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Dopamine receptor agonists, partial agonists and psychostimulant addiction
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27 De Lanerolle, I? and Paul, R J. (lY91) Aw. 1. P/?@f. 261, Ll-L14 12 Torphy,T. J.,Zhou, H-L., Burman,M. and Huang, L. 8. F. (1991) &till 28 Miller, J. R., Silver, I’. J. and Stull, J. T. (1983) Mol. Plmrsmcct 24, PJ~mtrtwl.39. 3M.W 2x?-242 13 Torphy. T. J.t.faf. (19931J. P/I~I~~IIz,-I~~. Eqr. %?iiP. 265, 1’13-1223 29 Tang, D-C., Siull, J. T., Kubota, Y. and Kamm, I;. E. (1992) J. &of. 14 Francis,S. H., Nob&, 8. LX,Todd, B. W., W&i, j. K and Corbin,j. ii. Cfrc’n.267, 11839-l 1845 (1988) Mol. P/mm-of. 34.506-517 15 Heaslip. R. J., F&a. F. R.. Rimele,T. J.and Grimes, D. (1987) J.Plmr- 30 Huang, I-C.,Garcia, M. L., Reuben,J.I’. and Kaczzorowski,G.j. (1993) Ew. J. Plm?mlc@f,l. 234 3713 ntami.Eq’. T/wP. 243, 1016iO26 31 Jones,T. R..Charette, L.,Garcia, M. I,. and Kaczorowski,G. J, (1990) 16 Giembvcz, M. A. .md Diamond, J. 119%) Biocknz. PItarr~?rof.39, /. Prrar~t~~ca~. Exp. ~~z~r~p. 255,697~Xl6 27x-2ti 32 Miura. M., B&&i, M. C., Stretton,D., Yacoub,M. H. and Barnes,i? J, 17 Torphy,T. J‘.Freese,W. B., Rinard, G. A., hJntO77. L. 1. and Mayer, (1992) Am. Rtv. Rcspir. Dis. 146,132-136 S. E. (1982) /. Bbl. Clax 257, 11609-11616 33 Small, R. C., Foster, R. W. and Boyle,J. I? (1988) Apr$ Actiotls23, 18 jiang, H.. Shabb.J. B. and Corbin. 1. D. (1992) BiocIwllcr,r. WI Biol.70, w-s94 l’a-i-12$9 W Weston, A. H. (1989) Q?i@n A& 414(Suppl. I),%@-5105 19 Hofmann, F. and Fluckcrzi,V. (19831Ew. J. Bie&w. 130,599-603 20 Lindgraf, W., Hullin, R., GibeI. C and Hofmann, EY1986f Ew. 1. 35 Cook,S. J. ttnf. 11993)Br. J.P~117~tt~~~. 109,114&1118 36 Chiu, P. et d. 119933Br. J. Plmrttmcco/. 109,114%1156 81dk?N. 154 1E-117 37 Kume, H., Tabi, A., Tokuno, H. and Tomita, T. (1989) Nalrtn 341, 21 Miller, C. A., Bamette,M. S., Chmsbw. H. S., 111and Torphy, T. j. 152-IS4 (19861Am. 1.Pll+. 251, G794-G8003 22 Jiang.H., Colbran,J. L., Fmncis,S. H. and Corbhin,J. D. Ilv42) I. &of. 38 Hamaguchi, M., Ishihashi,T. and Imai. S. (1992) J. Plwtw-of. E.rP. Tltt*mP.262.263-270 clrtnr. 267,1015-1019 23 Lincoln,T. M.. Cornwell, f. L. and Taylor, A. E. ( 1990)AIIZ.1.P~~~~il~j. 39 Robertson,E.. Schubert,R., Eschler,J.and Nelson, M. ‘Z (1993) Am. J. Plyiof. 265, C299-C303 2: ,Cw9-Cut7 -. -_ -.. 40 Brown, A. M. and Birnbaumer, L. (1988) Am. /, Pbysiol. 254, 24 Takuwa, Y., Takuwa, N. and Rasmussen,H. (1987) Aw. I. Pk~rol. H401-H410 253, C817-C827 41 Kume, H., Graziano, M. P. and Kotlikoff, M. I. (19921Pmt. Nafl Ad. 25 Felbel. J.. Trockur, B.. Ecker, T.. Landgraf, W. and Hoifmann, F. Sri. USA 89, 11051-11055 (1988) J.Bi& C&w. 263, 16X4-16771 26 Sparrow, M. P., I’fitzer, C., Gagelmann. M. and Rtiegg, J,C. (19841 42 Kume, H.. Hall, 1.I’., Washa~u, R. J.,Takagi, K. and Kotlikoff, M. 1. (1994) J.Clifl. blw.Q.93, 371-379 Aal. J. Pltysial.246.C34SC314 .I
Dopamine receptor agonists, partial agonists and psyc~osti~u~ant addiction luigi Pulvirenti and George F. Koob Despite the epidemic growth of psvchostimulant addiction over the past years, few phsrmacological means of intervention are available to date for clinical
treatment. This is of importance since the withdrawal syndrome that follows abstinence from drugs such as cocaine and the amphetamines
is characterized,
among
other symptoms, by intense craving forthe abused drug,
and this is considered a critical factor leading into relapse of drug use. In this article, luigi Pulvirenti and George Koob focus on the modu!atory role shown by drugs acting at the dopamine receptor on the various phases of psvchostimulant dependence
in preclinical
models and in human studies, and suggest that a class of compounds with partial agonist properties at the dopamine receptor may have ~erapeutic The term ‘psychostimulant
potential.
drugs’ refers to compounds that~~sss~~thomimetica~vi~and producea state of beha~oural activation in humans and experimental
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animals.
After earlier misconceptions that considered psychostimulants as ‘recreational’ and harmless drugs, the addictive potential of some of these substances is now well known’. Cocaine and the amphetamines, in particular, have very high abuse liability. The recent ‘crack’(the free alkaloid base of cocaine) epidemic and the appearance on the illicit market of amphetamine derivatives such as methamphetamine has prompted considerable experimental studies on attempts to solve the problem of psychostimulant addiction. Preclinical studies in laboratory animals have been developed to model the various aspects of the natural history of psychostimulant addiction, which include acquisition of drug self-admi~stmtion, maintenance of drug reinforcement, withdrawal and craving*. Drug self-administration in rodents and monkeys has predictive validity for the abuse potential of drugs in humans. More recently, hov ?ver, i.v. self-administration in rats or monkeys carrying indwelling catheters and trained to press a lever to obtain infusion of a drug under different reinforcement schedules has also been used as a tool for preclinical screening of potent~i ~eatments for drug addiction. The acute reinforcing properties of drugs can be assessed in animals that are allowed limited daily exposure to drugs of abuse in order to induce stable intake”. Alternati~,ely, longer access to self-administration may be permitted in order to induce higher intake of drug, a procedure that produces a withdrawal syndrome upon cessation of drug availability4J. By contrast to opiate drugs such as heroin that are used daily, stimulant abuse is characterized by drug consumption in heavy binge&. This is particularly true for cosaine and its related chemical derivatives such as ‘crack’. Interestingly, if rats are allowed unlimited access to stimulant self-adminis~a~~on, the pattern of intake shown is su~risingly similar to that 8
1994,ElsevierScienceLtd 016S- ht47/94/$07.00
R of human addicts, with binges of intake lasting hours to several day+:. Thus, the various phases of stimulant addiction can be mimicked using different self-administration schedules providing reliable models for the preclinical study of the therapeutic potential of new compounds in a systematic and controlled manner.
