only the isoquinoline sulfonamide derivatives meet all these criteria. CaJxnoduJin

C’

0

antagonists, polypeptides, polyamines, local anesthetics, doxorubicin (adriamycin) and other lipids are lipophylic and interact with phospholipids, resulting in an indirect inhibition of protein

Directinhibitors

Mffeot inhibttwe

Phannacol. Biockem. Bekav. 16,63-6b

kinase C. Moreover, these inhibitors are relatively nonselective

in their action on phospholipidl Ca*+- and calrnodulin/Ca2+-dependent enzymesj. At higher concentiations, W-7, a novel calmodulin antagonist, inhibits protein kinase C activity, in a manner competitive with that of phospholipid. During the synthesis and selection of cal-

21 ‘22 23

Pdypeptides

Cytotoxins PolymixinB Neurotoxins

:z 25

Pa’vamineS

@ermine 1.I P-Diaminododecane LocalAneslhetics Dibucaine

26 26 27

Others

Adriamycin PalinitOylcemitine Alkyllysophospholipid Gangliosides Sphingosine Staurosporin Quercetin Neomycin

MLCK inhibil~r

I Cl+,) Nlim

msnipuWon Of pmtein kinase inhibitors. (Data taken from Aefs

@ 1987.Ebevin hbliostiom, Cambridge 01b.9 - h147#/$@2.~1

t

Phenoffiiazines w-7 Calmidazolium

. ..-.___.*_________

, Z4,6,6.)

References

An&elmadulins

A kinam inhibilor .aa_-e-_-m-.________

1. sbwR@

1-12 8 Elliot, M. L. and Sbordone, W.L. (1982)

H-7 Hg

(H-8) Q.

co@y 59, 71-74 7 Colbem, D. L., Sharek, P. and Zimmermann, E. G. (1986) Bekav. Neural Bid. 46,

lsoquinolinesulfanamides

0

vSo,-NH

and Izquierdo, I. (1978) Psyckopkarma-

TABLEI. Inhibitorsof proteinkinase C

0

I

6 Prado de Carvalho, L., Vendite, D.A.

21 21 :t :: 32 (unpublished)

modulin inhibitors derived from naphthalenesulfonamide, we discovered that a shorter alkyl chain derivative, termed .A-3 (N-[daminoethyl]-5-chloro-naphthalene sulfonamide), markedly inhibited protein kinases such as myosin light chain (MLC) kinase, CAMPdependent protein kinase, cGMPdependent protein kinase, and protein kinase C, through a mechanism different from that of W-74. A-3 directly inhibited these protein kinases without interacting with calmodulin. When the alkyl chains of W-7 were replaced by diazepine, the derivative (ML-9) was found to be a selective and direct inhibitor of MLC kinase5. On the other hand, when the amino residue at the end of the