- Email: [email protected]
Self-administration studies on psychological dependence
TIPS - February, 1980
ItI1
-
Control
- -+ Cdchime
105M
Fig. 1. Dose-response curve IO onkvorensrn m rhe presence of co/chicineH.
‘uncovering’ of additional angiotensin receptors. The diminished degradation of peptide by angiotensinase would increase its availability at the receptor site. Thus, these two factors:- increased number of receptors and decreased degradation of angiotensin, may indeed explain the increased maximal response to angiotensin after angiotensinase blockade by angiotensinase inhibitors. Our work on angiotensin tachyphylaxis. work with angiotensinase inhibitors, and the results of Meyer’s group clearly point out that angiotensin receptors are not rigid entities in cell membrane but rather mobile macromolecules in constant- flux regulated by the supply of agonist and angiotensinase activity. Like any membrane protein the angiotensin receptor must be synthesized intracellularly and delivered to the cell membrane.
\h
F25y?.yY__~__---3” F
-20
\ .-*
Drugs which block protein synthesis. like cycloheximide. or interrupt the flow of intracellular proteins, like colchicine. do indeed block the vascular response to angiotensin (Fig. I). The possibilities of attacking the angiotensin-renin system by pharmacological means and of bringing about a change in sensitivity of vascular tissue exist at different levels. One can block renin and converting enzyme activity with specific agents. Recently, a specific inhibitor of angiotensin converting enzyme was introduced as an antihypertensive agent. Specific antagonists of angiotensin have already been known for some time, all of them being angiotensin analogs with very limited clinical use. The manipulation of vascular response to angiotensin is also possible through the change of sodium load and other factors. However, most of these changes are reversible and of short duration. One wonders whether a long-term or permanent change of receptors would be of greater therapeutic significance. One possible way of doing it is immunological manipulation of angiotensin receptors. The angiotensin receptor can be solubilized from the cell membrane by deoxycholic acid. This procedure successfu!ly separates the receptor protein from angiotensinase” (Fig. 21. However. the pure angiotensin receptors are still not
One area ir. the field of esperimental pharmacology in which norrworthy n- - a Solubilired fraction progress has been ashieted :s that A--A Pellet after solubiliration concerning drug dependence. parrisularl!: the psychological aspects thereof. The 16 2 4 of methods for seifdeveiopment TI& (min) administration of drugs in laboratory Frg. 2. Angiolensinase ac1iwr.vcnplasma membrane animals has contributed greatly both to fraction before and afrer solubilirarron wtrh 7-deoxyrholic ocrd (IO mg+j. The pressor dJec; of the body of pharmacological knobledge resrduol angtorenrin qfrer tncubaiion with di/ferenl and to the conceptual understanding of fracrrons ww measured on rar blood pressure rhe phenomenon. Some of rhe progress ,wr,~~rurron. 0.3 ,, V anjyown.wn WI\ mctrbulrd wrrh made in this area will be brietl:? introIOOIJO j4g of prorem/ml. lp cO.05: l*P cO.01; duced in this article. “‘p
t
Control
Reading list I
z
3. 4.
5
6 3
8.
9. 10.
Tigcrstedt. R and Bergman. P <, ( IHYHI Skond .Arch. Phurrol R. X3-2:1 Page. Ci. H ll%R) In I H Page and J \h McCubbm led\) Renal Hyperrentron. tmr Rook Mcdtcal Publl\hrrs Inc , (‘hIsago. pp 391-3%. Dcrynck. M. 4 and Steyver. P ,I9’61 .AW .! Med. 61.758-‘67 LeMonan P. md PalalL. DI tlTcl J Pharmoco: Exp. Ther 195. 16’-I’!: Palm. DJ ant LeMorran. P (19’ I J Pharn ocol Erp. Thu. 179. 5X!-‘3 I karrucgla. P . Sachs. 5 and PdlalL. DJ I IY’Y) Mol. ?harmacol. I?. 525530 LeMorban. P , Palax. DJ and I-ergu\cm. 0 (19771 Can J Phwor Phormut-ur G5, 652-65:. LeMonan. P aid Palax. DJ (19’21 c‘m J Ph,wo/. Phormo. ol. 50, -lYX-!o’ Palax. DJ.. Ktullar. H. anr! Farrugp.s. P funpubhrhedl Paials. DJ. aid Farrug~a. P I i9-91 C/m Erp H.vperrensron(KI press)
Self-administration studies on psychological dependence
Introduction O---O
isolated. This worh is hampered by the reiative scarcity of angiorensin receptor\ in vascular tissue. However, it is only ? matter of time before this lechriical obstacle is removed, thus opening a neu era of research in this field.
Self administrat;on
of drugs in ph!sicell)
dependent subjects Until
lY64.
when
Sect\cr\
t’f u[.’
at the
Unit,enit\ of blichigan firs1 dsmon~trated the :‘acr that rhesus monhrrs ~111Fe& and self.adminisrer t1.r prin
TIPS
162 demonstrated that chimpanzees made physically dependent on morphine chose a banana when their physical dependence was well maintaineci but chose a morphine syringe when their ‘supply of morphine had been deprived. At that time, it was a rather new concept to regard the existence of the craving 21sa necessary condition in! addiction. Kruger, Eddy and Sumwatt’ concluded in their intensive 1941 review on the craving for drugs in animals that, “Except for Spragg’s experiment, acidic tion in the sense of his restricted defini tion has not been demonstrated in an5 infrahuman organism”. Although in the past two decades the view that physical dependence is the major cause of craving has prov,ed to b+z not necessarily true in all cases, it wai found to be quite true for the opioids. tt was demonstrated by a number of earlw pioneers in the field-Headtee. ,Coppock and Nichols using intravenous injection of morphine to morphinedependent rats; Nichols er ol.. Beach, and Wikler et ol. using methods of administering opioids through drinking in physically dependent rats;‘. * Weeks using the intravenous sc,tfadministration technique in mcrphinedependent rats; and Schuster and Thompson using intravenous selfadministration of morphine in chairrestrained. physically dependent rhesus monkeysl-that animah sought and selfadministered opioids under the condition of physical dependence. There has since been a considerable accumulation of evidence from many investigators, and today the phenomenon is understood as negative reinforcement due to avoidance or escape from withdrawal discomfort and/or stimulus control of the dragtaking behavior by such conditiclned stimulus propertiss as drug effects and environmental fa-tars’. !. I Self-ndministratioa of drugs in gbysicrll dependence-free subjects
Voluntary* development of the delpendence state in laboratory animaJs, under the condition of free drug availability and without any previous treatment with or conditioning toward drugs air drugseeking behavior, WZi intensively attempted with alcohol and op;dds i,~ the early years mostly by giving access to the drugs by drinking methods. Today these efforts can be understood &s attempts to demonstrate the development of primary -Strictlyspeaking,~hcword ‘r&mary’ may mt an appropriatetechnical Icrm. bal is used here l
facililau understanding.
