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Narcotic dependence, narcotic action and dopamine receptors
Life Sciences Vol . 17, pp .483-496 Printed in the O.s .l1.
Pergamon Press
MINIREVIBfi NABCOTIC D~SNCB, NABCOTIC ACTION AND DOPAMINH B8C8PT085 Harbans Lal Departsmt of Pharmacology â Tosi.cology, Collage of Pha:aacy IIaiversity of Bhoda Llaad, Ringeton, 8. I. 02881 Mute systeaic administration of narcotic analgesics increases the firing rata of nerve calls in the soaa caapacta of the substaatia nigra, causes an increase in the rate of dopamine turnover is striatal and maeolimbic areas of the brain, stimulates prolactin release, inhibits brain calf-stimulation and discrimiasted ehockavoidance, blocks cardiovascular effeçts of systmically injected dopamine, blocks aggression ae veil ae compulsive juaping in mice treated with DOPA sad amphetamine, aatagonisae stereotypy induced by apomorphine or amphntaminn, and blocks apomorphine-induced vomiting is dogs, Chronic administration of narcotic analgesics results in withdrawal signs upon the cessation of the drug administration . These signs include, toleraacn to the iacraaea is striatal dopamine turnover cansad by narcotic analgesics or haloparidol, aggressive behaviors which am further stimulated by directly or indirectly acting dopamina~raceptor agoniste sad am blocked by dopamine-receptor blocknrs, facilitation of recovery from the "lateral hypothalamic syadrom," an iacreaea is basal levels of striatal adeaylate cyclase which shows greater sensitivity to dopa~.nn, and, as aahaaced sensitivity to apomorphinn-induced reduction of dopamine turaowr, It is therefore, concluded that acute administration of narcotic drugs results in as inhibition of dapasinn-receptor activity while chronic administration of thaw drugs results in as iacraased response of these dopamine receptors to dopamine agoniste, Heceat ezperimeate on the interaction of other drugs with narcotic analgesics suggest that, unlike the direct action of neuroleptics on the dopamiina receptors, the narcotic action oa dopamine receptors is indirect . Narcotic depeadencn has often bnea attributed to a latent hyperactivity of central nervous system (CNS) synapses, which is developed after repeated administration of narcotic drugs (1, 2) . Since this hyperactivity is overtly manifeatad only in the absence of narcotic drugs, it 18 assumed that in the praaeaca of narcotic drugs those synapses remain inhibited while only is the abeaace of the narcotics am that' overactive in the dependent animal . The activity of neuronal synapses is a result of an iateractioa of the released naurotraasmitters with their respective receptors . Therefore, their hyperactivity implies that either theta ie as increase in transmitter release, a dnThe ezperimeats from author's laboratory reviewed in this paper were supported by PNS Grants 801 1~ 18346, 803 I~ 20115, RO1 DA00418, 1T01 8500104 sad other grants from Noffmaan-LaBoche, McNeil Laboratorisa and Jeassm ~+~~~eutica . Secretarial assietaace of Lucia Johnson ie gratefully acknowledged .
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crease is transaitter degradation, or that there ie an enhancement of the interaction betrem the receptors and the nmrotraasadtter, The latter can be accomplished either by en access to a greater uus~ber of receptors or by a change is the intrinsic activity of the receptors, For the purpose of this review, the increased activity of synapses is the absence of increased release of neurotransmitter will be termed "receptor supersensitivitq," without implying a specific uadarlyisg mechanism, Since the supersensitivity theory of narcotic dependence was first proposed by Saevnrs sad his co-+rorkers, several modifications of the original theory have been offered by a number of iaveetigators (3-6) . The first set of modifications were concerned with the nature and nachaaism of the receptor changes while the later modifications began to specify particular neurotransmitters involved . By now, the involvement of many transmitters have bean postulated, Tha presort review will be li.mitad to focus attention on the direct and indirect evidence that relates to the role of one neurotransmitter, dopamine, in narcotic dependence and narcotic action . While doing so, it is not my in tentien to iu~ply that receptors sensitive to other ~urotraasmittere are not affected . As a natter of fact, there is a growing belief among various investigator~ that narcotic action is mediated by more than one aeurotraasmitter and that more than one type of neurotransmitter receptor is altered during narcotic depmdesca . Abatiaençe Syndrome A eyadrome of body symptoms some of which are objectively observed while others ~ra only subjectively esparinnced following withdrawal from narcotic drugs is to diagnose narcotic dependence and also employed in research on the physiological nechaaism that uader]Ye< that dependence (7) . This withdrawal syndrome has been divided into a primary phase and a protracted phase (8-9) . Symptame of the primary phase are short-lived (from a few hours to a few days) but those of the protracted phase last for longer periods (from several days to several weeks) . Morphine-Withdrawal Aireeeion Among the sigma of narcotic withdrawal is included hyperirritability to environmental stimuli (10) and aggressiveness (il) . Besides the high iacidence of violence-related crimes reported in areas of high heroin abuse, acts of violence are often seen in the hospital wards which admit narcotic addicts . Laboratory animals undergoing abstinence are difficult to handle and, when appropriate stimuli are provided, they show intense aggression which consists of rearing, vocalisation, attacks, biting and killing of other animals (11), The withdrawal aggression was first observed in the rat by Thor and his corworkers in 1966 (12) . Since then, their findings have been confirmed by many wrkers . By now, there are published reports of morphine withdrawal ag gression in the rat (13-14), the guinea pig (15), and the muse (16) . Seevers and Denesu (1) reported aggressive vocalisation in monkeys and dogs although actual aggression was not observed because of lack of opportunity to fight when withdraws animle are housed in single cages, The withdrawal aggression is reported both is the primary sad protracted phase of withdrawal (17) . Careful study of morphinerwithdrawal aggression was the first line of i~estigations which produced evidence to suggest that dopamine-receptor superseneitivity may be involved in narcotic dependence (13, 18) . Aggression