The role of dolpamine Psychostimulants enhance noracir?naline, dopamine and 5-HT neurotransmission in the central and peripheral nervous systems by in~easing the release of the neuro~ansmit~r from the presynaptic terminal (dmphetamine, methamphetamine) or by inhibiting its reuptake (cocainey.
Reinforcing effects
ofcocaine and amphetamines
An important role for central dopamine neurotransmission in the reinforcing effects of cocaine and amphetamines is indicated by many sources of complemental information. While administration of adrenoceptor antagonists did not modify cocaine or amphetamine selfadministrationY, systemic injections of dopamine receptor antagonists decreased the interval between injections in animals trained to press a lever for i.v. cocaine self-adminis~ationl~,*i. This is a pattern of r~ponding similar to that observed after lowering the dose of cocaine dispensed per injection, thus suggesting a reduction of the acute reinforcing effect of cocaine. Lesions of the mesocorticolimbic dopamine system produced by 6-hydroxydopamine resulted in extinction-like patterns of cocaine self-administration’z, decreased the progressive ratio performance fur cocaine!” and produced selective termination of cocaine self-administration in a multiple schedule”. Furthermore, microdialysis studies in rats during cocaine self-administration have shown an increase in the release of dopamine within the nucleus accumbensl j, a critical site of the mesocorticoiimbic dopamine system thought to be the specific neuroanatomical substrate mediating cocaine reward’b. For these effects, activation of dopamine D,, DZand D3 receptors may be involved, as shown by a number of studies in rats and monkey+“).
The withdrawal phase An importar:t component of the natural history of psychostimulant addiction is the abstinence or withdrawal phase. This was recently documented clinically and is characterized by a lowering of mood, hypersomnia, hyperphagia, psychomotor retardation, anhedonia and intense craving for the abused drug*O. Some of these symptoms have also been success~lly rn~ell~ in rats withdrawing from prolonged exposure to i.v. cocaine or amphetamine self-administration. In particular, a state of psychomotor retardation has been shown to occur in rats 48 to 96 h after abrupt cessation of prolonged exposure to i.v. self-administration of high doses of amphetamines. SimilarIy, an elevation of the current threshold for intracranial electrical seIf~timula tion has been documented after withdrawal from 12-and 24-h binges of i,v. cocaine self-administration4.
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Neumchemically, it appears that a functional reduction of dopamine neurotransmission may be one important component of cocaine abstinence. Significant reduction in dopamine overflow in the nucleus accumbens of rats ~thdrawing from unlimited access to cocaine selfadministration has been reportedzl, and this is thought to be an adaptive consequence of sustained cocaine exposure. The functional impairment of dopamine neuro_ transmission during abstinence may also be secondary to an increased sensitivity of release-regulating dopamine autore~pto~~, which could be specific to the subsensitivity of dopamine somat~end~tic autorecepto~ of the A10 area, reported after repeated exposure to cocairGJ4.
Dopamine hypothesis Taken togetlter, all these findings suggest that activation of dopamine neuro~ansmission within specific structures of the basal forebrain is a major determinant for cocaine self-administration in laboratory animals, while decreased dopamine function may be responsible for some of the aspects of the withdrawal phase. This hypothesis has stimulated experimental efforts aimed at the identi~cation of pha~a~lo~ca1 means of manipulating psychostimulant dependence with drugs acting at the dopamine receptor.
Dopamine receptoragonists The success of methadone detoxification, the nicotine patch, and ~n~iazepines for alcohol detox~cation rep resents a solid rational background for the use of dopamine receptor agonists as adjuncts for treatment of psychostimulant addiction. A number of experimental and clinical studies support this possibility, further strengthened by the non-addictive nature of many clinically used dopamine receptor agonists.
Bromocriptine, an ergot derivative and agonist at the D2 receptoP, was the first drug to be used in this sense. Clinically used as a prolactin-lowering and antiparkinsonian agenP, bromocriptine was shown to reduce the intake of cocaine in rats that sea-admi~stered the drug iv. (Ref. 27). In addition, it showed promise in an animal model of cocaine withdrawal since it reversed the increase in the threshold for intracranial electrical self-stimulation observed in rats after cessation of cocaine self-administrationz”. This paradigm has been hypothesized to be a model of post-cocaine anhedonia, one of the cardinal symptoms of cocaine withdrawal in humand. Amelioration of cocaine withdrawal by bromocriptine in humans has also been reported, but the results are more controversial. While bromocriptine reduced some symp toms of cocaine withdrawal in a double-blind trial and craving evoked by cocaine in a single-dose placebo-controlled studyzq-32,other studies reported no effects of bromocriptine on cocaine craving and bromocriptine did not alter the subjective effects of cocainP”j”.
TjPS-October 1994(VOI.Is) 375
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In summary, the possibility that dopamine receptor agonists may ameliorate some of the symptoms of psy&ostimulant withdrawal has been confirmed in experimental studies and in some clinical trials. The results showing that bromocriptine and iisuride reverse some symptoms of psychostimulant withdrawal suggest that these, as well as other dopamine receptor agonists are promising therapeutic agents for psychostimulant withdrawal. Furthermore, considering, that significant biochemical and behavioural evidence indicates that dopamine receptor agonists effectively modulate various aspects of stimulant dependence in laboratory animals, carefully conducted clinical trials are warranted to estab lish how treatment regimens with the non-addictive dopamine receptor agonists may be used as substitution therapies in human stimulant addicts.
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liswide Lisuride, also an ergot derivative that acts at the D, receptor, has recently shown promising therapeutic activity in psychostimulant dependence. In rats trained to self-administer cocaine with limited dailv access, lisuride reduced cocaine intake, acting as a partial substitute for cocaine’“. In a separateexperiment, rats allowed access to self-administration of amphetamine at high doses, displayed a state of psychomotor retardation (hypolocomotion and catalepsy) following discontinuation of oxposure to amphetamme. During this withdrawal phase, daily treatment with lisuride prevented the occurrence of the symptoms of motor retardation in rats+. In a clinical double-blind study, lisuride was used in hospitalized stimulant abusers during acute withdrawal from cocaine or amphetamine. Lisuride normalized some of the sleep changes of psvchostimulant withdrawal, prolonging rapid eye-moviment (REM) latency and reducing REM time, while it did not modify subjective ratings of craving and moodl:. However, the reports of craving and mood changes were very low in the control group im this study, possiblv reflecting the inpatient setting.
Finally, the dopamine receptor agonists amantadine and pergolide have been used with some success in a double-blind and an open-pilot trial, respectively, in stimulant abusersJ5-“. However, further studies are necessary before these drugs can be considered as potential treatments for psychostimulant dependence.
Recently, the concept of partial agonist action has received considerable attention in the field of dopamine receptor pharmacology. Partial agonist properties refer to the efficacy of a given receptor ligand that shows high affinity for the receptor, but low intrinsic activity~“. The first compounds characterized with partial agonist activity at dopamine receptors were the dopamine analogue preclamol and the aminoergolines SDZ208911, SDZ208912and tergurideab*’ trig. 1).Ail these compounds possess partial agonist activity at the Dz receptor. In eiectrophysiological studies, SDZ208911 and SD2208912 weakly inhibited the firing of dopaminergic neurones of the A10 area of the rat, while they reversed the inhibition induced by the full agonist quinpiroIeJ? Terguride showed a similar profile on neurones of the substantia nigraJJ. By contrast, biochemical studies revealed that SDZ208~11and terguride acted as full agonists with a potency similar to that of quinpirole in rats depleted of monoamines after treatment with reserpine, as measured by a reduction in the accumulation of t.-dopa’;. However, the ergolines produced the opposite effect in non-reserpinizcd rats, a profile similar to dcpamine receptor antagonists and thought to reflect functional inhibition of postsynaptic receptors and compensatory activation of presynaptic tyrosine hydroxylase via a feedback loopdi. Finally, behaviourai studies showed that SDZ208911,SDZ208912and terguride produced contralateral turning in rats subjected to unilateral striatal 6-hydroxydopamine lesions, but they reduced amphetamine-induced locomotion and stereotyped behaviour while only marginally reducing spontaneous locomotion in intact animal+. Altogether, these various lines of evidence suggest that dopamine receptor partial agonists possess a unique pharmacological profile since their net effect depends on the level of existing synaptic activity (that is, the degree of concurrent receptor occupancy), thus confirming earlie; hypotheses’;. This also provides a rationale for testing :-he effects of these compounds in psychostimulant addiction.