be to
psychological dependence on drugs in laboratory animals, a subject to be discussed later. In 1964 Mardones” reviewed the results on alcohol and concluded that no animal st,udy had been successful in demonstrating human-like appentency for alcohol, because (I) the voluntary consumption of alcohol by animals was only exceptionally followed bly overt signs of the drug effects, (2) the animals’ appetency for alcohol was not really a craving since it decreased when an alternative of sugar solution was offered, and (3) no withdrawal signs were ever observed in animals even after long periods of free or forced ingestion of alcohol. With opioids the situation was somewhat different because of the more rearly development of pkysicat dependence on these drugs. By the use of drinking methods with opioids, some of the previously mentioned investigators observed the eventual development of physical dependence. For example, Yanagita. Deneau and Seevers found that in a test offering a choice between morphine solution and tap water, drugnaive rhesus monkeys ingested the drug solution and developed physical dependence. Such a result, however, did not present firm evidence for voluntary development of the state of dependence, because even for animals ingesting drug solution less than water, if the amount of ingested drug is sufficient to lead to the development of physical dependence, an eventual preference for the drug will naturally develop. This ;nd result obscures the crucial point of whether or not the drug itself has a positive reinforcing property. It then came to be felt that an ideal method for demonstrating the voluntary development of the dependence state in laboratory animals would be the intravenous self-administration by operant procedures in naive subjects of such physical dependence-free drugs as cocaine. The sophisticated views of Nathan B. Eddy. Abraham Wikler, and Maurice H. Seevers on the psychological aspects of drug dependence encouraged conquest of the methodological difficulties. In 1964, Deneau. Yanagita and Seevers’ first reported evidence that naive monkeys wilt initiate and maintain intravenous self-administration not only of morphine but also of cocaine and d-amphetamine at enormously high dose levels with extreme overt signs of drug effects. Later using the same technique and procedures which are today called ‘continuous self-administration’. this evidence was confirmed with some other
- February,
1980
principle drugs of abuse including codeine, alcohol, pentobarbital-Na, and meperidine (Table I). The results on alcohol and pentobarbital-Na were somewhat surprising as they were frequently self-administered up’to the point of selfanesthetization of the subjects’. The property of drugs to increase the animals’ response rate in self-administration was behaviorally termed as their reinforcing effect, and the major trend of setfadministration studies in laboratory animals has proceeded towards detecting and anatysing this effect for various types of drugs, since it is regarded as the property most closely related to the psychological dependence potential of drugs. Many studies have been conducted along these lines, mostly in rhesus monkeys and rats. The early results of these studies were broadly reviewed by Schuster and Thompson in 1969, and the major data obtained in rhesus monkeys was recently summarized by Johanson and Balstep representing the ‘International Study Group Investigating Drugs as Reinforcers (ISGIDAR)‘. The major portion of these results matched o,r was thought not to conflict with the facts known in humans. However. the results of some drugs did not agree: monkeys did not take LSD, mescaline, STP (DOM) or Ay-THC, and yet they eagerly took procaim?. In self-administration experiments, a variety of methods have since been applied by many investigators to various types of drugs in a wider range of animal species. Some of these studies will be briefly introduced below. strddies on 1. Self-administration alcohol have greatly progressed since Mardones’ review. and today ail points to which he referred as being evidence of distinction between animals and humans have been overcome and made eastly demonstrable not only in monkeys but in small animals as well. Folk9 developed a technique to condition the drinking behavior of rats which is termed as ‘polydipsia’. With this technique it was demonstrated that rats will consume large amounts of alcohol and manifest the overt drug signs as well as withdrawal signs. Details of the progress in this area, including intravenous and intragas:ric self-administration of alcohol by rhesus monkeys, have been reviewed by Mello’. 2. One of the limitations of the abolvementioned experiments was that compounds which are not soluble ln pharmacologically inactive vehicles could not be tested. For this purpose an intragastric
TIPS - February, 1980
I63
TABLE I. Major drugs of abuse self~administcred by rhesus monkeyc Self-adminirtralion and route
Drug Morphine Codeine Meperidine Pcnlazocinc Cocaine Amphetamine Cathinoner Pentobarbiral Alcohol Diazepam Volati,le ancslhetics Nicotine Caffeine
+ + I.“. + + i.v. + + + + + + + + + + + + + + + + + + f
i.v. i.v. i.\. i.v. i.v. iv. intragartric ibid. ibid. inhalation i.v. smoking i.v.
Paltern
Owrt vgn< of effcw
Wnhdraual \Q2”‘
+ + . .