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in naive aaiaals can be produced either by large doses of apomorphine (19), a direct agoniet of dopasüna receptors (20-22), or by a coebiaatioa of dihydro~cyphenylalanlnw (pOPA) and d-amphetaaine (23) which causas a large preferential increase of brain dopamine (23-24) and its release . This drug-induced aggreesioa ie affattive]a blocked by specific blotiars of dopamine-receptors and also by morphiaa suggesting that acute administration of narcotics may bloat dopamine receptors . !lorphinn-~rithdrawal aggression is soon after mre vithdraaal of narcotic drugs sad withoat any other stimulation (11, 25) . Horevar, it is eahaated by directly and indirectly acting dopamine-receptor stimulants, such aa, amphata miaas, DOPA, or apomorphine (25) . The aggression ie blocked by narcotic analgesics such ae morphine and mathadoan (11, 17) and also by dopa~na-receptor blocking naurolaptics such as haloperidol (25) and thlorpramasine (11) or by lasioning of the nigroetriatal boodle (17), the major serve tract which carries dopaminergic nerve fibers to higher brain caatera. Ia addition, doses of dopamiaerrecnptor atinulaats which era capable of eliciting intense aggreseion in the narcotic withdraaa rata are saveralfold smaller than those needed to elicit aggression in normal animals. The effect of amphetamine in eliciting morphinerwithdraral aggression tea be blocked by prior treatment with alpharnethyl-pare-tyrosine (A1~T) while apomorphine ie still able to elicit aggressioa after A1~IPT (25) . AëPT inhibits syatheaie of tatacholsminea and therefore blocks the actions of indirectly acting drugs which dapaad as the release of catecholaniaea for their action . These data suggest that there is a euperaensitivity of the receptors which are responsive to dopamine agoniste . In the absents of ezogaaously A, i~ia tnred dopandae agoniste which am directly acting, aadogaaoue dopamine release ie sufficiaat to cause aggression-eliciting chemical stimuli. But in the absence of endogenous release of dopamine ae after Aè~T, direct action of an agoniet (apomorphine) ie readlly even . $nhaatemeat of Apomorphine Action s Apomrphine is a known stimulator of dopamine receptors (20-22), and by virtue of that property, it induces aggression (19, 26), stereotypy (27) and inhibition of etriatal dopamine turnover (28-29) . These actions of apomor phine are markedly enhanced in the organism in which dopamine receptors are rendered aupereaneitive either through chronic blockade of dopamine receptors by potent nauroleptica (30), or by deetruttioa of presynaptic nerve endings (31) . After chronic treatment rith haloperidol or lesioaiag of the nigroetriatal bundle, there is a reduction is the apomorphins dose required to cause aggression or stereotypy . Also, in chronic haloperidol treated rate, there is a shift towards the left 1n the dose-response curve of apomorphine is causing inhibition of etriatal dopamine turnover (29) . These ehifta of apomorphine action are often employed to document as eatabliahmeat of dopamiaerecaptor aupnrsensitivity . 8etently, a shift is the dose response curve of apomorphine was also observed during the primary se cell ae protracted phases of narcotic abetineate . Doses of apomorphine needed to elicit aggression (17, 19, 32-33), or to inhibit dopamine turnover (17, 33-34) rare significantly reduced is dependent rats auggestiag that dopamine-receptor euparseasitivity had takes place ae a result of narcotic dependence . Toleranca to Haloparidol The acute admiaistratioa of morphine sad other analgesics (35) or haloperldol (36) produced reliable immobility rith a concomitant increase in striatal dopamine turnover (37-38) . Toleraatn to both of these effects of morphine are wall known (see 37 for rasriew) . However, of iatnrest is a recent report (37) that there ie a marked reduction is the ability of haloperidol to
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produce an increase in etriatal dopamine-turnover or cause catalepsy in aorphine dependent rats ; that is, there vas as apparent croaeover of tolerance in aorphine dependent rate to haloperidol, Ia that study, a direct interaction of haloparidol with morphine vas not i~olved because ao snrphine vas injected for at least 3 days prior to the haloperidol test, Also, those rats did not have any prior e~oeure to haloperidol, Therefore, the loss is haloperidol potency suggests that there is developient of pharuacodyaamic tolerance to haloperidol during the davelopuent of tolerance to the narcotics . This finding can be interpreted to aeaa that morphine-dependant rate had developed eupareaneitiva dopamine receptors . The increased dopamine turnover sad catalepsy caused by haloparidol am known to ba ~ndiated through the blockade of dopamine receptors, The superseaeitive receptors would require larger quantities of the receptor-blocking drug to cause their inhibition and, ae a consequence, the activity of the receptor blockar would seas to hewn bean reduced, It should bn noted that there is ao tolerance to the effects of ~or phinn or haloparidol in the rate chronically treated with haloperidol. It therefore seems that the mechanism of action of morphine on dopamine receptors is qualitatively different from that of haloperidol because one results in tolerance and dependence while the other does not, Juspiag-Ras~onea A jumping syndrome which is elicited by a narcotic antagonist has been suggested as a useful measure of narcotic withdrawal (39-40) sad narcotic aatagoniam (41), These suggestions era based upon the empirical observations that narcotic antagonists elicit a jumping response in mice sad rate which have been pretreated with large doses of narcotic drugs. Although the physiological basis of mouse jumping is not known, a permal of the known literature is related to the subject of review, Mouse juupiag is of two types, For lack of any other term, one may be described as cliff jumping and the other as an upward jna~ping, Cliff jumping consists of jumping off of as elevated platform which is aarrw sad fance7.ees . IIpward jumping ie as urge to jump up and out of a confined apace, usually e glass jar with tall side walls . If the test an imal is not placed is the jar, ~1if g jumping and upward jumping cannot be dist inguished, Cliff jumping ie caused either by desipramine (42-43) or amphetamine (44) when either one is injected after tatrabenasine-like drugs. Apomorphina given intravenously also produced cliff jumping in the rat (45) . Colpaart et !1 (46), recently traatnd ice with the above drugs and all other antidapresaant drugs is doses ranging frog sub-phsrsacological to those lethal and found that they do not produce upward jumping with or without a challenge dose of RO-4-1284, IIpward jumping is caused by antagonist-precipitated narcotic withdrawal or treatment of naive mica with dinethylbutylathyl barbiturate (DR~1) (47), naphthylozyacetic acid (NOAA) (16), a combination of amphetamine and DOPA (24), or thaophyllinn injected with other drug combinations (48-49), It is therefore clear that upward jumping ie not limited to narcotic withdrawal because Dl~B, NOAH, DOPA, amphetamine, and. thaophyllin are neither narcotic nor produce physical dependence, With the eueption of ~~ which ie a coavulsaat and NOAA whose pharmacology is imlmowa, the other drugs fall in a category of those which directly or indirectly stimulate catacholami.na receptors, Large doses of DOPA which increase brain dopamine are known to cause mouse jumping (50-51) but the incidence ie very wall, probably because dopamine which is accuwlated following DOPA injection is inhibited from release in the presence of DOPA (52~ However, if amphetamine, which causes release of dopamine, is combined with DOPA, the jumping ie markedly increased (24), Theophyllia nay cease jvapinB