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In rats self-administering cocaine i.v., acute systemic administration of the partial agonist SDZ20891I reduced the rewarding value of cocaine as shown by reduction of the inter-reinforcement intervaP (Fig. 2). Therefore, despite its slight intrinsic activity, SDZ208911behaved as a dopamine receptor antagonist on cocaine self-administration. It is reasonable to speculate that partial agonists at dopamine receptors may also be useful during withdrawal from cocaine and amphetamine, a condition characterized by tunctional dupamine hypoactivity. Of importance in this respect could be the impuise-reguMing activity of the aminoergolines SDZ208911 and terglride, which reduced the firing rates of dopaminergic neurones in n&e animals4Jm, but reversed the inhibitory effects of dopamine receptor agonists. Therefore, it is possible that dopamine receptor partial agonists may represent potentiat candidates for nor‘nalizing dopamine neurotransmission during the various phases of the natural history of psychostimulant addiction. The ~nctional efficacy of a partial agonist depends on the level of occupancy of a given receptor by full agonists, such as the endogenous transmitter dopamine“). Consequently, partial agonists may act as agonists in conditions of low receptor occupancy by the transmitter as, for example, in the case of denervation. Similarly, the same con~poLlnds may function as antagonists in the case of high endogenous transmitter tone (Fig. 3), such as during
intense presynaptic activity or after p~~arn~acolo~cal stimulation (for example, exposure to cocaine or amphetamine). Hence, by occupying dopamine receptors and exerting low intrinsic activity, partial agonists might rep resent novel antipsychotic agents that possibly are devoid of the extrapyramidal side-effects”‘eJ’,a problem that limits the clinical use of neuroleptics. Hence, tetitguride was shown to reduce r-dopa-induced dyskinesias in patients with Parkin:on’s disease’? and to decrease the total score on a rating scaie for extrapyramidal side-effects in schizopl~renicpatients treated with neurolepticdntgs”. In addition, the occurrence of side-effects that tire commonly associated with the administration of dopamine receptor agonists (such as dyskinesia or em&s) was not observed in humans with preciamol”, and SDZ208911reduced neuroleptic-induced oral dyskinesia in monkey+. Finally, although dopamine receptor partial agonists produce amphetamine-likei*, but not cocaine-like’7 discriminative stimulus effects, they do not possess psycl~e stimulating activity in naive animaW, an effect Ihat is observed with dopamine receptor agonists with abuse liability. This further supports the hypothesis that dop amine receptor partial agonists possess a unique pharmacological profile, Thus, in the presence of a physiological level of dopamine tone, partial agonists would pr~umably be devoid of abuse liability. However, selfadministration studies with Tartin agonists in either
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Fig. 3. HypothetIcal acnon of dopamme receptor partial agonrsts on dopamme neurotransmission during various phases of cacalne addiction. a: Norrlal response. b: The augmented response that follows exposure to cocaine may be reversed by partial agomsts because of their low mtrinslc activity and fur,:tronal antagonism shown by these compounds under condmons of dopaminz hyperactivity c: During cocame withdrawal. the reduced response that accompanies dopamcne depletion may be corrected by the agonist activity shown by partial agonists in condmons of low dopamine tone.
L nai’veor cocaine-trained rats have not yet been performed, and the effects of these compounds on the threshold for brain stimulation reward have not been described.
Concluding remarks In conclusion, there is enough substantial evidence to indicate that compounds with partial agonist activity at dopamine receptors may in the future represent novel psychoactive agents with important advantages compared to previously used antipsychotic drugs or full dopamine receptor agonists. The various phases of psychostimulant addiction, in particular, may represent a specific field of therapeutic application for these drugs and the scarcity of pharmacological means of intervention in cocaine and amphetamine dependence certainly warrants further studies, Selectedreferences I Adams, E. H.. Cforer.
J. C.. Roose, 8. A. and Kczcl. N. J, (19%) Adrl. Ahrh0f srIl’+. AlrrrQ* 6, 4Y-71 2 Stolerman. 1. (IW?)TrmkPhmuk~l. 53.13,1711-176
