Design and interpretation of opiate antagonist trials in dementia

Prog. Neum-Psychophormacol. Printed in Great Britain.

6 Biol. Psychiat.

027&5646/66 1966 Pergamon

1966, Vol. 10. pp. 611-626

DESIGN AND INTERPRETATION

OF OPIATE ANTAGONIST

$0.00 + .50 Journals Ltd.

TRIALS IN DEMENTIA

PIERRE N. TARIOTI, TREY SUNDERLANDI, DENNIS L. MURPHYI, MARTIN R. COHEN*, JULIE A. WELKOWITZI, HERBERT WEINGARTNERI, PAUL A. NEWHDUSEI, ROBERT M. COHEN1

INational Institute of Mental Health, *University of South Carolina,

Bethesda, Columbia,

(Final Form, February

Maryland, U.S.A.; S.C., U.S.A.

1986)

Contents

::

E

2.3 2.4 2.5

:: 4.1 5. 5.1 5.2 6. ::: 7.

Abstract Introduction Background Endogenous Opiates Anatomy of Endogenous Opiate Systems Opiate Receptors Localization of Opiate Receptors Functions of Endooenous Opiate Systems Rationales for Study of Endogenous Opiate Systems Strategies for Study of Endogenous Opiate Systems The Use of Opiate Antagonists in Dementia A Multidose Naloxone Study in Dementia Rationale Design Results and Discussion Cognitive Effects Behavioral Effects Summary References

611 612 612 612

in Dementia in Dementia

612 612 613 613 613 614 614 615 615 615 616 618 618 622 622

Abstract Tariot, Pierre, N., Trey Sunderland, Dennis L. Murphy, Martin R. Cohen, Julie A. Welkowitz, Herbert Weingartner, Paul A. Newhouse and Robert M. Cohen: Design and interpretation of opiate antagonist trials in dementia. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1986, g (3-5): 611-626. 1. In view of the reports of possible beneficial effects of naloxone in dementia, rationales and strategies for studying endogenous opiate systems are reviewed, Important considerations in the design and interpretation of clinical investigations using naloxone are also reviewed. 2. The nature and distribution of endogenous opiate systems are summarized from an historiEndogenous opiate systems are distributed throughout the central cal perspective. nervous system and play important roles in a variety of brain functions, including memory and learning. 3. In view of this, several rationales are evident for studying endogenous opiate systems in dementia, since it is a syndrome in which structures known to contain opiate systems are disturbed, functions modulated by opiate systems are disturbed, and other neurotransmitter systems (functionally linked to endogenous opiate systems) are disturbed. 4. Different strategies for studying endogenous opiate systems are reviewed, including Naloxone hydrochloride, examination of body fluids and pharmacologic challenge studies. a competitive opiate receptor antagonist, is a commonly used pharmacologic agent.

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612

5. The design of a multidose naloxone study of 12 dementia patients is discussed, with reference to the oharmacokinetics. pharmacodynamics, and specificity of naloxone as Well as to the nature of the dependent measures selected for'this study. Behavioral arousal was observed at 6. No cognitive benefit was observed in this study. naloxone doses, with more evident psychomotor retardation at higher doses. These findings are contrasted with the results of naloxone challenges in other studies. 7. The varying effects of naloxone within and across populations can be conceptualized in terms of the basic and clinical considerations previously discussed. The importance of dose-finding studies is stressed for this and other drug trials. Keywords:

Alzheimer,

Abbreviations:

Dementia,

endoqenous

opiate

Brief Psychiatric Rating Scale Profile of Mood States (POMS).

systems,

naloxone,

(BPRS); dementia

peptides.

of the Alzheimer

type (OAT);

1. Introduction Beneficial effects of the opiate receptor antagonist naloxone in patients with dementia of the Alzheimer type (DAT) were first reported in 1983 (Reisberg et al., 1983a; 1983b) and resulted in considerable interest. This paper attempts to outline some possible rationales for the study of endogenous opiate systems in DAT, and to review pharmacologic and clinical considerations in the design and interpretation of a multidose naloxone trial in this population. These include the nature and timing of observations made, as well as the importance of considering the differential effects of varying doses of naloxone. Such design features are relevant to the interpretation of other drug trials as well.

2. Background 2.1

Endogenous

Opiates.