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through accumulation of cyclic AMP which causes as increase is dopaztina eynthasis (53-54) and rector etimulatian (55) . Since the upward jumping is blocked by haloperidol, pimozida and other neuroleptics (24, 56), this jumping can ba considered to be dun to the stimulation of dopamine receptors. A similar ezplaaation spay be offered to explain upward jumping in narcotic dependent enimala, liaruyama end Takemori (57) and Iwamoto et al . (58) showed that jumPiag behavior in opiate dependent ~.ce is related tô changes in brain concentrations of dopamine, Hnrz et al . (59) reported that upward jumping in morphine-withdrawn rata ie potmti.âtndwith los doeea of apasbrphiae . Moreover, morphine sulfate inhibits the upward jumping elicited by DOPA-amphetamine combination in the naive mouse (19, 56) . Acute Açtioas of Narcotic_ Analgesics Morphine and other narcotic analgesics shw a multitude of pharmacological actions. Several of these actions seam to ba based upon en altaratian in the functioning of brain dopaminergic systems, and, ae such, resemble many actions of other drugs well known to affect dopaminergic system . Brain Dopamine In rate, one hour after morphine injection, theta is no change in eteadystata levels of dopamiaa is any of the brain areas studies (34, 37, 60-63), although at 2 and 4 hours after the morphine a transient and small increase in levels was reported (63) . Moat kaawn agoniste or entagonists of dopamine receptors also do sot alter steady-state levels of brain dopamine . It is well known that drugs which block dopamine receptors always increase etriatal dopamine turnover, This is also the case with morphine . Accumulation of DOPA after as inhibition of brain DOPA decarbozylaee (64) and conversion of tyrosine to dopamine (64-70) is increased by an acute injection of morphi~ suggesting that morphine treatment causes as increase in the eyathneie of brain dopamine, Likewise, brain coacentratioa of hoaavaaillic acid, a metabolite of dopamine, is increased (34, 71-75) after morphine or methadone suggesting that these drugs cause en increase is catabolism of brain dopamine . In addition, acute administration of morphine accelerates the depletion of brain dopamine after the administration of a catacholsmine synthesis inhibitor, AMPT (34, 60, 62, 74) . The abavn effects of morphine am readily antagonized by naloxona (34, 62), Ia the absence of uaaltared steady-state levels of brain dopa~.an, a simultaneous increase is synthesis and metabolism by acute injections of narcotic analgesics implies that the turnover rate of brain dopamine is increased by these drugs, The mnchsaiems vaderlying the stimulating action of narcotics on dopamine turaovar am sot knows. Morphine does sot alter either in vitro (76), or is vivo (77) activity of tyrosine hydrozylaan . Ia vitro, morphine done not alter the affinity of tyrosine hydrozylase for aithai tieêubstrate or cofactor (77) . Also, morphine dose sot interfere with the inhibition of tyrosine hydro:y].aee by the catecholaaiaee (77) the machaaism presently thought to ba most critically i~olved in the regulation of mtabolic fluz along the catacho].amiae pathway (78) . Therefore, tyrosine hydrorylses, en enzyme considered to be rata limiting is the synthesis of catncho].amines, is sot directly affected by narcotics . There are several iadirnct mechanisms kavwa to cause en iacrnase is the dopaniaa turnover, Firstly, removal of dopamine free cytoplaemic compartmsat of presynaptic ~erve aadings will remove product inhibition (through a compati tioa with a critical cofactor) of the synthetic process and thereby cause etimu].ation of its synthesis . Secondly, blockade of dopamine receptors, invariably causes compeaaatory stimulation of dopamine synthesis and release . To
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keep the homeostasis of catecholamine turnover intact, the iacreaee in syatheeis often results in as iacrnase is release and catabolism, thus maintaining a constant steady-state level in the presence of an increased turnover . Whether narcotic drugs cause release of dopaalae or blockade of dopamine receptors or both is a matter of conjecture at this time se no direct evidence is available to reach a conclusion . HaPnver, there are several indirect lines of evidence available and they rill ovexvhelmingly suggest that there is an inhibition of dopandaergic activity iaduced by narcotics, Adenylata cyclase, cyclic AMP sad Prostaglandins Collier and Roy (79) summarised evidence to indicate that narcotic analgesics produce their pharmacological action through inhibition of prostaglandin (PGE) induced stimulation of cyclic AMP . Firstly, soma actions of PGE (effects on pain, temperature and gaetroiatestinal fuactione) are such that their antagoni .em weld ezplain soma of the main pharmacological effects of opiates. Secondly, cyclic AMP antagonises the antinociceptive effect of mrphina and mrphinn aataganizes some effects of PGE, Thirdly, the relationship betraen heroin, mrphine, methadone, deztrophan and naloxone in in vitro eaperiments an PGE and cyclic AMP largely corresponds rith their pharmacological relationship eeea i~a vivo, Fourthly, the coaceatrations at rhich heroin, morphine, and aethadone n~ibit PGE T i n vitro, roughly correspond rith their effective concentrations is brain in vivo, Collier and Roy (79) further proposed that the above affect of mrp i e ie exerted through the neuronal adanylate cyclesa . Tolerance and dnpendaace rhich arise from the agoaist action of opiates and are enhanced by cyclic AMP and partly blocked by indomethacia represent a compensatory hypertrophy of a part of the inhibited PGE cyclic AMP mechanism, Since the striatum is the richest of the brain areas containing n~TrOtiC receptors (80) and is also the richest dopamine-containing area is the brain, the anatomical aitn for the Collier-Roy mechanism is likely to be located is the etriatu~ and involve the adenylate cyclase contained is that area . Therefore, the target adeaylate cyclase rith all probability rill bn that rhich is sensitive to dopamine, The direct effects of narcotic drugs on dopamine-seaeitive adeaylate cyclasn have not been fully investigated yet . Acute doses of mrphine increase the adanylate cyclasn activity in the caudate rhea given in high doses (34, 81-83) and resemble a similar effect of haloperi dol is this respect (82), Ia vitro affects of mrphiae on the striatal adenylate cyclaen am not specific