3 Koob, C. F. and Goeders, N. E. (1989) in Tlrr Nrrrnq~lmrrtmro/o,picnl Bnais of Rrrtnrd (Liebman, J. and Cooper, 5.. eds), pp. 215-263, Clxendon Press 4 Markou, A. and Knob, G. F. (1991) N~~rrrc~~~~!/clro~drnnrmml!p!! 4, 17-26 5 Pulvircnti, L. and Koob,C. F. (1993) N~~rrro~~~~rlro~drnrrlmmk!~l~~.~~8,213-218 ,. 6 Bozartb. M. A. and Wise, R. A. (198% J. AM. hd. Assock4,81-83 7 Griffith, R. R., Big&w, G. E. and Henningfield, j. E. (1980) in Adznnin in Srrbsfflrr~~Abrrsc (Mello, N. K., ed.), pp. I-RO, JAI Press 8 Groppetti, A., Znmbotti, F., Biazzi, A. and Mantegazza, P. (1973) in Fn~rf;cn in ClrII,clr[,lnrsirrl, Rt~cxrc-h (Usdin. E. and Snyder, S. H., eds), pp. 917-925, Pergamon Prt3s 9 Roberts, D. C. S., Corcoran, M. E. and Fib@, H C. (1977) Plmrrrm1-o/. t?ilU~hcr!r.Bckaz’. 6, 61 S-620 10 Roberts, D. C. S. and Vickers. G. (1984) P.*!/dr~qdrnrrrrorfl/[~~!/ 82, 1%13Y 11 Johann. C. E. (1976) Plmrrr~rrnd. Rril. 27, 343-355 12 Roberts, D. C. 5. Koob, G. F., Klonofr, P. and Fibiger. H. C. (19RO) Phl~l~l~?id.BlWhr. &hw. 12, 781-787 I3 Koob, C. F., Vaccarino, F. J., Amalric, M. and Bloom, F. E. (1987) in Bmirr Rntnnf Sysfrrr~ wd Ahrw (Engel, J. and Oreland, L., eds), pp.3-S-50, Raven Press 14 Caine, S. B. and Knob, C. F. (1494) J. Exp. Am/. Bdrn~~.61,213-221 15 Hurd. Y. L., Weiss, F., Knob. G. F., Anden, N. E. and Ungerstedt, U. (1YXY) Iirnin Rcs. 199-203 16 Maldrmado, R., Robledo, I’., Clover, A. J. Caine, S. B. and Koob, G. F. I IY93) P/I~~uI/u~~~/,B~~~dr~~rrr. Bc’/r,rrf,45, 239-242
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Koob, G. F., Le. H. T. and Creese, 1.(1987) Ntwosci. l&t.79,335-320 41 Karobath, M. et al. (1988) in Prqrl’-zs irt Crrferkohmi~rr Raenrclt: Woolverton, W. L. (1986) P~~arn~rm?l. Eiocken~. Belm 24,531-535 Cehd Aspecfs (Belmakerh, H., Sandier. M. and Dahlstrom, A., eds), Caine, S. B. and Koob, G. F. (1993) Scic~~ce 260, 1814-1816 pp. 19-26, Liss Gawin, F. H. and Kleber, H. D. 09%) Arch. Ge,r. Psyc~zi~~r!/ 43, 42 Kehr, W. (1984) Ettr. I. P~ar~iac~l.97. Ill-119 107-113 43 Ackerman, J., Johansen, P. A., Clark, D. and White, F. J. f1993) Weiss, F., Markou, A., Lorang, M. T. and Koob,G. F. (1992)Brabr Rcs. J. Plmrr~t~&.EwP.7Ier. 265,963-970 593.314-318 44 Piercey, M. F.. Hoffman, W. E.. Vogelsang, G. D. and Travis, M. Dwoskin, L. I’., Peris, J., Yasuda, R. P., Philpott, K. and Zahniser, 11987)1. P~~~~~~/,ErP. TIzer.254,391-3% N. R. 11988)Lift Sci. 42,25.%262 45 Svensson, K. ef RI. (1991) ~~~~tly~r-Sc~tjrfi~. Ardz. ~~~~~I~c~~. 344, Weiss, F., Paulus, M. P., Lorang, M. T. and Koob, G. F. (1992) 263-274 f. Nefrrosci.12,4372-4380 46 Clark, D. ef RI.(1991)Psyclro~rlmntmcafo~ 105,381-392 Ng, J. I’., Hubert, G. W. and Justice, J. B., Jr (1991) J. Nrrrroc/ze!h.56, 47 Car&on, A. (1983);. Net& Tmtzsw.60,205-223 1485-1492 48 Pufvirenti, L., Smith, D. and Koob, G. F. f1994) Psy~~~~i~~~llllrtn~ffco~o~ Vance, M. L., Evans, W. S. and Thorner, M. 0. (1984) Aetr. lnferu. 313.518-520 Med. !00,7@-91 49 Clark, D.. Hiorth, S. and Carlsson. A. (198511. Nrsral Transra. 62, Ho, K. Y. and Thomcr, M. 0. (1988) Drqs 3667-82 171-207 Hubner, C, B. ar.d Koob, G. F. (1990) N~rru~.~~ru~lJrar 3, 50 Coward, D. d nl. 11989)~yc~f~P~~~rtt?aca~. Bzdf.25,393-397 101-108 51 Coward, D. et et. (199th i. Pftnrrrmrol.Exp. Tkr. 252,279-Z@ Markou, A. and Koob,C. F. (1992)N~~rr~Psyc~roP~~arr~rcolo~7,213-22452 Baronti, F. et nl. (1992)Newofqqy 42,1241-lL43 Da&s, C. A. and Gold, M. S. (1985) LRnceti, 1151-l 152 53 Filip, V., Mar&k, M., Halkova, E. and Kamn, P. (1992) Psycbi~:ry Giannini, A. J.. Baumga~el, P. and Dimanio, L R. (1987) 1. CIih. Rcs. 41,9-16 Plmrttnrcol.27,267-270 54 Tamminga. C. A. ef d (19921J. Netof Tramnr. 88,lM175 Giannini, A. J and Billet, W. (1987) /. Glib. Plmrrrmcol.27,549-554 55 Peacock, L. and Gerlach, J (1993) Eur. /. Plrawmcol. 237,329~340 Tennant, F. S. and Sagherian, A. A. (1987) 4x/r. krlem. Med. 147, 56 Exner, M. and Clark. D. (1992) Bd:as. Pl~arrmcol.3.609-619 1G9-112 57 Callahan, I? M. and Cunningham, K. A. (1993)J. ~f~~r,,~~~~~.fxp. T&r. Kumor, K., Sheber, M. and Jaffe, J. (1989) P~f~r~f?~fcu~. &&em. B&n. 266,585592 33,829-S37 Krenzler, H. R. and Bauer, L. 0. (1992) Br. J. Addict. 87,1537-1548 Wedd~gt~,W. W.elnf.~199l~At~r.J.D~r~Alc~~~u~Abr~~l7,137-152 Chamieainames Pulvirenti, L. and Kc.&, G. F. 11994) P~iff~?~acol. B~~~I~~~I, B&n. 47, 819-822 Gilhn, J. C., Pulvirenti, L., Withers, N., Golshan, S. and Koob, G. F. SDZ208911:N-~(8u)-2,6-dimethylergohne-B-yl]-2,2(19941Biol.Psycfd&y 35,&U-849 djethyipropanamide Malcom, R., Hutto, B, R., Phillips, J. D. and Bailenger, J. C. (1991) J. Clirl. Psycfrinfry 52,39-40 SDZZO8912:N-[(8cY)-2-chtoro-6-methylergoline-&yl]Hoyer, D. and Eoddeke, H. W. G. M. (1993) Trords Plmmmcol.Sci. 14, 2,2-diethylpropanamide 270-275 Hjorth, S, ef at. (1983) Ps~~i~~l~rartrrnacuf~~ 81,89-99
The current endotherm receptor classification: time for reconsideration? ~iiern
A. Bax and Pramod R. Saxena
The possible involvement of endothelins in a variety of diseases has attracted the attention of many pharmacologists in search of a novel therapeutic approach. The rapid development of ~ndothelin research has resulted in the molecular characterization and pharmacological recognition of ET, and ET, receptors, and in the development of compounds selective for these receptors. However, the characterization of receptors in various assays has shown that a number of effects are mediated by receptors that do not fit the present criteria for ETA or ET, receptors. In this article, Willem Bax and Pramod Saxena address endothelin receptors in general, and atypical receptors in particular.