+ + + 1 + f
regular regular. frequent ibld. ibid. irregular. frequent ibld ibld. regular. frequent lbld regular. infrequent Irregular. frequent regular m i.b. mfreaueni
+ + + +* + + + l
1
+
*
l
l
_. -9 _* + 1
.
l
. . +
+
Not self-administered: LSD-25. mescaline, STP (DOhI). A”-THC. l
Usually exhausted and fell inro sleep. + + , marked; posirwe; -- . negative +
,
self-administration technique was developed, and by this new route also, rhesus monkeys were found to selfadminister several water-insoluble, sedative-hypnotics up to the point of manifesting motor impairment or to anesthesia, depending on the drugto. 3. A self-inhalation technique for organic solvents was developed using a nostril catheter for rapors, and it was demonstrated that m ankeys will strongly seek and inhale volatile anesthetics from ether and chloroform to lacquer thinner, frequently to the point of selfanesthletization I’. Re,cently Wood et al. I2 demonstrated with another self-inhalation technique that nitrous oxide, well known to have been abused by humans, is also reinforcing to squirrel monkeys. 4. Still another form of selfadministration, namely smoking, has been investigated ‘In rhesus monkeys. Jarvik” has intensively studied this matter in rhesus monkeys and found that cigarette smoke is reinforcing; however, he could not establish human-like smoking behavior in the monkeys, i.e. maintained without any reinforcer other than the cigarette smoke itself. Yanagita, Ando et al.“, also using rhesus monkeys, workeNdon this problem for many years and have finally achieved success in establishing smoking behavior in some monkeys. Two of these monkeys have been voluntarily smoking cig;arettes for longer than 2 years without any other identifiable reinforcers than the cigarette smoke itself. In this study, nicotine was proved to be a major reinforcer in maintaining the monkeys’ smoking behavior, because they ceased such behavior when their regular cigarettes were replaced with de-nicotinized ones, but resumed it upon return to ordinary cigarettes.
5. The species of animals applicable to self-administration studies is not limited to monkeys and rats. In fact, Jones and his associates’! for example have developed a technique for intravenous self-administration of drugs in spinal dogs. The results with various types of drugs are quite similar to those obtained in monkeys except that, contrary to the monkeys, dogs do not initiate the selfadministration of morphine although they will maintain it once they have been made physically dependent on the drug.
tained dose regimen; and (2) to demonstrate in animais intense drug seeking and taking behavior for the drug in question. Concerning the first point, there is ample evidence for most of the principle abused drugs that experimental anrmals have manifested overt signs similar to those known in man at self-regulated dose levels. In contrast to this, satisfying the second point proved rather difficult. When Kruger er a/. used the term ‘craving’, certainly something stronger than a simple desire to take a drug was being implied, although the discussion there was limited to the topic of the desire to obtain drugs under the physically dependent state. In this sense, although several reported observations of the selfadministration of opioids under the phjsitally dependent state were introduced earlier in this paper, none of them indeed demonstrated such a strong decire with the possible exception in the case of Spragg’s observation, assuming that the competing desire for bananas in rhe chimpanzees studied had been very strong. several Thus, inrestigatori attempted to develop methods to quantify the reinforcing imensit): of drugs in laboratory animals. Among them, the methods that are at present established are the progressive ratio procedures m rhesus monkeys’“,
Lkmonstration
of the
psychological dependence state in laboratory
animals
The major purpose for which these self-administration techniques have been developed in laboratory animals is twofold: (1) to reproduce a self-developed dependence state in laboratory animals for the analysis of the psychopharmacological etiology of drug dependence; and (2) to assess the psychological dependence potential of known and new substances in laboratory animals. There has been prolonged discussion in this field on such topics ar how to define psychological dependence and whether it would be pussible to demonstrate such a state in laboratory animals. Certainly the mere facts that a certain drug had been selfadministered by the experimental animals and its positive reinforcing effect demonstrated were not absolutely sufficient evidence to declare that the animals in question had developed psychological dependence on the drug. In response to this, the following criteria have been put forth for the experimental development of psychological dependence? (I) to demonstrate overt signs of drug effects in animals under a self-initiated and main-
and baboons’-
and the
choice procedure” in rhesus monkeys. The essential technique involved in th,ese procedures is intravenous drug selfadministration. Csing these methods. Ihe substantial
intensity
of
the
reinforcing
for oploids. stimulants and depressants. For example. using the progressive ratio procedure Yanagita has demcnstrated the fact that rhesus monkeys will press a lexer smirch
effect has been demo+xtrated
up to 12.800 times to obtain just one dxe of morphine. codeine. or cocaine. and up to 6400 times for alcohol. Such effort bk laboratory animals :o obtain drugs can certainly be regardsd as fulfilling the second criterion. The development of phxjiial dependence is not an csser.rlal aspect of dependence. It is rather to hs seen a4 a son$equence of the L‘ontmuous drug from psyihOlogl&il intake resulting dependence. But, as dissussed previousI!, its presence may intensify the drug seeking and taking beha\ ior. In order to prove the progressive ratio
this in animals,
studies have been conducted without pretreatment
and
on the drug to be an intensification of behavior by pretreat-
physical dependenie tested. As a result,
the drug-seeking
both with producing
TIPS - February, 1980
164 TABLE
II. done results of progressive ratio test.scondlrcted by intravenous self-administration in rhesus
monkeys Unir close
Drug
(mg:kg in each mjeclion) --0.5 0.25 0.21 0.11** 800
Morphine Codeine Pcnlazocine Cocarne Alcohol
Final ratios in each monkey Ivatreated-Prclreat~.) xw-64OO 16aLl2.800. wlO-12.800, 16OO-l&XI 4530-IO.-60. 6400-12.800. 2690-3200 3200-320). 6400-3200. 6400-3200 1600-Ha). 6400-3200 16@3-6401. 32006400. 3200-3200. 6400-6400
-. Pretreated for development of physical dependence. **The ratio of 12,800 achieved al. a unit dose of 0.48.
ment has been observed with morphine .md codeine, but not with cocaine or sntazocine (Table 11). The result with alcohol falls between those of the opiates and pentazoclne because pretreatment was found to intensify the behavior less markediy thas that of opiates. These results have proved that although the ‘craving or ‘appetancy’ spoken of by Kruger et al. and Mardones have been clearly demonstrated without the necessity for prior development of physical dependence, still it is clear that such strong and active desire can be intensified by physical dependence when such dependence is developed on the opiates in particular, and to a lesser extent on alcohol.