set can be produced by the inactive isomers ae sell as by nalozonn (34), Chronic administration of either mrphine (34, 82) or haloperidol (82) causes as iacraaae in the basal levels of the adenylata cyclase and increases the sensitivity of this enayma to dopamine (82) . Behavioral and Endocrinolo~ical Actions , There are many pharmacological actions of mrphiae rhich suggest blockade of dopaniae receptors . Morphine induces asysmetric turning of rats is rhich the nigrostriatal bundle, consisting of dopaminnrgic fibers, ie unilaterally lesioned (83), 3lailar turning is sell knam after haloparidol treataeat Morphine (28, 84) sad all other narcotics (19, 85) block stereotypy iaduced by apomrphina or amphataaine ; the blockade of the same stereotypy by haloperidol sad pimsidn is roll kaara (85), In dogs, mrphine~ methadone, demnrol, featanyl, deztromra~ide, pheaopnridine, piritremidn, and several other narcotic analgnsica block aposwrphiae-induced vomiting is very small doses (19, 84, 86). Only mrphiae may initially Gauss soma vomiting, but that action is not common to other narcotic drugs such as fantanyl, methadone, deztramra~de and piritramids, sad, therefore, may not ba considered as a specific narcotic action . Potent neuroleptics are also knam to block apomrphine vomiting and, tharefora, narcotic drugs can be considered to reaaabln nsurolaptice in this respect . In nice, acute administration of DOPA in combination rith amphetasdna
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muses aggression which is blocked by either morphine or haloperidol (23) . In these mica DOPA also counteracts mrphina analgesia (87-88) . Apamorphiae sad anaatadiae aLo aatsgoniae the acute effects of morphine (73) . Morphiaa muses muscls rigidity which can bs reversed by lesianing of brain dopasinergic nuclei (89) . It also causes an iacreaee is the suitability of mudate nucleus calls (90) which can ba interpreted to be dus to removal of inhibitory influences of dopamine . Morphine ~ad other narcotics inhibit coaditionsd avoidsace bar pressing (84) sad brain self-stimulation (36, 91) which hava been coasiderad to ba actions of specific dopamine receptor blocking drugs (92) . Dhasnana at al, (93) reported blockade of cardiovascular eflacts of syatemimlly injaçted dopamine by morphine and codeine. It h~e been recently shows that prior e~riotration of drugs, such as haloperidol sad alpha nethyl~para-tyrosine, which reduce activity of brain dopasinnrgic activity facilitate recovery from aphasia and adipeia produced by lateral hypothalamic lesions is the rat (94-95) . In a similar a:perimant prior ~~+++i~tratioa of morphine sulfate also facilitated recovery from the affects of those lesioaa (96-97), It is lmowa that blockade of central dopsmiae receptors muses an increase in serum prolactin levels (98) and a decrease in the levels of leutiaisiag hormones. Recently Dobrin and Mares (99) reported an increase in serm prolactin and decrease in lautiaitiag hormone after acute administration of morphine . Coaclusioa The data sumarizad in the previous sections ware selected from the ezpnrimaats which warn ralevaat to the determination of morphine effects on dopaminargic systems . These data suggest that morphine-like narcotic drugs produce many effects which have been conventionally interpreted to be due to blockade of dopamine receptors, such as is the case of non-narcotic drugs. Firstly, morphine produces many behavioral, eadocriaological and naurocheniml effects which are ~~++i~ ceat of dopamine aatagoniam, Secondly, narcotim show aatiamphetamiae and antiapamorphine activity in a masher of tests which are often designed to measure anti-dopaainargic activity of new chemicals . Thirdly, morphine tolerant rate show tolerance to other dopamine receptor blocking drugs . Fourthly, chronic treatnmt with morphine results in a decrease in the threshold doses of dopamine agoniste in a number of behavioral sad naurochaaical tests as wall as it causes an increase in the basal levels of dopamine sensitive adaaylate cyclaan activity (34, 82) . All of the cited data suggest that morphine may be a dopamine receptor-Mocker . However, it may be mentioned that the evidence is only indirect . Rzperineata providing direct evidence of dopamine receptor blockade by narcotics are scarce . Although morphine-like narcotics resemble co~eatioaal dopamine-rnmptor blocking asuroleptics, there are significant differences . First, in comparable situations whore narcotic antagoniste ware employed, the actions of aar cotice but not of neuroleptics ware either blocked or reversed by the aatagonieta . These paradigms include iacreaae in atriatal dopamine turnover (28, 62 ),, antiaggreseioa activity (unpublished data), inhibition of brain self-etimulation (36) sad drug induced iuaoobility (36-37) . Sacand, whereas many actions of neuroleptim are reversed by anticholiaergic drugs (100), the same anticholinergic drugs do not reverse the similar actions of narcotics . Thesa actions include drug induced immobility (36, 100), blockade of apamorphina aggression (unpublished data) sad blockade of brain self-stimulation (91) . Third, immobility caused by narcotics is qualitatively diffareat from that caused by aauroleptica . Nauroleptic catalepsy is accompanied by muscular hypotonic but narcotic catatonia consists of muscular hypertoaia (36) . Fourth, haloperidol does not substitute for morphine (101) or featanyl (102) in produo-
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ing drug-induced diacrimiaabln stimuli, Fifth, narcotic drugs are abused and produce dependence while there is ao report of drug dependence with aeurolnptics . A narcotic (fentanyl), when used is combination with a aaurolaptic (dropreridol), is not known to be ever abused, Sizth, the ma:imun effect of morphine on dopasdne turnover is leas than that of haloperidol, and haloperidol can still produce as additional effect when given after the mnsimum effective dose of morphine (34), Seventh, whereas systemic administration of either haloperidol or morphine produces a significant increase is dopaminasenaitive etriatal adaaylata-cyclase (34, 81-g2), i~ vitro application of only haloperidol blocks dopamine stimulation of that enzyme 82, 103) . Similarly, systemic admiaiatratioa of morphine or haloparidol increases firing of dopaadne-sensitive cells of the zone co~acta in the subatantia nigra, but only morphine action is antagonized by nalomoae . Haloperidol can still stimulate the firing even after morphine and/or naloune have been administered (104), Because of these differences between the actions of haloparidol and aorphine, it is suggested that the site of antidopaminergic activity of narcotics is different from that of a aeuroleptic, Neuroleptice are known to directly act on dopamine-receptor sites, Therefore, the narcotics may block dopamiaergic syeteme indirectly, possibly through transeynaptic mechanisms which may even involve other neurotransmitters . References 1.