5 1994, Elsevicr Science Ltd 0165 - 6147/94/$07.00
Endothelin was discovered and recognized as a potent vasoconstrictor peptide only six years ago’. Threedistinct endogenous endothelin isoforms endothelin 1 (ET-I), ET-2and ET-3are cleaved from the endothelin precursors big-ET-l, big-ET-2 and big-ET-3 by an endothelin converting enzyme. Increased concentrations of endothelins have been observed after myocardial infarction, in atherosclerosis, (pulmonary) hypertension, migraine and many other diseasesr. Although recent advances towards the elucidation of the molecular structure of endothelin converting enzymes” will undoubtedly be followed by the development of inhibitors of endothelin converting enzymes, efforts have so far primarily been directed to the devefopment of endotheiin receptor antagonists for clinical purposes. Indeed ET,, and ET, receptors were clonedQ, and selective ligands for these receptors have been recognized. The current criteria for endothelin receptor classification In general, receptor classification should be based on three criteriab? (1) gene nucleotide and amino acid sequence of the receptor protein, (21~ptor-eff~t coupling, and (3) interaction between receptors and agonists or antagonists, Endothelin receptors are currently classified by the consensus view of the subcommittee of the international Union of Pharmacology (IUPHAR), primarily
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27 De Lanerolle, I? and Paul, R J. (lY91) Aw. 1. P/?@f. 261, Ll-L14 12 Torphy,T. J.,Zhou, H-L., Burman,M. and Huang, L. 8. F. (1991) &till 28 Miller, J. R., Silver, I’. J. and Stull, J. T. (1983) Mol. Plmrsmcct 24, PJ~mtrtwl.39. 3M.W 2x?-242 13 Torphy. T. J.t.faf. (19931J. P/I~I~~IIz,-I~~. Eqr. %?iiP. 265, 1’13-1223 29 Tang, D-C., Siull, J. T., Kubota, Y. and Kamm, I;. E. (1992) J. &of. 14 Francis,S. H., Nob&, 8. LX,Todd, B. W., W&i, j. K and Corbin,j. ii. Cfrc’n.267, 11839-l 1845 (1988) Mol. P/mm-of. 34.506-517 15 Heaslip. R. J., F&a. F. R.. Rimele,T. J.and Grimes, D. (1987) J.Plmr- 30 Huang, I-C.,Garcia, M. L., Reuben,J.I’. and Kaczzorowski,G.j. (1993) Ew. J. Plm?mlc@f,l. 234 3713 ntami.Eq’. T/wP. 243, 1016iO26 31 Jones,T. R..Charette, L.,Garcia, M. I,. and Kaczorowski,G. J, (1990) 16 Giembvcz, M. A. .md Diamond, J. 119%) Biocknz. PItarr~?rof.39, /. Prrar~t~~ca~. Exp. ~~z~r~p. 255,697~Xl6 27x-2ti 32 Miura. M., B&&i, M. C., Stretton,D., Yacoub,M. H. and Barnes,i? J, 17 Torphy,T. J‘.Freese,W. B., Rinard, G. A., hJntO77. L. 1. and Mayer, (1992) Am. Rtv. Rcspir. Dis. 146,132-136 S. E. (1982) /. Bbl. Clax 257, 11609-11616 33 Small, R. C., Foster, R. W. and Boyle,J. I? (1988) Apr$ Actiotls23, 18 jiang, H.. Shabb.J. B. and Corbin. 1. D. (1992) BiocIwllcr,r. WI Biol.70, w-s94 l’a-i-12$9 W Weston, A. H. (1989) Q?i@n A& 414(Suppl. I),%@-5105 19 Hofmann, F. and Fluckcrzi,V. (19831Ew. J. Bie&w. 130,599-603 20 Lindgraf, W., Hullin, R., GibeI. C and Hofmann, EY1986f Ew. 1. 35 Cook,S. J. ttnf. 11993)Br. J.P~117~tt~~~. 109,114&1118 36 Chiu, P. et d. 119933Br. J. Plmrttmcco/. 109,114%1156 81dk?N. 154 1E-117 37 Kume, H., Tabi, A., Tokuno, H. and Tomita, T. (1989) Nalrtn 341, 21 Miller, C. A., Bamette,M. S., Chmsbw. H. S., 111and Torphy, T. j. 152-IS4 (19861Am. 1.Pll+. 251, G794-G8003 22 Jiang.H., Colbran,J. L., Fmncis,S. H. and Corbhin,J. D. Ilv42) I. &of. 38 Hamaguchi, M., Ishihashi,T. and Imai. S. (1992) J. Plwtw-of. E.rP. Tltt*mP.262.263-270 clrtnr. 267,1015-1019 23 Lincoln,T. M.. Cornwell, f. L. and Taylor, A. E. ( 1990)AIIZ.1.P~~~~il~j. 39 Robertson,E.. Schubert,R., Eschler,J.and Nelson, M. ‘Z (1993) Am. J. Plyiof. 265, C299-C303 2: ,Cw9-Cut7 -. -_ -.. 40 Brown, A. M. and Birnbaumer, L. (1988) Am. /, Pbysiol. 254, 24 Takuwa, Y., Takuwa, N. and Rasmussen,H. (1987) Aw. I. Pk~rol. H401-H410 253, C817-C827 41 Kume, H., Graziano, M. P. and Kotlikoff, M. I. (19921Pmt. Nafl Ad. 25 Felbel. J.. Trockur, B.. Ecker, T.. Landgraf, W. and Hoifmann, F. Sri. USA 89, 11051-11055 (1988) J.Bi& C&w. 263, 16X4-16771 26 Sparrow, M. P., I’fitzer, C., Gagelmann. M. and Rtiegg, J,C. (19841 42 Kume, H.. Hall, 1.I’., Washa~u, R. J.,Takagi, K. and Kotlikoff, M. 1. (1994) J.Clifl. blw.Q.93, 371-379 Aal. J. Pltysial.246.C34SC314 .I
Dopamine receptor agonists, partial agonists and psyc~osti~u~ant addiction luigi Pulvirenti and George F. Koob Despite the epidemic growth of psvchostimulant addiction over the past years, few phsrmacological means of intervention are available to date for clinical
treatment. This is of importance since the withdrawal syndrome that follows abstinence from drugs such as cocaine and the amphetamines
is characterized,
among
other symptoms, by intense craving forthe abused drug,
and this is considered a critical factor leading into relapse of drug use. In this article, luigi Pulvirenti and George Koob focus on the modu!atory role shown by drugs acting at the dopamine receptor on the various phases of psvchostimulant dependence
in preclinical
models and in human studies, and suggest that a class of compounds with partial agonist properties at the dopamine receptor may have ~erapeutic The term ‘psychostimulant
potential.
drugs’ refers to compounds that~~sss~~thomimetica~vi~and producea state of beha~oural activation in humans and experimental
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animals.
After earlier misconceptions that considered psychostimulants as ‘recreational’ and harmless drugs, the addictive potential of some of these substances is now well known’. Cocaine and the amphetamines, in particular, have very high abuse liability. The recent ‘crack’(the free alkaloid base of cocaine) epidemic and the appearance on the illicit market of amphetamine derivatives such as methamphetamine has prompted considerable experimental studies on attempts to solve the problem of psychostimulant addiction. Preclinical studies in laboratory animals have been developed to model the various aspects of the natural history of psychostimulant addiction, which include acquisition of drug self-admi~stmtion, maintenance of drug reinforcement, withdrawal and craving*. Drug self-administration in rodents and monkeys has predictive validity for the abuse potential of drugs in humans. More recently, hov ?ver, i.v. self-administration in rats or monkeys carrying indwelling catheters and trained to press a lever to obtain infusion of a drug under different reinforcement schedules has also been used as a tool for preclinical screening of potent~i ~eatments for drug addiction. The acute reinforcing properties of drugs can be assessed in animals that are allowed limited daily exposure to drugs of abuse in order to induce stable intake”. Alternati~,ely, longer access to self-administration may be permitted in order to induce higher intake of drug, a procedure that produces a withdrawal syndrome upon cessation of drug availability4J. By contrast to opiate drugs such as heroin that are used daily, stimulant abuse is characterized by drug consumption in heavy binge&. This is particularly true for cosaine and its related chemical derivatives such as ‘crack’. Interestingly, if rats are allowed unlimited access to stimulant self-adminis~a~~on, the pattern of intake shown is su~risingly similar to that 8
1994,ElsevierScienceLtd 016S- ht47/94/$07.00
R of human addicts, with binges of intake lasting hours to several day+:. Thus, the various phases of stimulant addiction can be mimicked using different self-administration schedules providing reliable models for the preclinical study of the therapeutic potential of new compounds in a systematic and controlled manner.
The role of dolpamine Psychostimulants enhance noracir?naline, dopamine and 5-HT neurotransmission in the central and peripheral nervous systems by in~easing the release of the neuro~ansmit~r from the presynaptic terminal (dmphetamine, methamphetamine) or by inhibiting its reuptake (cocainey.