Reading list I.
2.
3.
4.
5. 6.
Deneau. G. A . Yanagita, T. and Sewers. M. H. (1964) Prmmiings of the 26th Annual Scienrific Meeting, Commit&e on Problems of N.R.C.. N.A.S.. Dependence, DW? Washington, D.C., pp. 3812-3821. Kruger. H.. Eddy. N. B. and Sumwalt. M. (1941) ne phormacologv of the Opium Alkaloids, Supplement No. 165. Public Health Reports. U.S. Governmem Printing Office. for references see Schuster, C. R. and Thompson, T. (I%91 Annu. SPY. Pharmocol. 9.483-502. Wikler. A., Green. P. C.. Smith, H. D. and Pescor. F. T. (1960) Proceedings oJ rhe Zlsr rlnnwl &ienrijic Meeting. Committee on Problems of Drug Dependence, N.A.S.. N.R.C.. Washington, D.C.. pp.2244-2259. Seevers. M. H. (1968)JAMA 206.1263-1266. Mardones, J. (1963) In: W. S. Root, and F. G. Hofmann, @is), Physiologicul Phormucology.
Prostacyclinand atherosclerosis R. J, Gryglewski fiPnrtmClt Poland.
ofPharmacology, fli’. Copernicus .Ued~cal Academy,
Concepts of the dewlopmeat of atberoszluosis Varic~s hypotheses and conceptions of the pathogenesi s of atherosclerosis continually transform our clinical approach to the problems of prevenrion and treatment of this disease. The hundred years’ dispute between follower! of &?!I Rokitansky’s ‘incrustation hypothesis” and Vircliow’s ‘infiltrat.ion hypothesis” is still not closed. Do intravascular thrombi initiate atherosclerotic dam&e of arterial wall or do thq crown arterial iesions already ushered in by lipid infiltration? This last point of view has PrevaiIed among scientists for many years owing ~XZSIYto &ichkor’s experimental demonaration that lipid streaks crmr in arteries of rabbit:; which have been fed a ‘F!.mm
Ym+
Hd!aod
Rmewr,~d
Pm,,
,9*0
31-531 Cmcow. Gmegdmecko 16,
Vol I. Academic Press. New York and London. pp. 99-183. 7. Deneau. G. A.. Yanagrta. f. and Seevers, Al. tl (I %‘?I P~.~ho~~Jhormocol~Jgiaf i9erl.I 16. 10-48. 8. Johanson. C. E. and Balster. R. I.. (IY78) Bull. .Varc. 30,43-54. 9. Uello. N. K. (1973) Phormclr. Bwhrm. Hehav. I, RP-lOI. IO. Yanagita, T. and Takahashi. S. (1973) .1. Pharmacol. Exp. Ther. IIJS. 307-3 16. II. Yanagits, f. el al. (1970) Jap. 1. Clime. Pharmarol. I, 13-16. I?. Wood, IR. W., Grubman, J. and Weiss, B. (1977) J. Pharmacol. Esp. The,. 202.491-499. 13. Jarvik. M. E. (1967) Ann. N. Y. Arad. Sci. 142.280-294. 14. Ando, K. and Yanaaita. T. Submitted IO Psychopharmocologia. 15. Jones, 8. E. and Prada, J. A. (1973) Psychopharmarologra 30, I -I 2. 16. Yanagitr. T. (1976) P’tormacol. Rev. 27, 503-509. If. Griffitha, R. R., Brady. J. V. and Snell. J. D. (1978) Psychophermaco’ogy 56. S-13. 111. Johanson. C. E. and Sc’tuster, C. R. (1975) J. Pharmocol. E&p. Ther. !93.676-688.
Tomoji Yanogrra grodiaored in meddrcinefroa rhe Jikei Universi?v, Tok 1’0 b 1955. .After dorng research there he worked af rho University of Michigan from 1960 to 1’965. He fhen rerurned ro rhe Jikei University and was oppoinred Direcror of rhe Freriinical Research Luhorarories in 196.9. His mon.v public offices include membership of rhe WHO Advisory Panel on Drug Dependence.
We may also reverse this question: why are platelets not activated inside arteries of healthy subjects? Our answer is that in healthy subjects platelets are prevented from activation by prosta.cyclin (PGI,)4*B-the hormone generated continuously by blood vessels, kidneys and hmgsb. By raising CAMP levels in platelets3 prostacyclin keeps them in a non-agressive state, i.e. it suppresses their natural tendency to adhesion, aggregation and release reaction. By raising CAMP levels in arterial walls’ prostacyclin decreases the permeability of the intimo. and prevents hyperplasia of thr media. We suggest, consequently, that atherosclerosis develops when secretion of prostacyclin is impaired. In other words, we propose that atherosclerosis is a disease due to a deficiency of prostacyclin’.
diet rich in lipids. On the other hand, in the early stages of human atherosclerosis blood platelets and fibrin indeed appear to ‘incrust’ the arterial wall while myointimal oells of arteries grow over them and thus form an atheromatic plaque. Ross and Glom& believe that intravascular activation of platelets is the key event for development of an atheromatic plaque. Activated platelets release a growth fi4ctor that stimulates prolifera. tion of arterial myocytes and promoteFS Prostacydin and tbromboxane A2 their migration towards the arising atheromatic plaque. This attractive The products of cycle-oxygenation of concept provokes the next question: what arachidonic acid, cyclic endoperoxides makes platelets release their growth (PGG, and PGH,). give rise to prostafactor as well as other factors inside (e.g. in noids, i.e. lo prostacyclin arteries of a subject in whom the atheroarteries), to thromboxane A, (e.g. in sclerotic process is just about to begin? platelets) and to a number of prosta-
ItI1
-
Control
- -+ Cdchime
105M
Fig. 1. Dose-response curve IO onkvorensrn m rhe presence of co/chicineH.