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MINIREVIBfi NABCOTIC D~SNCB, NABCOTIC ACTION AND DOPAMINH B8C8PT085 Harbans Lal Departsmt of Pharmacology â Tosi.cology, Collage of Pha:aacy IIaiversity of Bhoda Llaad, Ringeton, 8. I. 02881 Mute systeaic administration of narcotic analgesics increases the firing rata of nerve calls in the soaa caapacta of the substaatia nigra, causes an increase in the rate of dopamine turnover is striatal and maeolimbic areas of the brain, stimulates prolactin release, inhibits brain calf-stimulation and discrimiasted ehockavoidance, blocks cardiovascular effeçts of systmically injected dopamine, blocks aggression ae veil ae compulsive juaping in mice treated with DOPA sad amphetamine, aatagonisae stereotypy induced by apomorphine or amphntaminn, and blocks apomorphine-induced vomiting is dogs, Chronic administration of narcotic analgesics results in withdrawal signs upon the cessation of the drug administration . These signs include, toleraacn to the iacraaea is striatal dopamine turnover cansad by narcotic analgesics or haloparidol, aggressive behaviors which am further stimulated by directly or indirectly acting dopamina~raceptor agoniste sad am blocked by dopamine-receptor blocknrs, facilitation of recovery from the "lateral hypothalamic syadrom," an iacreaea is basal levels of striatal adeaylate cyclase which shows greater sensitivity to dopa~.nn, and, as aahaaced sensitivity to apomorphinn-induced reduction of dopamine turaowr, It is therefore, concluded that acute administration of narcotic drugs results in as inhibition of dapasinn-receptor activity while chronic administration of thaw drugs results in as iacraased response of these dopamine receptors to dopamine agoniste, Heceat ezperimeate on the interaction of other drugs with narcotic analgesics suggest that, unlike the direct action of neuroleptics on the dopamiina receptors, the narcotic action oa dopamine receptors is indirect . Narcotic depeadencn has often bnea attributed to a latent hyperactivity of central nervous system (CNS) synapses, which is developed after repeated administration of narcotic drugs (1, 2) . Since this hyperactivity is overtly manifeatad only in the absence of narcotic drugs, it 18 assumed that in the praaeaca of narcotic drugs those synapses remain inhibited while only is the abeaace of the narcotics am that' overactive in the dependent animal . The activity of neuronal synapses is a result of an iateractioa of the released naurotraasmitters with their respective receptors . Therefore, their hyperactivity implies that either theta ie as increase in transmitter release, a dnThe ezperimeats from author's laboratory reviewed in this paper were supported by PNS Grants 801 1~ 18346, 803 I~ 20115, RO1 DA00418, 1T01 8500104 sad other grants from Noffmaan-LaBoche, McNeil Laboratorisa and Jeassm ~+~~~eutica . Secretarial assietaace of Lucia Johnson ie gratefully acknowledged .
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crease is transaitter degradation, or that there ie an enhancement of the interaction betrem the receptors and the nmrotraasadtter, The latter can be accomplished either by en access to a greater uus~ber of receptors or by a change is the intrinsic activity of the receptors, For the purpose of this review, the increased activity of synapses is the absence of increased release of neurotransmitter will be termed "receptor supersensitivitq," without implying a specific uadarlyisg mechanism, Since the supersensitivity theory of narcotic dependence was first proposed by Saevnrs sad his co-+rorkers, several modifications of the original theory have been offered by a number of iaveetigators (3-6) . The first set of modifications were concerned with the nature and nachaaism of the receptor changes while the later modifications began to specify particular neurotransmitters involved . By now, the involvement of many transmitters have bean postulated, Tha presort review will be li.mitad to focus attention on the direct and indirect evidence that relates to the role of one neurotransmitter, dopamine, in narcotic dependence and narcotic action . While doing so, it is not my in tentien to iu~ply that receptors sensitive to other ~urotraasmittere are not affected . As a natter of fact, there is a growing belief among various investigator~ that narcotic action is mediated by more than one aeurotraasmitter and that more than one type of neurotransmitter receptor is altered during narcotic depmdesca . Abatiaençe Syndrome A eyadrome of body symptoms some of which are objectively observed while others ~ra only subjectively esparinnced following withdrawal from narcotic drugs is to diagnose narcotic dependence and also employed in research on the physiological nechaaism that uader]Ye< that dependence (7) . This withdrawal syndrome has been divided into a primary phase and a protracted phase (8-9) . Symptame of the primary phase are short-lived (from a few hours to a few days) but those of the protracted phase last for longer periods (from several days to several weeks) . Morphine-Withdrawal Aireeeion Among the sigma of narcotic withdrawal is included hyperirritability to environmental stimuli (10) and aggressiveness (il) . Besides the high iacidence of violence-related crimes reported in areas of high heroin abuse, acts of violence are often seen in the hospital wards which admit narcotic addicts . Laboratory animals undergoing abstinence are difficult to handle and, when appropriate stimuli are provided, they show intense aggression which consists of rearing, vocalisation, attacks, biting and killing of other animals (11), The withdrawal aggression was first observed in the rat by Thor and his corworkers in 1966 (12) . Since then, their findings have been confirmed by many wrkers . By now, there are published reports of morphine withdrawal ag gression in the rat (13-14), the guinea pig (15), and the muse (16) . Seevers and Denesu (1) reported aggressive vocalisation in monkeys and dogs although actual aggression was not observed because of lack of opportunity to fight when withdraws animle are housed in single cages, The withdrawal aggression is reported both is the primary sad protracted phase of withdrawal (17) . Careful study of morphinerwithdrawal aggression was the first line of i~estigations which produced evidence to suggest that dopamine-receptor superseneitivity may be involved in narcotic dependence (13, 18) . Aggression