Reinforcing effects
ofcocaine and amphetamines
An important role for central dopamine neurotransmission in the reinforcing effects of cocaine and amphetamines is indicated by many sources of complemental information. While administration of adrenoceptor antagonists did not modify cocaine or amphetamine selfadministrationY, systemic injections of dopamine receptor antagonists decreased the interval between injections in animals trained to press a lever for i.v. cocaine self-adminis~ationl~,*i. This is a pattern of r~ponding similar to that observed after lowering the dose of cocaine dispensed per injection, thus suggesting a reduction of the acute reinforcing effect of cocaine. Lesions of the mesocorticolimbic dopamine system produced by 6-hydroxydopamine resulted in extinction-like patterns of cocaine self-administration’z, decreased the progressive ratio performance fur cocaine!” and produced selective termination of cocaine self-administration in a multiple schedule”. Furthermore, microdialysis studies in rats during cocaine self-administration have shown an increase in the release of dopamine within the nucleus accumbensl j, a critical site of the mesocorticoiimbic dopamine system thought to be the specific neuroanatomical substrate mediating cocaine reward’b. For these effects, activation of dopamine D,, DZand D3 receptors may be involved, as shown by a number of studies in rats and monkey+“).
The withdrawal phase An importar:t component of the natural history of psychostimulant addiction is the abstinence or withdrawal phase. This was recently documented clinically and is characterized by a lowering of mood, hypersomnia, hyperphagia, psychomotor retardation, anhedonia and intense craving for the abused drug*O. Some of these symptoms have also been success~lly rn~ell~ in rats withdrawing from prolonged exposure to i.v. cocaine or amphetamine self-administration. In particular, a state of psychomotor retardation has been shown to occur in rats 48 to 96 h after abrupt cessation of prolonged exposure to i.v. self-administration of high doses of amphetamines. SimilarIy, an elevation of the current threshold for intracranial electrical seIf~timula tion has been documented after withdrawal from 12-and 24-h binges of i,v. cocaine self-administration4.
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Neumchemically, it appears that a functional reduction of dopamine neurotransmission may be one important component of cocaine abstinence. Significant reduction in dopamine overflow in the nucleus accumbens of rats ~thdrawing from unlimited access to cocaine selfadministration has been reportedzl, and this is thought to be an adaptive consequence of sustained cocaine exposure. The functional impairment of dopamine neuro_ transmission during abstinence may also be secondary to an increased sensitivity of release-regulating dopamine autore~pto~~, which could be specific to the subsensitivity of dopamine somat~end~tic autorecepto~ of the A10 area, reported after repeated exposure to cocairGJ4.
Dopamine hypothesis Taken togetlter, all these findings suggest that activation of dopamine neuro~ansmission within specific structures of the basal forebrain is a major determinant for cocaine self-administration in laboratory animals, while decreased dopamine function may be responsible for some of the aspects of the withdrawal phase. This hypothesis has stimulated experimental efforts aimed at the identi~cation of pha~a~lo~ca1 means of manipulating psychostimulant dependence with drugs acting at the dopamine receptor.
Dopamine receptoragonists The success of methadone detoxification, the nicotine patch, and ~n~iazepines for alcohol detox~cation rep resents a solid rational background for the use of dopamine receptor agonists as adjuncts for treatment of psychostimulant addiction. A number of experimental and clinical studies support this possibility, further strengthened by the non-addictive nature of many clinically used dopamine receptor agonists.
Bromocriptine, an ergot derivative and agonist at the D2 receptoP, was the first drug to be used in this sense. Clinically used as a prolactin-lowering and antiparkinsonian agenP, bromocriptine was shown to reduce the intake of cocaine in rats that sea-admi~stered the drug iv. (Ref. 27). In addition, it showed promise in an animal model of cocaine withdrawal since it reversed the increase in the threshold for intracranial electrical self-stimulation observed in rats after cessation of cocaine self-administrationz”. This paradigm has been hypothesized to be a model of post-cocaine anhedonia, one of the cardinal symptoms of cocaine withdrawal in humand. Amelioration of cocaine withdrawal by bromocriptine in humans has also been reported, but the results are more controversial. While bromocriptine reduced some symp toms of cocaine withdrawal in a double-blind trial and craving evoked by cocaine in a single-dose placebo-controlled studyzq-32,other studies reported no effects of bromocriptine on cocaine craving and bromocriptine did not alter the subjective effects of cocainP”j”.
TjPS-October 1994(VOI.Is) 375
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HxNH-CO-N,CIH5
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H+\NHCO-I-CH3 kH,
SD220891 1
\ H’
CH,
OH HO
dopamine -NH,
C”,
In summary, the possibility that dopamine receptor agonists may ameliorate some of the symptoms of psy&ostimulant withdrawal has been confirmed in experimental studies and in some clinical trials. The results showing that bromocriptine and iisuride reverse some symptoms of psychostimulant withdrawal suggest that these, as well as other dopamine receptor agonists are promising therapeutic agents for psychostimulant withdrawal. Furthermore, considering, that significant biochemical and behavioural evidence indicates that dopamine receptor agonists effectively modulate various aspects of stimulant dependence in laboratory animals, carefully conducted clinical trials are warranted to estab lish how treatment regimens with the non-addictive dopamine receptor agonists may be used as substitution therapies in human stimulant addicts.
OH
G
Partial agonists
preclamol N-
SDZ208Sl2
Q, fig. 1. Chemical slruciures of the dopamme receptor partial agonists SDZ208911. SfJZ208912. preclamol and tergunde compared wth dopamme
liswide Lisuride, also an ergot derivative that acts at the D, receptor, has recently shown promising therapeutic activity in psychostimulant dependence. In rats trained to self-administer cocaine with limited dailv access, lisuride reduced cocaine intake, acting as a partial substitute for cocaine’“. In a separateexperiment, rats allowed access to self-administration of amphetamine at high doses, displayed a state of psychomotor retardation (hypolocomotion and catalepsy) following discontinuation of oxposure to amphetamme. During this withdrawal phase, daily treatment with lisuride prevented the occurrence of the symptoms of motor retardation in rats+. In a clinical double-blind study, lisuride was used in hospitalized stimulant abusers during acute withdrawal from cocaine or amphetamine. Lisuride normalized some of the sleep changes of psvchostimulant withdrawal, prolonging rapid eye-moviment (REM) latency and reducing REM time, while it did not modify subjective ratings of craving and moodl:. However, the reports of craving and mood changes were very low in the control group im this study, possiblv reflecting the inpatient setting.
Finally, the dopamine receptor agonists amantadine and pergolide have been used with some success in a double-blind and an open-pilot trial, respectively, in stimulant abusersJ5-“. However, further studies are necessary before these drugs can be considered as potential treatments for psychostimulant dependence.
Recently, the concept of partial agonist action has received considerable attention in the field of dopamine receptor pharmacology. Partial agonist properties refer to the efficacy of a given receptor ligand that shows high affinity for the receptor, but low intrinsic activity~“. The first compounds characterized with partial agonist activity at dopamine receptors were the dopamine analogue preclamol and the aminoergolines SDZ208911, SDZ208912and tergurideab*’ trig. 1).Ail these compounds possess partial agonist activity at the Dz receptor. In eiectrophysiological studies, SDZ208911 and SD2208912 weakly inhibited the firing of dopaminergic neurones of the A10 area of the rat, while they reversed the inhibition induced by the full agonist quinpiroIeJ? Terguride showed a similar profile on neurones of the substantia nigraJJ. By contrast, biochemical studies revealed that SDZ208~11and terguride acted as full agonists with a potency similar to that of quinpirole in rats depleted of monoamines after treatment with reserpine, as measured by a reduction in the accumulation of t.-dopa’;. However, the ergolines produced the opposite effect in non-reserpinizcd rats, a profile similar to dcpamine receptor antagonists and thought to reflect functional inhibition of postsynaptic receptors and compensatory activation of presynaptic tyrosine hydroxylase via a feedback loopdi. Finally, behaviourai studies showed that SDZ208911,SDZ208912and terguride produced contralateral turning in rats subjected to unilateral striatal 6-hydroxydopamine lesions, but they reduced amphetamine-induced locomotion and stereotyped behaviour while only marginally reducing spontaneous locomotion in intact animal+. Altogether, these various lines of evidence suggest that dopamine receptor partial agonists possess a unique pharmacological profile since their net effect depends on the level of existing synaptic activity (that is, the degree of concurrent receptor occupancy), thus confirming earlie; hypotheses’;. This also provides a rationale for testing :-he effects of these compounds in psychostimulant addiction.