‘uncovering’ of additional angiotensin receptors. The diminished degradation of peptide by angiotensinase would increase its availability at the receptor site. Thus, these two factors:- increased number of receptors and decreased degradation of angiotensin, may indeed explain the increased maximal response to angiotensin after angiotensinase blockade by angiotensinase inhibitors. Our work on angiotensin tachyphylaxis. work with angiotensinase inhibitors, and the results of Meyer’s group clearly point out that angiotensin receptors are not rigid entities in cell membrane but rather mobile macromolecules in constant- flux regulated by the supply of agonist and angiotensinase activity. Like any membrane protein the angiotensin receptor must be synthesized intracellularly and delivered to the cell membrane.
\h
F25y?.yY__~__---3” F
-20
\ .-*
Drugs which block protein synthesis. like cycloheximide. or interrupt the flow of intracellular proteins, like colchicine. do indeed block the vascular response to angiotensin (Fig. I). The possibilities of attacking the angiotensin-renin system by pharmacological means and of bringing about a change in sensitivity of vascular tissue exist at different levels. One can block renin and converting enzyme activity with specific agents. Recently, a specific inhibitor of angiotensin converting enzyme was introduced as an antihypertensive agent. Specific antagonists of angiotensin have already been known for some time, all of them being angiotensin analogs with very limited clinical use. The manipulation of vascular response to angiotensin is also possible through the change of sodium load and other factors. However, most of these changes are reversible and of short duration. One wonders whether a long-term or permanent change of receptors would be of greater therapeutic significance. One possible way of doing it is immunological manipulation of angiotensin receptors. The angiotensin receptor can be solubilized from the cell membrane by deoxycholic acid. This procedure successfu!ly separates the receptor protein from angiotensinase” (Fig. 21. However. the pure angiotensin receptors are still not
One area ir. the field of esperimental pharmacology in which norrworthy n- - a Solubilired fraction progress has been ashieted :s that A--A Pellet after solubiliration concerning drug dependence. parrisularl!: the psychological aspects thereof. The 16 2 4 of methods for seifdeveiopment TI& (min) administration of drugs in laboratory Frg. 2. Angiolensinase ac1iwr.vcnplasma membrane animals has contributed greatly both to fraction before and afrer solubilirarron wtrh 7-deoxyrholic ocrd (IO mg+j. The pressor dJec; of the body of pharmacological knobledge resrduol angtorenrin qfrer tncubaiion with di/ferenl and to the conceptual understanding of fracrrons ww measured on rar blood pressure rhe phenomenon. Some of rhe progress ,wr,~~rurron. 0.3 ,, V anjyown.wn WI\ mctrbulrd wrrh made in this area will be brietl:? introIOOIJO j4g of prorem/ml. lp cO.05: l*P cO.01; duced in this article. “‘p
t
Control
Reading list I
z
3. 4.
5
6 3
8.
9. 10.
Tigcrstedt. R and Bergman. P <, ( IHYHI Skond .Arch. Phurrol R. X3-2:1 Page. Ci. H ll%R) In I H Page and J \h McCubbm led\) Renal Hyperrentron. tmr Rook Mcdtcal Publl\hrrs Inc , (‘hIsago. pp 391-3%. Dcrynck. M. 4 and Steyver. P ,I9’61 .AW .! Med. 61.758-‘67 LeMonan P. md PalalL. DI tlTcl J Pharmoco: Exp. Ther 195. 16’-I’!: Palm. DJ ant LeMorran. P (19’ I J Pharn ocol Erp. Thu. 179. 5X!-‘3 I karrucgla. P . Sachs. 5 and PdlalL. DJ I IY’Y) Mol. ?harmacol. I?. 525530 LeMorban. P , Palax. DJ and I-ergu\cm. 0 (19771 Can J Phwor Phormut-ur G5, 652-65:. LeMonan. P aid Palax. DJ (19’21 c‘m J Ph,wo/. Phormo. ol. 50, -lYX-!o’ Palax. DJ.. Ktullar. H. anr! Farrugp.s. P funpubhrhedl Paials. DJ. aid Farrug~a. P I i9-91 C/m Erp H.vperrensron(KI press)
Self-administration studies on psychological dependence
Introduction O---O
isolated. This worh is hampered by the reiative scarcity of angiorensin receptor\ in vascular tissue. However, it is only ? matter of time before this lechriical obstacle is removed, thus opening a neu era of research in this field.
Self administrat;on
of drugs in ph!sicell)
dependent subjects Until
lY64.
when
Sect\cr\
t’f u[.’
at the
Unit,enit\ of blichigan firs1 dsmon~trated the :‘acr that rhesus monhrrs ~111Fe& and self.adminisrer t1.r prin
TIPS
162 demonstrated that chimpanzees made physically dependent on morphine chose a banana when their physical dependence was well maintaineci but chose a morphine syringe when their ‘supply of morphine had been deprived. At that time, it was a rather new concept to regard the existence of the craving 21sa necessary condition in! addiction. Kruger, Eddy and Sumwatt’ concluded in their intensive 1941 review on the craving for drugs in animals that, “Except for Spragg’s experiment, acidic tion in the sense of his restricted defini tion has not been demonstrated in an5 infrahuman organism”. Although in the past two decades the view that physical dependence is the major cause of craving has prov,ed to b+z not necessarily true in all cases, it wai found to be quite true for the opioids. tt was demonstrated by a number of earlw pioneers in the field-Headtee. ,Coppock and Nichols using intravenous injection of morphine to morphinedependent rats; Nichols er ol.. Beach, and Wikler et ol. using methods of administering opioids through drinking in physically dependent rats;‘. * Weeks using the intravenous sc,tfadministration technique in mcrphinedependent rats; and Schuster and Thompson using intravenous selfadministration of morphine in chairrestrained. physically dependent rhesus monkeysl-that animah sought and selfadministered opioids under the condition of physical dependence. There has since been a considerable accumulation of evidence from many investigators, and today the phenomenon is understood as negative reinforcement due to avoidance or escape from withdrawal discomfort and/or stimulus control of the dragtaking behavior by such conditiclned stimulus propertiss as drug effects and environmental fa-tars’. !. I Self-ndministratioa of drugs in gbysicrll dependence-free subjects
Voluntary* development of the delpendence state in laboratory animaJs, under the condition of free drug availability and without any previous treatment with or conditioning toward drugs air drugseeking behavior, WZi intensively attempted with alcohol and op;dds i,~ the early years mostly by giving access to the drugs by drinking methods. Today these efforts can be understood &s attempts to demonstrate the development of primary -Strictlyspeaking,~hcword ‘r&mary’ may mt an appropriatetechnical Icrm. bal is used here l
facililau understanding.