Exogenously administered opiates have long been known to have substantial behavioral and physiologic effects (Jaffe and Martin, 1980). These effects were postulated to result from interactions of opiates with specific receptors (Beckett and Casy, 1954). The discovery opiate receptors in the brain in 1973 supported this hypothesis (Simon et al., 1973; Pert and Snyder, 1973; Terenius, 1973) and raised the possibility of the existence of naturally occurring ligands. The first of these, the pentapeptides methionine- and leucineenkephalin, were identified in 1975 (Hughes et al., 1975). There are now believed to be three distinct opioid prohormone systems: 1) proenkephalin, from which enkephalins are derived, 2) proopiomelanocortin, from which beta endorphins (as well as the non-opioid hormones ACTH and MSH) are derived, and 3) proneoendorphin-dynorphin, from which dynorphins are derived. These three peptide precursors give rise to multiple other peptide products (endogenous opioids), each with varying effects and potencies (Khachaturian et al., 1985). 2.2

Anatomy

of Endogenous

Opiate

Systems.

Studies of the anatomical distribution of the endogenous opioids in animals have shown that the different precursor peptides and their products are distributed in widespread networks in the brain and periphery, with multiple cell groups and projections (Hokfelt et al., 1980; Watson et al., 1982; Bouras et al., 1984 Khachaturian et al., 1985). These cell bodies have been identified in areas believed to play an important role in the modulation of behavior and cognition such as the hippocampus, frontal cortex, and locus coeruleus (Scoville and Milner, 1957; Martinez et al., 1979; Adams and Victor, 1977; Mann et al., 1980; Squire, 1982). 2.3

Opiate Receptors.

The heterogeneity of effects exerted by different opiates had been postulated to result from the interaction of exogenous opiates with different types or classes of receptors (Martin et al., 1976). Based on biological assays, cross-tolerance studies, and the development of selective ligands, evidence has accrued to support the concept that there are

Opiate agonists in dementia

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multiple opioid receptors (Lord et al., 1977; Chang et al., 1979,lSgO; Zukin and Zukin, 1981; Wood, 1982; cox, 1982). It is believed that there are at least 3 opiate receptor types called mu, delta, and kappa. nther opiate binding sites have been postulated (e.g. sigma, epsilon, and lambda) for which the evidence is less convincing. Possible isoreceptEach receptor type is presumed to have ors exist for some of these receptor classes. variable affinities for the different endogenous and exogenous opiates. Thus, mu receptors appear to preferentially bind morphine-like opiates (mediating analgesic effects); delta receptors appear to be relatively selective for endogenous enkephalins; kappa receptors may be more selective for ketocyclazocine-like opiates (mediating ataxic and sedative effects), and sigma receptors may be more selective for N-allynorcyclozocine-related opiates (mediating stimulant and psychotomimetic effects) (Chang et al., 19Rn; Zukin and 7ukin, 1981). 2.4

Localization

of Opiate

Receptors.

The regional distributions of different receptor systems have been mapped through studies of the relative binding capacities and affinities of different opiate-like peptides and ooiate antagonists (chanq et al.. 1479: Terenius. 19Pfl: Rise and Herkenham. 19821. In a manner analagous to that'of opiate-containing neurons,- the receptor subclasses are widely distributed in the CM and periphery, including regions playin important roles in copnition and behavior such as cerebral cortex, hippocampus, and limbic structures. The densities of the subclasses appear to vary across regions, with, for example, roughly equal numbers of mu and-delta receptors in the cerebral cortex and striatum, and roughly twice as many mu receptors as delta receptors in the limbic system and hippocampus. The anatomical relationships between opiate receptors and endogenous ligands are poorly understood (Khachaturian et al., 19nS), although evidence from anatomic studies has permitted new inferences regardin the function of onioid systems. 2.6

Functions

of Endogenous

npiate

Systems.