a pretreatment
0-g kg-? vehicle sm2089i
3
0.025 0.1 0.4
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II
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Fig.2.a: Event record of cocaine self-admimstratian for a rat followmg acute pretreatment with SDZ209911. Each record represents a separate session and each mark represents an I v mfusmn of cflcaine SDZZOE911 dose.dependently reduced the Inter-remforcement intervals, while the regular pattern of responding was rnalnlal~ed. b: The behaviour of a rat se~i-adrni~~st~i~ the usual trainj~ dose (0 75mgkg ‘1 and a lower dose of cocaine {O 37mgkg ‘1 Mod,fled. w&h permIssion, from Ref. 47.
In rats self-administering cocaine i.v., acute systemic administration of the partial agonist SDZ20891I reduced the rewarding value of cocaine as shown by reduction of the inter-reinforcement intervaP (Fig. 2). Therefore, despite its slight intrinsic activity, SDZ208911behaved as a dopamine receptor antagonist on cocaine self-administration. It is reasonable to speculate that partial agonists at dopamine receptors may also be useful during withdrawal from cocaine and amphetamine, a condition characterized by tunctional dupamine hypoactivity. Of importance in this respect could be the impuise-reguMing activity of the aminoergolines SDZ208911 and terglride, which reduced the firing rates of dopaminergic neurones in n&e animals4Jm, but reversed the inhibitory effects of dopamine receptor agonists. Therefore, it is possible that dopamine receptor partial agonists may represent potentiat candidates for nor‘nalizing dopamine neurotransmission during the various phases of the natural history of psychostimulant addiction. The ~nctional efficacy of a partial agonist depends on the level of occupancy of a given receptor by full agonists, such as the endogenous transmitter dopamine“). Consequently, partial agonists may act as agonists in conditions of low receptor occupancy by the transmitter as, for example, in the case of denervation. Similarly, the same con~poLlnds may function as antagonists in the case of high endogenous transmitter tone (Fig. 3), such as during
intense presynaptic activity or after p~~arn~acolo~cal stimulation (for example, exposure to cocaine or amphetamine). Hence, by occupying dopamine receptors and exerting low intrinsic activity, partial agonists might rep resent novel antipsychotic agents that possibly are devoid of the extrapyramidal side-effects”‘eJ’,a problem that limits the clinical use of neuroleptics. Hence, tetitguride was shown to reduce r-dopa-induced dyskinesias in patients with Parkin:on’s disease’? and to decrease the total score on a rating scaie for extrapyramidal side-effects in schizopl~renicpatients treated with neurolepticdntgs”. In addition, the occurrence of side-effects that tire commonly associated with the administration of dopamine receptor agonists (such as dyskinesia or em&s) was not observed in humans with preciamol”, and SDZ208911reduced neuroleptic-induced oral dyskinesia in monkey+. Finally, although dopamine receptor partial agonists produce amphetamine-likei*, but not cocaine-like’7 discriminative stimulus effects, they do not possess psycl~e stimulating activity in naive animaW, an effect Ihat is observed with dopamine receptor agonists with abuse liability. This further supports the hypothesis that dop amine receptor partial agonists possess a unique pharmacological profile, Thus, in the presence of a physiological level of dopamine tone, partial agonists would pr~umably be devoid of abuse liability. However, selfadministration studies with Tartin agonists in either
377
R
E
V
1
E
W
S
1 a
I ) J
normal response
dopamine
b
n stimulated
‘normalized response
response
i
partial agonist
Fig. 3. HypothetIcal acnon of dopamme receptor partial agonrsts on dopamme neurotransmission during various phases of cacalne addiction. a: Norrlal response. b: The augmented response that follows exposure to cocaine may be reversed by partial agomsts because of their low mtrinslc activity and fur,:tronal antagonism shown by these compounds under condmons of dopaminz hyperactivity c: During cocame withdrawal. the reduced response that accompanies dopamcne depletion may be corrected by the agonist activity shown by partial agonists in condmons of low dopamine tone.
L nai’veor cocaine-trained rats have not yet been performed, and the effects of these compounds on the threshold for brain stimulation reward have not been described.
Concluding remarks In conclusion, there is enough substantial evidence to indicate that compounds with partial agonist activity at dopamine receptors may in the future represent novel psychoactive agents with important advantages compared to previously used antipsychotic drugs or full dopamine receptor agonists. The various phases of psychostimulant addiction, in particular, may represent a specific field of therapeutic application for these drugs and the scarcity of pharmacological means of intervention in cocaine and amphetamine dependence certainly warrants further studies, Selectedreferences I Adams, E. H.. Cforer.
J. C.. Roose, 8. A. and Kczcl. N. J, (19%) Adrl. Ahrh0f srIl’+. AlrrrQ* 6, 4Y-71 2 Stolerman. 1. (IW?)TrmkPhmuk~l. 53.13,1711-176
3 Koob, C. F. and Goeders, N. E. (1989) in Tlrr Nrrrnq~lmrrtmro/o,picnl Bnais of Rrrtnrd (Liebman, J. and Cooper, 5.. eds), pp. 215-263, Clxendon Press 4 Markou, A. and Knob, G. F. (1991) N~~rrrc~~~~!/clro~drnnrmml!p!! 4, 17-26 5 Pulvircnti, L. and Koob,C. F. (1993) N~~rrro~~~~rlro~drnrrlmmk!~l~~.~~8,213-218 ,. 6 Bozartb. M. A. and Wise, R. A. (198% J. AM. hd. Assock4,81-83 7 Griffith, R. R., Big&w, G. E. and Henningfield, j. E. (1980) in Adznnin in Srrbsfflrr~~Abrrsc (Mello, N. K., ed.), pp. I-RO, JAI Press 8 Groppetti, A., Znmbotti, F., Biazzi, A. and Mantegazza, P. (1973) in Fn~rf;cn in ClrII,clr[,lnrsirrl, Rt~cxrc-h (Usdin. E. and Snyder, S. H., eds), pp. 917-925, Pergamon Prt3s 9 Roberts, D. C. S., Corcoran, M. E. and Fib@, H C. (1977) Plmrrrm1-o/. t?ilU~hcr!r.Bckaz’. 6, 61 S-620 10 Roberts, D. C. S. and Vickers. G. (1984) P.*!/dr~qdrnrrrrorfl/[~~!/ 82, 1%13Y 11 Johann. C. E. (1976) Plmrrr~rrnd. Rril. 27, 343-355 12 Roberts, D. C. 5. Koob, G. F., Klonofr, P. and Fibiger. H. C. (19RO) Phl~l~l~?id.BlWhr. &hw. 12, 781-787 I3 Koob, C. F., Vaccarino, F. J., Amalric, M. and Bloom, F. E. (1987) in Bmirr Rntnnf Sysfrrr~ wd Ahrw (Engel, J. and Oreland, L., eds), pp.3-S-50, Raven Press 14 Caine, S. B. and Knob, C. F. (1494) J. Exp. Am/. Bdrn~~.61,213-221 15 Hurd. Y. L., Weiss, F., Knob. G. F., Anden, N. E. and Ungerstedt, U. (1YXY) Iirnin Rcs. 199-203 16 Maldrmado, R., Robledo, I’., Clover, A. J. Caine, S. B. and Koob, G. F. I IY93) P/I~~uI/u~~~/,B~~~dr~~rrr. Bc’/r,rrf,45, 239-242