be to
psychological dependence on drugs in laboratory animals, a subject to be discussed later. In 1964 Mardones” reviewed the results on alcohol and concluded that no animal st,udy had been successful in demonstrating human-like appentency for alcohol, because (I) the voluntary consumption of alcohol by animals was only exceptionally followed bly overt signs of the drug effects, (2) the animals’ appetency for alcohol was not really a craving since it decreased when an alternative of sugar solution was offered, and (3) no withdrawal signs were ever observed in animals even after long periods of free or forced ingestion of alcohol. With opioids the situation was somewhat different because of the more rearly development of pkysicat dependence on these drugs. By the use of drinking methods with opioids, some of the previously mentioned investigators observed the eventual development of physical dependence. For example, Yanagita. Deneau and Seevers found that in a test offering a choice between morphine solution and tap water, drugnaive rhesus monkeys ingested the drug solution and developed physical dependence. Such a result, however, did not present firm evidence for voluntary development of the state of dependence, because even for animals ingesting drug solution less than water, if the amount of ingested drug is sufficient to lead to the development of physical dependence, an eventual preference for the drug will naturally develop. This ;nd result obscures the crucial point of whether or not the drug itself has a positive reinforcing property. It then came to be felt that an ideal method for demonstrating the voluntary development of the dependence state in laboratory animals would be the intravenous self-administration by operant procedures in naive subjects of such physical dependence-free drugs as cocaine. The sophisticated views of Nathan B. Eddy. Abraham Wikler, and Maurice H. Seevers on the psychological aspects of drug dependence encouraged conquest of the methodological difficulties. In 1964, Deneau. Yanagita and Seevers’ first reported evidence that naive monkeys wilt initiate and maintain intravenous self-administration not only of morphine but also of cocaine and d-amphetamine at enormously high dose levels with extreme overt signs of drug effects. Later using the same technique and procedures which are today called ‘continuous self-administration’. this evidence was confirmed with some other
- February,
1980
principle drugs of abuse including codeine, alcohol, pentobarbital-Na, and meperidine (Table I). The results on alcohol and pentobarbital-Na were somewhat surprising as they were frequently self-administered up’to the point of selfanesthetization of the subjects’. The property of drugs to increase the animals’ response rate in self-administration was behaviorally termed as their reinforcing effect, and the major trend of setfadministration studies in laboratory animals has proceeded towards detecting and anatysing this effect for various types of drugs, since it is regarded as the property most closely related to the psychological dependence potential of drugs. Many studies have been conducted along these lines, mostly in rhesus monkeys and rats. The early results of these studies were broadly reviewed by Schuster and Thompson in 1969, and the major data obtained in rhesus monkeys was recently summarized by Johanson and Balstep representing the ‘International Study Group Investigating Drugs as Reinforcers (ISGIDAR)‘. The major portion of these results matched o,r was thought not to conflict with the facts known in humans. However. the results of some drugs did not agree: monkeys did not take LSD, mescaline, STP (DOM) or Ay-THC, and yet they eagerly took procaim?. In self-administration experiments, a variety of methods have since been applied by many investigators to various types of drugs in a wider range of animal species. Some of these studies will be briefly introduced below. strddies on 1. Self-administration alcohol have greatly progressed since Mardones’ review. and today ail points to which he referred as being evidence of distinction between animals and humans have been overcome and made eastly demonstrable not only in monkeys but in small animals as well. Folk9 developed a technique to condition the drinking behavior of rats which is termed as ‘polydipsia’. With this technique it was demonstrated that rats will consume large amounts of alcohol and manifest the overt drug signs as well as withdrawal signs. Details of the progress in this area, including intravenous and intragas:ric self-administration of alcohol by rhesus monkeys, have been reviewed by Mello’. 2. One of the limitations of the abolvementioned experiments was that compounds which are not soluble ln pharmacologically inactive vehicles could not be tested. For this purpose an intragastric
TIPS - February, 1980
I63
TABLE I. Major drugs of abuse self~administcred by rhesus monkeyc Self-adminirtralion and route
Drug Morphine Codeine Meperidine Pcnlazocinc Cocaine Amphetamine Cathinoner Pentobarbiral Alcohol Diazepam Volati,le ancslhetics Nicotine Caffeine
+ + I.“. + + i.v. + + + + + + + + + + + + + + + + + + f
i.v. i.v. i.\. i.v. i.v. iv. intragartric ibid. ibid. inhalation i.v. smoking i.v.
Paltern
Owrt vgn< of effcw
Wnhdraual \Q2”‘
+ + . .