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in naive aaiaals can be produced either by large doses of apomorphine (19), a direct agoniet of dopasüna receptors (20-22), or by a coebiaatioa of dihydro~cyphenylalanlnw (pOPA) and d-amphetaaine (23) which causas a large preferential increase of brain dopamine (23-24) and its release . This drug-induced aggreesioa ie affattive]a blocked by specific blotiars of dopamine-receptors and also by morphiaa suggesting that acute administration of narcotics may bloat dopamine receptors . !lorphinn-~rithdrawal aggression is soon after mre vithdraaal of narcotic drugs sad withoat any other stimulation (11, 25) . Horevar, it is eahaated by directly and indirectly acting dopamine-receptor stimulants, such aa, amphata miaas, DOPA, or apomorphine (25) . The aggression ie blocked by narcotic analgesics such ae morphine and mathadoan (11, 17) and also by dopa~na-receptor blocking naurolaptics such as haloperidol (25) and thlorpramasine (11) or by lasioning of the nigroetriatal boodle (17), the major serve tract which carries dopaminergic nerve fibers to higher brain caatera. Ia addition, doses of dopamiaerrecnptor atinulaats which era capable of eliciting intense aggreseion in the narcotic withdraaa rata are saveralfold smaller than those needed to elicit aggression in normal animals. The effect of amphetamine in eliciting morphinerwithdraral aggression tea be blocked by prior treatment with alpharnethyl-pare-tyrosine (A1~T) while apomorphine ie still able to elicit aggressioa after A1~IPT (25) . AëPT inhibits syatheaie of tatacholsminea and therefore blocks the actions of indirectly acting drugs which dapaad as the release of catecholaniaea for their action . These data suggest that there is a euperaensitivity of the receptors which are responsive to dopamine agoniste . In the absents of ezogaaously A, i~ia tnred dopandae agoniste which am directly acting, aadogaaoue dopamine release ie sufficiaat to cause aggression-eliciting chemical stimuli. But in the absence of endogenous release of dopamine ae after Aè~T, direct action of an agoniet (apomorphine) ie readlly even . $nhaatemeat of Apomorphine Action s Apomrphine is a known stimulator of dopamine receptors (20-22), and by virtue of that property, it induces aggression (19, 26), stereotypy (27) and inhibition of etriatal dopamine turnover (28-29) . These actions of apomor phine are markedly enhanced in the organism in which dopamine receptors are rendered aupereaneitive either through chronic blockade of dopamine receptors by potent nauroleptica (30), or by deetruttioa of presynaptic nerve endings (31) . After chronic treatment rith haloperidol or lesioaiag of the nigroetriatal bundle, there is a reduction is the apomorphins dose required to cause aggression or stereotypy . Also, in chronic haloperidol treated rate, there is a shift towards the left 1n the dose-response curve of apomorphine is causing inhibition of etriatal dopamine turnover (29) . These ehifta of apomorphine action are often employed to document as eatabliahmeat of dopamiaerecaptor aupnrsensitivity . 8etently, a shift is the dose response curve of apomorphine was also observed during the primary se cell ae protracted phases of narcotic abetineate . Doses of apomorphine needed to elicit aggression (17, 19, 32-33), or to inhibit dopamine turnover (17, 33-34) rare significantly reduced is dependent rats auggestiag that dopamine-receptor euparseasitivity had takes place ae a result of narcotic dependence . Toleranca to Haloparidol The acute admiaistratioa of morphine sad other analgesics (35) or haloperldol (36) produced reliable immobility rith a concomitant increase in striatal dopamine turnover (37-38) . Toleraatn to both of these effects of morphine are wall known (see 37 for rasriew) . However, of iatnrest is a recent report (37) that there ie a marked reduction is the ability of haloperidol to
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produce an increase in etriatal dopamine-turnover or cause catalepsy in aorphine dependent rats ; that is, there vas as apparent croaeover of tolerance in aorphine dependent rate to haloperidol, Ia that study, a direct interaction of haloparidol with morphine vas not i~olved because ao snrphine vas injected for at least 3 days prior to the haloperidol test, Also, those rats did not have any prior e~oeure to haloperidol, Therefore, the loss is haloperidol potency suggests that there is developient of pharuacodyaamic tolerance to haloperidol during the davelopuent of tolerance to the narcotics . This finding can be interpreted to aeaa that morphine-dependant rate had developed eupareaneitiva dopamine receptors . The increased dopamine turnover sad catalepsy caused by haloparidol am known to ba ~ndiated through the blockade of dopamine receptors, The superseaeitive receptors would require larger quantities of the receptor-blocking drug to cause their inhibition and, ae a consequence, the activity of the receptor blockar would seas to hewn bean reduced, It should bn noted that there is ao tolerance to the effects of ~or phinn or haloparidol in the rate chronically treated with haloperidol. It therefore seems that the mechanism of action of morphine on dopamine receptors is qualitatively different from that of haloperidol because one results in tolerance and dependence while the other does not, Juspiag-Ras~onea A jumping syndrome which is elicited by a narcotic antagonist has been suggested as a useful measure of narcotic withdrawal (39-40) sad narcotic aatagoniam (41), These suggestions era based upon the empirical observations that narcotic antagonists elicit a jumping response in mice sad rate which have been pretreated with large doses of narcotic drugs. Although the physiological basis of mouse jumping is not known, a permal of the known literature is related to the subject of review, Mouse juupiag is of two types, For lack of any other term, one may be described as cliff jumping and the other as an upward jna~ping, Cliff jumping consists of jumping off of as elevated platform which is aarrw sad fance7.ees . IIpward jumping ie as urge to jump up and out of a confined apace, usually e glass jar with tall side walls . If the test an imal is not placed is the jar, ~1if g jumping and upward jumping cannot be dist inguished, Cliff jumping ie caused either by desipramine (42-43) or amphetamine (44) when either one is injected after tatrabenasine-like drugs. Apomorphina given intravenously also produced cliff jumping in the rat (45) . Colpaart et !1 (46), recently traatnd ice with the above drugs and all other antidapresaant drugs is doses ranging frog sub-phsrsacological to those lethal and found that they do not produce upward jumping with or without a challenge dose of RO-4-1284, IIpward jumping is caused by antagonist-precipitated narcotic withdrawal or treatment of naive mica with dinethylbutylathyl barbiturate (DR~1) (47), naphthylozyacetic acid (NOAA) (16), a combination of amphetamine and DOPA (24), or thaophyllinn injected with other drug combinations (48-49), It is therefore clear that upward jumping ie not limited to narcotic withdrawal because Dl~B, NOAH, DOPA, amphetamine, and. thaophyllin are neither narcotic nor produce physical dependence, With the eueption of ~~ which ie a coavulsaat and NOAA whose pharmacology is imlmowa, the other drugs fall in a category of those which directly or indirectly stimulate catacholami.na receptors, Large doses of DOPA which increase brain dopamine are known to cause mouse jumping (50-51) but the incidence ie very wall, probably because dopamine which is accuwlated following DOPA injection is inhibited from release in the presence of DOPA (52~ However, if amphetamine, which causes release of dopamine, is combined with DOPA, the jumping ie markedly increased (24), Theophyllia nay cease jvapinB