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Koob, G. F., Le. H. T. and Creese, 1.(1987) Ntwosci. l&t.79,335-320 41 Karobath, M. et al. (1988) in Prqrl’-zs irt Crrferkohmi~rr Raenrclt: Woolverton, W. L. (1986) P~~arn~rm?l. Eiocken~. Belm 24,531-535 Cehd Aspecfs (Belmakerh, H., Sandier. M. and Dahlstrom, A., eds), Caine, S. B. and Koob, G. F. (1993) Scic~~ce 260, 1814-1816 pp. 19-26, Liss Gawin, F. H. and Kleber, H. D. 09%) Arch. Ge,r. Psyc~zi~~r!/ 43, 42 Kehr, W. (1984) Ettr. I. P~ar~iac~l.97. Ill-119 107-113 43 Ackerman, J., Johansen, P. A., Clark, D. and White, F. J. f1993) Weiss, F., Markou, A., Lorang, M. T. and Koob,G. F. (1992)Brabr Rcs. J. Plmrr~t~&.EwP.7Ier. 265,963-970 593.314-318 44 Piercey, M. F.. Hoffman, W. E.. Vogelsang, G. D. and Travis, M. Dwoskin, L. I’., Peris, J., Yasuda, R. P., Philpott, K. and Zahniser, 11987)1. P~~~~~~/,ErP. TIzer.254,391-3% N. R. 11988)Lift Sci. 42,25.%262 45 Svensson, K. ef RI. (1991) ~~~~tly~r-Sc~tjrfi~. Ardz. ~~~~~I~c~~. 344, Weiss, F., Paulus, M. P., Lorang, M. T. and Koob, G. F. (1992) 263-274 f. Nefrrosci.12,4372-4380 46 Clark, D. ef RI.(1991)Psyclro~rlmntmcafo~ 105,381-392 Ng, J. I’., Hubert, G. W. and Justice, J. B., Jr (1991) J. Nrrrroc/ze!h.56, 47 Car&on, A. (1983);. Net& Tmtzsw.60,205-223 1485-1492 48 Pufvirenti, L., Smith, D. and Koob, G. F. f1994) Psy~~~~i~~~llllrtn~ffco~o~ Vance, M. L., Evans, W. S. and Thorner, M. 0. (1984) Aetr. lnferu. 313.518-520 Med. !00,7@-91 49 Clark, D.. Hiorth, S. and Carlsson. A. (198511. Nrsral Transra. 62, Ho, K. Y. and Thomcr, M. 0. (1988) Drqs 3667-82 171-207 Hubner, C, B. ar.d Koob, G. F. (1990) N~rru~.~~ru~lJrar 3, 50 Coward, D. d nl. 11989)~yc~f~P~~~rtt?aca~. Bzdf.25,393-397 101-108 51 Coward, D. et et. (199th i. Pftnrrrmrol.Exp. Tkr. 252,279-Z@ Markou, A. and Koob,C. F. (1992)N~~rr~Psyc~roP~~arr~rcolo~7,213-22452 Baronti, F. et nl. (1992)Newofqqy 42,1241-lL43 Da&s, C. A. and Gold, M. S. (1985) LRnceti, 1151-l 152 53 Filip, V., Mar&k, M., Halkova, E. and Kamn, P. (1992) Psycbi~:ry Giannini, A. J.. Baumga~el, P. and Dimanio, L R. (1987) 1. CIih. Rcs. 41,9-16 Plmrttnrcol.27,267-270 54 Tamminga. C. A. ef d (19921J. Netof Tramnr. 88,lM175 Giannini, A. J and Billet, W. (1987) /. Glib. Plmrrrmcol.27,549-554 55 Peacock, L. and Gerlach, J (1993) Eur. /. Plrawmcol. 237,329~340 Tennant, F. S. and Sagherian, A. A. (1987) 4x/r. krlem. Med. 147, 56 Exner, M. and Clark. D. (1992) Bd:as. Pl~arrmcol.3.609-619 1G9-112 57 Callahan, I? M. and Cunningham, K. A. (1993)J. ~f~~r,,~~~~~.fxp. T&r. Kumor, K., Sheber, M. and Jaffe, J. (1989) P~f~r~f?~fcu~. &&em. B&n. 266,585592 33,829-S37 Krenzler, H. R. and Bauer, L. 0. (1992) Br. J. Addict. 87,1537-1548 Wedd~gt~,W. W.elnf.~199l~At~r.J.D~r~Alc~~~u~Abr~~l7,137-152 Chamieainames Pulvirenti, L. and Kc.&, G. F. 11994) P~iff~?~acol. B~~~I~~~I, B&n. 47, 819-822 Gilhn, J. C., Pulvirenti, L., Withers, N., Golshan, S. and Koob, G. F. SDZ208911:N-~(8u)-2,6-dimethylergohne-B-yl]-2,2(19941Biol.Psycfd&y 35,&U-849 djethyipropanamide Malcom, R., Hutto, B, R., Phillips, J. D. and Bailenger, J. C. (1991) J. Clirl. Psycfrinfry 52,39-40 SDZZO8912:N-[(8cY)-2-chtoro-6-methylergoline-&yl]Hoyer, D. and Eoddeke, H. W. G. M. (1993) Trords Plmmmcol.Sci. 14, 2,2-diethylpropanamide 270-275 Hjorth, S, ef at. (1983) Ps~~i~~l~rartrrnacuf~~ 81,89-99
The current endotherm receptor classification: time for reconsideration? ~iiern
A. Bax and Pramod R. Saxena
The possible involvement of endothelins in a variety of diseases has attracted the attention of many pharmacologists in search of a novel therapeutic approach. The rapid development of ~ndothelin research has resulted in the molecular characterization and pharmacological recognition of ET, and ET, receptors, and in the development of compounds selective for these receptors. However, the characterization of receptors in various assays has shown that a number of effects are mediated by receptors that do not fit the present criteria for ETA or ET, receptors. In this article, Willem Bax and Pramod Saxena address endothelin receptors in general, and atypical receptors in particular.
5 1994, Elsevicr Science Ltd 0165 - 6147/94/$07.00
Endothelin was discovered and recognized as a potent vasoconstrictor peptide only six years ago’. Threedistinct endogenous endothelin isoforms endothelin 1 (ET-I), ET-2and ET-3are cleaved from the endothelin precursors big-ET-l, big-ET-2 and big-ET-3 by an endothelin converting enzyme. Increased concentrations of endothelins have been observed after myocardial infarction, in atherosclerosis, (pulmonary) hypertension, migraine and many other diseasesr. Although recent advances towards the elucidation of the molecular structure of endothelin converting enzymes” will undoubtedly be followed by the development of inhibitors of endothelin converting enzymes, efforts have so far primarily been directed to the devefopment of endotheiin receptor antagonists for clinical purposes. Indeed ET,, and ET, receptors were clonedQ, and selective ligands for these receptors have been recognized. The current criteria for endothelin receptor classification In general, receptor classification should be based on three criteriab? (1) gene nucleotide and amino acid sequence of the receptor protein, (21~ptor-eff~t coupling, and (3) interaction between receptors and agonists or antagonists, Endothelin receptors are currently classified by the consensus view of the subcommittee of the international Union of Pharmacology (IUPHAR), primarily
TiPS -October
1994 (Vol. 151 379