+ + + 1 + f
regular regular. frequent ibld. ibid. irregular. frequent ibld ibld. regular. frequent lbld regular. infrequent Irregular. frequent regular m i.b. mfreaueni
+ + + +* + + + l
1
+
*
l
l
_. -9 _* + 1
.
l
. . +
+
Not self-administered: LSD-25. mescaline, STP (DOhI). A”-THC. l
Usually exhausted and fell inro sleep. + + , marked; posirwe; -- . negative +
,
self-administration technique was developed, and by this new route also, rhesus monkeys were found to selfadminister several water-insoluble, sedative-hypnotics up to the point of manifesting motor impairment or to anesthesia, depending on the drugto. 3. A self-inhalation technique for organic solvents was developed using a nostril catheter for rapors, and it was demonstrated that m ankeys will strongly seek and inhale volatile anesthetics from ether and chloroform to lacquer thinner, frequently to the point of selfanesthletization I’. Re,cently Wood et al. I2 demonstrated with another self-inhalation technique that nitrous oxide, well known to have been abused by humans, is also reinforcing to squirrel monkeys. 4. Still another form of selfadministration, namely smoking, has been investigated ‘In rhesus monkeys. Jarvik” has intensively studied this matter in rhesus monkeys and found that cigarette smoke is reinforcing; however, he could not establish human-like smoking behavior in the monkeys, i.e. maintained without any reinforcer other than the cigarette smoke itself. Yanagita, Ando et al.“, also using rhesus monkeys, workeNdon this problem for many years and have finally achieved success in establishing smoking behavior in some monkeys. Two of these monkeys have been voluntarily smoking cig;arettes for longer than 2 years without any other identifiable reinforcers than the cigarette smoke itself. In this study, nicotine was proved to be a major reinforcer in maintaining the monkeys’ smoking behavior, because they ceased such behavior when their regular cigarettes were replaced with de-nicotinized ones, but resumed it upon return to ordinary cigarettes.
5. The species of animals applicable to self-administration studies is not limited to monkeys and rats. In fact, Jones and his associates’! for example have developed a technique for intravenous self-administration of drugs in spinal dogs. The results with various types of drugs are quite similar to those obtained in monkeys except that, contrary to the monkeys, dogs do not initiate the selfadministration of morphine although they will maintain it once they have been made physically dependent on the drug.
tained dose regimen; and (2) to demonstrate in animais intense drug seeking and taking behavior for the drug in question. Concerning the first point, there is ample evidence for most of the principle abused drugs that experimental anrmals have manifested overt signs similar to those known in man at self-regulated dose levels. In contrast to this, satisfying the second point proved rather difficult. When Kruger er a/. used the term ‘craving’, certainly something stronger than a simple desire to take a drug was being implied, although the discussion there was limited to the topic of the desire to obtain drugs under the physically dependent state. In this sense, although several reported observations of the selfadministration of opioids under the phjsitally dependent state were introduced earlier in this paper, none of them indeed demonstrated such a strong decire with the possible exception in the case of Spragg’s observation, assuming that the competing desire for bananas in rhe chimpanzees studied had been very strong. several Thus, inrestigatori attempted to develop methods to quantify the reinforcing imensit): of drugs in laboratory animals. Among them, the methods that are at present established are the progressive ratio procedures m rhesus monkeys’“,
Lkmonstration
of the
psychological dependence state in laboratory
animals
The major purpose for which these self-administration techniques have been developed in laboratory animals is twofold: (1) to reproduce a self-developed dependence state in laboratory animals for the analysis of the psychopharmacological etiology of drug dependence; and (2) to assess the psychological dependence potential of known and new substances in laboratory animals. There has been prolonged discussion in this field on such topics ar how to define psychological dependence and whether it would be pussible to demonstrate such a state in laboratory animals. Certainly the mere facts that a certain drug had been selfadministered by the experimental animals and its positive reinforcing effect demonstrated were not absolutely sufficient evidence to declare that the animals in question had developed psychological dependence on the drug. In response to this, the following criteria have been put forth for the experimental development of psychological dependence? (I) to demonstrate overt signs of drug effects in animals under a self-initiated and main-
and baboons’-
and the
choice procedure” in rhesus monkeys. The essential technique involved in th,ese procedures is intravenous drug selfadministration. Csing these methods. Ihe substantial
intensity
of
the
reinforcing
for oploids. stimulants and depressants. For example. using the progressive ratio procedure Yanagita has demcnstrated the fact that rhesus monkeys will press a lexer smirch
effect has been demo+xtrated
up to 12.800 times to obtain just one dxe of morphine. codeine. or cocaine. and up to 6400 times for alcohol. Such effort bk laboratory animals :o obtain drugs can certainly be regardsd as fulfilling the second criterion. The development of phxjiial dependence is not an csser.rlal aspect of dependence. It is rather to hs seen a4 a son$equence of the L‘ontmuous drug from psyihOlogl&il intake resulting dependence. But, as dissussed previousI!, its presence may intensify the drug seeking and taking beha\ ior. In order to prove the progressive ratio
this in animals,
studies have been conducted without pretreatment
and
on the drug to be an intensification of behavior by pretreat-
physical dependenie tested. As a result,
the drug-seeking
both with producing
TIPS - February, 1980
164 TABLE
II. done results of progressive ratio test.scondlrcted by intravenous self-administration in rhesus
monkeys Unir close
Drug
(mg:kg in each mjeclion) --0.5 0.25 0.21 0.11** 800
Morphine Codeine Pcnlazocine Cocarne Alcohol
Final ratios in each monkey Ivatreated-Prclreat~.) xw-64OO 16aLl2.800. wlO-12.800, 16OO-l&XI 4530-IO.-60. 6400-12.800. 2690-3200 3200-320). 6400-3200. 6400-3200 1600-Ha). 6400-3200 16@3-6401. 32006400. 3200-3200. 6400-6400
-. Pretreated for development of physical dependence. **The ratio of 12,800 achieved al. a unit dose of 0.48.
ment has been observed with morphine .md codeine, but not with cocaine or sntazocine (Table 11). The result with alcohol falls between those of the opiates and pentazoclne because pretreatment was found to intensify the behavior less markediy thas that of opiates. These results have proved that although the ‘craving or ‘appetancy’ spoken of by Kruger et al. and Mardones have been clearly demonstrated without the necessity for prior development of physical dependence, still it is clear that such strong and active desire can be intensified by physical dependence when such dependence is developed on the opiates in particular, and to a lesser extent on alcohol.