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through accumulation of cyclic AMP which causes as increase is dopaztina eynthasis (53-54) and rector etimulatian (55) . Since the upward jumping is blocked by haloperidol, pimozida and other neuroleptics (24, 56), this jumping can ba considered to be dun to the stimulation of dopamine receptors. A similar ezplaaation spay be offered to explain upward jumping in narcotic dependent enimala, liaruyama end Takemori (57) and Iwamoto et al . (58) showed that jumPiag behavior in opiate dependent ~.ce is related tô changes in brain concentrations of dopamine, Hnrz et al . (59) reported that upward jumping in morphine-withdrawn rata ie potmti.âtndwith los doeea of apasbrphiae . Moreover, morphine sulfate inhibits the upward jumping elicited by DOPA-amphetamine combination in the naive mouse (19, 56) . Acute Açtioas of Narcotic_ Analgesics Morphine and other narcotic analgesics shw a multitude of pharmacological actions. Several of these actions seam to ba based upon en altaratian in the functioning of brain dopaminergic systems, and, ae such, resemble many actions of other drugs well known to affect dopaminergic system . Brain Dopamine In rate, one hour after morphine injection, theta is no change in eteadystata levels of dopamiaa is any of the brain areas studies (34, 37, 60-63), although at 2 and 4 hours after the morphine a transient and small increase in levels was reported (63) . Moat kaawn agoniste or entagonists of dopamine receptors also do sot alter steady-state levels of brain dopamine . It is well known that drugs which block dopamine receptors always increase etriatal dopamine turnover, This is also the case with morphine . Accumulation of DOPA after as inhibition of brain DOPA decarbozylaee (64) and conversion of tyrosine to dopamine (64-70) is increased by an acute injection of morphi~ suggesting that morphine treatment causes as increase in the eyathneie of brain dopamine, Likewise, brain coacentratioa of hoaavaaillic acid, a metabolite of dopamine, is increased (34, 71-75) after morphine or methadone suggesting that these drugs cause en increase is catabolism of brain dopamine . In addition, acute administration of morphine accelerates the depletion of brain dopamine after the administration of a catacholsmine synthesis inhibitor, AMPT (34, 60, 62, 74) . The abavn effects of morphine am readily antagonized by naloxona (34, 62), Ia the absence of uaaltared steady-state levels of brain dopa~.an, a simultaneous increase is synthesis and metabolism by acute injections of narcotic analgesics implies that the turnover rate of brain dopamine is increased by these drugs, The mnchsaiems vaderlying the stimulating action of narcotics on dopamine turaovar am sot knows. Morphine does sot alter either in vitro (76), or is vivo (77) activity of tyrosine hydrozylaan . Ia vitro, morphine done not alter the affinity of tyrosine hydrozylase for aithai tieêubstrate or cofactor (77) . Also, morphine dose sot interfere with the inhibition of tyrosine hydro:y].aee by the catecholaaiaee (77) the machaaism presently thought to ba most critically i~olved in the regulation of mtabolic fluz along the catacho].amiae pathway (78) . Therefore, tyrosine hydrorylses, en enzyme considered to be rata limiting is the synthesis of catncho].amines, is sot directly affected by narcotics . There are several iadirnct mechanisms kavwa to cause en iacrnase is the dopaniaa turnover, Firstly, removal of dopamine free cytoplaemic compartmsat of presynaptic ~erve aadings will remove product inhibition (through a compati tioa with a critical cofactor) of the synthetic process and thereby cause etimu].ation of its synthesis . Secondly, blockade of dopamine receptors, invariably causes compeaaatory stimulation of dopamine synthesis and release . To
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keep the homeostasis of catecholamine turnover intact, the iacreaee in syatheeis often results in as iacrnase is release and catabolism, thus maintaining a constant steady-state level in the presence of an increased turnover . Whether narcotic drugs cause release of dopaalae or blockade of dopamine receptors or both is a matter of conjecture at this time se no direct evidence is available to reach a conclusion . HaPnver, there are several indirect lines of evidence available and they rill ovexvhelmingly suggest that there is an inhibition of dopandaergic activity iaduced by narcotics, Adenylata cyclase, cyclic AMP sad Prostaglandins Collier and Roy (79) summarised evidence to indicate that narcotic analgesics produce their pharmacological action through inhibition of prostaglandin (PGE) induced stimulation of cyclic AMP . Firstly, soma actions of PGE (effects on pain, temperature and gaetroiatestinal fuactione) are such that their antagoni .em weld ezplain soma of the main pharmacological effects of opiates. Secondly, cyclic AMP antagonises the antinociceptive effect of mrphina and mrphinn aataganizes some effects of PGE, Thirdly, the relationship betraen heroin, mrphine, methadone, deztrophan and naloxone in in vitro eaperiments an PGE and cyclic AMP largely corresponds rith their pharmacological relationship eeea i~a vivo, Fourthly, the coaceatrations at rhich heroin, morphine, and aethadone n~ibit PGE T i n vitro, roughly correspond rith their effective concentrations is brain in vivo, Collier and Roy (79) further proposed that the above affect of mrp i e ie exerted through the neuronal adanylate cyclesa . Tolerance and dnpendaace rhich arise from the agoaist action of opiates and are enhanced by cyclic AMP and partly blocked by indomethacia represent a compensatory hypertrophy of a part of the inhibited PGE cyclic AMP mechanism, Since the striatum is the richest of the brain areas containing n~TrOtiC receptors (80) and is also the richest dopamine-containing area is the brain, the anatomical aitn for the Collier-Roy mechanism is likely to be located is the etriatu~ and involve the adenylate cyclase contained is that area . Therefore, the target adeaylate cyclase rith all probability rill bn that rhich is sensitive to dopamine, The direct effects of narcotic drugs on dopamine-seaeitive adeaylate cyclasn have not been fully investigated yet . Acute doses of mrphine increase the adanylate cyclasn activity in the caudate rhea given in high doses (34, 81-83) and resemble a similar effect of haloperi dol is this respect (82), Ia vitro affects of mrphiae on the striatal adenylate cyclaen am not specific set can be produced by the inactive isomers ae sell as by nalozonn (34), Chronic administration of either mrphine (34, 82) or haloperidol (82) causes as iacraaae in the basal levels of the adenylata cyclase and increases the sensitivity of this enayma to dopamine (82) . Behavioral and Endocrinolo~ical Actions , There are many pharmacological actions of mrphiae rhich suggest blockade of dopaniae receptors . Morphine induces asysmetric turning of rats is rhich the nigrostriatal bundle, consisting of dopaminnrgic fibers, ie unilaterally lesioned (83), 3lailar turning is sell knam after haloparidol treataeat Morphine (28, 84) sad all other narcotics (19, 85) block stereotypy iaduced by apomrphina or amphataaine ; the blockade of the same stereotypy by haloperidol sad pimsidn is roll kaara (85), In dogs, mrphine~ methadone, demnrol, featanyl, deztromra~ide, pheaopnridine, piritremidn, and several other narcotic analgnsica block aposwrphiae-induced vomiting is very small doses (19, 84, 86). Only mrphiae may initially Gauss soma vomiting, but that action is not common to other narcotic drugs such as fantanyl, methadone, deztramra~de and piritramids, sad, therefore, may not ba considered as a specific narcotic action . Potent neuroleptics are also knam to block apomrphine vomiting and, tharefora, narcotic drugs can be considered to reaaabln nsurolaptice in this respect . In nice, acute administration of DOPA in combination rith amphetasdna
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muses aggression which is blocked by either morphine or haloperidol (23) . In these mica DOPA also counteracts mrphina analgesia (87-88) . Apamorphiae sad anaatadiae aLo aatsgoniae the acute effects of morphine (73) . Morphiaa muses muscls rigidity which can bs reversed by lesianing of brain dopasinergic nuclei (89) . It also causes an iacreaee is the suitability of mudate nucleus calls (90) which can ba interpreted to be dus to removal of inhibitory influences of dopamine . Morphine ~ad other narcotics inhibit coaditionsd avoidsace bar pressing (84) sad brain self-stimulation (36, 91) which hava been coasiderad to ba actions of specific dopamine receptor blocking drugs (92) . Dhasnana at al, (93) reported blockade of cardiovascular eflacts of syatemimlly injaçted dopamine by morphine and codeine. It h~e been recently shows that prior e~riotration of drugs, such as haloperidol sad alpha nethyl~para-tyrosine, which reduce activity of brain dopasinnrgic activity facilitate recovery from aphasia and adipeia produced by lateral hypothalamic lesions is the rat (94-95) . In a similar a:perimant prior ~~+++i~tratioa of morphine sulfate also facilitated recovery from the affects of those lesioaa (96-97), It is lmowa that blockade of central dopsmiae receptors muses an increase in serum prolactin levels (98) and a decrease in the levels of leutiaisiag hormones. Recently Dobrin and Mares (99) reported an increase in serm prolactin and decrease in lautiaitiag hormone after acute administration of morphine . Coaclusioa The data sumarizad in the previous sections ware selected from the ezpnrimaats which warn ralevaat to the determination of morphine effects on dopaminargic systems . These data suggest that morphine-like narcotic drugs produce many effects which have been conventionally interpreted to be due to blockade of dopamine receptors, such as is the case of non-narcotic drugs. Firstly, morphine produces many behavioral, eadocriaological and naurocheniml effects which are ~~++i~ ceat of dopamine aatagoniam, Secondly, narcotim show aatiamphetamiae and antiapamorphine activity in a masher of tests which are often designed to measure anti-dopaainargic activity of new chemicals . Thirdly, morphine tolerant rate show tolerance to other dopamine receptor blocking drugs . Fourthly, chronic treatnmt with morphine results in a decrease in the threshold doses of dopamine agoniste in a number of behavioral sad naurochaaical tests as wall as it causes an increase in the basal levels of dopamine sensitive adaaylate cyclaan activity (34, 82) . All of the cited data suggest that morphine may be a dopamine receptor-Mocker . However, it may be mentioned that the evidence is only indirect . Rzperineata providing direct evidence of dopamine receptor blockade by narcotics are scarce . Although morphine-like narcotics resemble co~eatioaal dopamine-rnmptor blocking asuroleptics, there are significant differences . First, in comparable situations whore narcotic antagoniste ware employed, the actions of aar cotice but not of neuroleptics ware either blocked or reversed by the aatagonieta . These paradigms include iacreaae in atriatal dopamine turnover (28, 62 ),, antiaggreseioa activity (unpublished data), inhibition of brain self-etimulation (36) sad drug induced iuaoobility (36-37) . Sacand, whereas many actions of neuroleptim are reversed by anticholiaergic drugs (100), the same anticholinergic drugs do not reverse the similar actions of narcotics . Thesa actions include drug induced immobility (36, 100), blockade of apamorphina aggression (unpublished data) sad blockade of brain self-stimulation (91) . Third, immobility caused by narcotics is qualitatively diffareat from that caused by aauroleptica . Nauroleptic catalepsy is accompanied by muscular hypotonic but narcotic catatonia consists of muscular hypertoaia (36) . Fourth, haloperidol does not substitute for morphine (101) or featanyl (102) in produo-
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ing drug-induced diacrimiaabln stimuli, Fifth, narcotic drugs are abused and produce dependence while there is ao report of drug dependence with aeurolnptics . A narcotic (fentanyl), when used is combination with a aaurolaptic (dropreridol), is not known to be ever abused, Sizth, the ma:imun effect of morphine on dopasdne turnover is leas than that of haloperidol, and haloperidol can still produce as additional effect when given after the mnsimum effective dose of morphine (34), Seventh, whereas systemic administration of either haloperidol or morphine produces a significant increase is dopaminasenaitive etriatal adaaylata-cyclase (34, 81-g2), i~ vitro application of only haloperidol blocks dopamine stimulation of that enzyme 82, 103) . Similarly, systemic admiaiatratioa of morphine or haloparidol increases firing of dopaadne-sensitive cells of the zone co~acta in the subatantia nigra, but only morphine action is antagonized by nalomoae . Haloperidol can still stimulate the firing even after morphine and/or naloune have been administered (104), Because of these differences between the actions of haloparidol and aorphine, it is suggested that the site of antidopaminergic activity of narcotics is different from that of a aeuroleptic, Neuroleptice are known to directly act on dopamine-receptor sites, Therefore, the narcotics may block dopamiaergic syeteme indirectly, possibly through transeynaptic mechanisms which may even involve other neurotransmitters . References 1.
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