Reading list I.
2.
3.
4.
5. 6.
Deneau. G. A . Yanagita, T. and Sewers. M. H. (1964) Prmmiings of the 26th Annual Scienrific Meeting, Commit&e on Problems of N.R.C.. N.A.S.. Dependence, DW? Washington, D.C., pp. 3812-3821. Kruger. H.. Eddy. N. B. and Sumwalt. M. (1941) ne phormacologv of the Opium Alkaloids, Supplement No. 165. Public Health Reports. U.S. Governmem Printing Office. for references see Schuster, C. R. and Thompson, T. (I%91 Annu. SPY. Pharmocol. 9.483-502. Wikler. A., Green. P. C.. Smith, H. D. and Pescor. F. T. (1960) Proceedings oJ rhe Zlsr rlnnwl &ienrijic Meeting. Committee on Problems of Drug Dependence, N.A.S.. N.R.C.. Washington, D.C.. pp.2244-2259. Seevers. M. H. (1968)JAMA 206.1263-1266. Mardones, J. (1963) In: W. S. Root, and F. G. Hofmann, @is), Physiologicul Phormucology.
Prostacyclinand atherosclerosis R. J, Gryglewski fiPnrtmClt Poland.
ofPharmacology, fli’. Copernicus .Ued~cal Academy,
Concepts of the dewlopmeat of atberoszluosis Varic~s hypotheses and conceptions of the pathogenesi s of atherosclerosis continually transform our clinical approach to the problems of prevenrion and treatment of this disease. The hundred years’ dispute between follower! of &?!I Rokitansky’s ‘incrustation hypothesis” and Vircliow’s ‘infiltrat.ion hypothesis” is still not closed. Do intravascular thrombi initiate atherosclerotic dam&e of arterial wall or do thq crown arterial iesions already ushered in by lipid infiltration? This last point of view has PrevaiIed among scientists for many years owing ~XZSIYto &ichkor’s experimental demonaration that lipid streaks crmr in arteries of rabbit:; which have been fed a ‘F!.mm
Ym+
Hd!aod
Rmewr,~d
Pm,,
,9*0
31-531 Cmcow. Gmegdmecko 16,
Vol I. Academic Press. New York and London. pp. 99-183. 7. Deneau. G. A.. Yanagrta. f. and Seevers, Al. tl (I %‘?I P~.~ho~~Jhormocol~Jgiaf i9erl.I 16. 10-48. 8. Johanson. C. E. and Balster. R. I.. (IY78) Bull. .Varc. 30,43-54. 9. Uello. N. K. (1973) Phormclr. Bwhrm. Hehav. I, RP-lOI. IO. Yanagita, T. and Takahashi. S. (1973) .1. Pharmacol. Exp. Ther. IIJS. 307-3 16. II. Yanagits, f. el al. (1970) Jap. 1. Clime. Pharmarol. I, 13-16. I?. Wood, IR. W., Grubman, J. and Weiss, B. (1977) J. Pharmacol. Esp. The,. 202.491-499. 13. Jarvik. M. E. (1967) Ann. N. Y. Arad. Sci. 142.280-294. 14. Ando, K. and Yanaaita. T. Submitted IO Psychopharmocologia. 15. Jones, 8. E. and Prada, J. A. (1973) Psychopharmarologra 30, I -I 2. 16. Yanagitr. T. (1976) P’tormacol. Rev. 27, 503-509. If. Griffitha, R. R., Brady. J. V. and Snell. J. D. (1978) Psychophermaco’ogy 56. S-13. 111. Johanson. C. E. and Sc’tuster, C. R. (1975) J. Pharmocol. E&p. Ther. !93.676-688.
Tomoji Yanogrra grodiaored in meddrcinefroa rhe Jikei Universi?v, Tok 1’0 b 1955. .After dorng research there he worked af rho University of Michigan from 1960 to 1’965. He fhen rerurned ro rhe Jikei University and was oppoinred Direcror of rhe Freriinical Research Luhorarories in 196.9. His mon.v public offices include membership of rhe WHO Advisory Panel on Drug Dependence.
We may also reverse this question: why are platelets not activated inside arteries of healthy subjects? Our answer is that in healthy subjects platelets are prevented from activation by prosta.cyclin (PGI,)4*B-the hormone generated continuously by blood vessels, kidneys and hmgsb. By raising CAMP levels in platelets3 prostacyclin keeps them in a non-agressive state, i.e. it suppresses their natural tendency to adhesion, aggregation and release reaction. By raising CAMP levels in arterial walls’ prostacyclin decreases the permeability of the intimo. and prevents hyperplasia of thr media. We suggest, consequently, that atherosclerosis develops when secretion of prostacyclin is impaired. In other words, we propose that atherosclerosis is a disease due to a deficiency of prostacyclin’.
diet rich in lipids. On the other hand, in the early stages of human atherosclerosis blood platelets and fibrin indeed appear to ‘incrust’ the arterial wall while myointimal oells of arteries grow over them and thus form an atheromatic plaque. Ross and Glom& believe that intravascular activation of platelets is the key event for development of an atheromatic plaque. Activated platelets release a growth fi4ctor that stimulates prolifera. tion of arterial myocytes and promoteFS Prostacydin and tbromboxane A2 their migration towards the arising atheromatic plaque. This attractive The products of cycle-oxygenation of concept provokes the next question: what arachidonic acid, cyclic endoperoxides makes platelets release their growth (PGG, and PGH,). give rise to prostafactor as well as other factors inside (e.g. in noids, i.e. lo prostacyclin arteries of a subject in whom the atheroarteries), to thromboxane A, (e.g. in sclerotic process is just about to begin? platelets) and to a number of prosta-