There are numerous endogenous opioid systems in which different opioid peptides, derived from the precursors localized in different brain regions, interact with variable affinity with different classes of widely distributed opiate receptors. These interactions mediate the function of the endogenous opiates as neurotransmitters or neuromodulators (Snyder, 19RD) which play a requlatory role in such varied functions as locomotion, pain perception, thermoregulation, cardiovascular responses, eating behavior, euphoria, neuroendocrine mechanisms, and memory and learning (Rloom et al., 1076; Peluzzi and Stein, 1977; Rigter, lo-In; Arnsten and Segal, 1979; Fleites et al., 1979; Izquierdo, 19RD; Izquierdo and Graudenz, 1980; Poladay, 19n3; llorley and Levine, lonO; Volavka et al., loDO; Gorris and van Abeleen, lW1; Koob and Bloom, 19W; Watkins and tiayer, 1982; Holaday, 1983; Kavaliers et al., 1983; Dlson et al., 1984). With regard to memory and learning, specifically, recent studies have sug- gested that learning studied in a number of animal paradigms is influenced by endorphins and enkephalins administered systemically both hefore and after the learning procedures. It has been hypothesized that one effect of endogenous opioids (particularly beta endorphin) is the impairment of retention by inhibition of hippocampal dopaminergic and noradrenergic systems involved in memory consolidation (Izquierdo and Graudenz, 1980; Izquierdo et al., loW1. 3. Rationales

for Studying

Endogenous

Opiate

Systems

in @AT

In the context of a general review of endogenous opiate systems, several rationales energe for their investigation in PAT. Dpioid pptides and their receptors are anatomically distributed in brain regions known to play important roles in behaviors commonly disordered in nAT, such as memory, learning, motor behaviors, and emotional control (Cummings and Benson, 19831. In addition, endogenous opiate systems appear to play important functional roles in these behaviors under experimental conditions. Since these behaviors are disturbed in DAT, and since many of the same structures in which endogenous opioid systems are contained are structurally disturbed in nAT, it is possible that both functional and anatomic assessment of the status of the endogenous opiate systems in DAT may provide insight into the pathophysiology of this disorder, with possible implications for treatment. An additional rationale emerges in view of the extensive interactions between endogenous opiate systems and other brain neurotransmitter systems. These include central cholinergic,

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serotonergic, and catecholaminergic systems (Domino, lo7n; Konishi et al., 1979; Pepper and Hender_on, 1980; Wellstrand and nellborg, 1981; Livett et al., 1981; Preziosi et al., 19o3; Somoza et al., 19n31 that may play important roles in the kinds of functions that are disturbed in DAT. In some cases, these systems are themselves disturbed in nAT, although whether such changes are primary or secondary remains uncertain (navies and Maloney, lo7fi; iiann et al., 1980; Rowen et al., 14831. Further understanding the potentially disordered interactions between endogenous opiate systems and other important neurotransmitter systems may likewise shed light on this disease. The known interactions between opiod and other neurotransmitter systems provided the basis for the first use of naloxone in DAT. It was hypothesized that tonic overactivity of endogenous opiate systems in DAT would in turn inhibit CAPAergic systems, therehy disinhibiting other central systems (including cholinergic systems, which are known to be disturbed in DAT). It was suggested that blocking this opiatergic effect with naloxone might be beneficial (Roberts, 1.981). 4. Strategies

for the Study of Endogenous

npioid

Systems

in nAT

Endogenous opioid systems can be, and have been, studied in a variety of ways. Evaluation of the cognitive, behavioral, physiologic, and neuroendocrine responses to the administration of a variety of opiate agonists in patients with nAT is a pharmacologically feasible approach that has been used in other hehavioral disorders (Cohen and Pickar, lonl), although the uncertainty of access of peptides to the C.6 is a potential problem, technically surmountable by intracerebroventricular administration. The selective use of agonists, exogenous and endogenous, for maximal specificity of interaction with receptor subclasses, would be optimal in delineatin? which opioid systems nay he playin crucial roles. Analogous concerns regarding specificity would apply to the use of opiate antagonists. Analysis of endorphins in brain and body fluid represents another approach. "eta-endorphin-like immunoreactivity has been reported to be lower in the cerehrospinal fluid of nAT patients than controls, and a positive correlation has been found hetween R-endorphin levels and severity of dementia symptoms (Kaiya et al., 1983). Replication studies have not yet heen Early imunohistochenical study of the distribution of enkephalins in hrains from reported. patients with DAT has been reported (Rouras et al., lo84). t'ore detailed regional studies of opioid systems will be possible using this technioue as well as in situ hybridization of opioid mRtlA (Khachaturian et al., 19851. Functional imaging of central opiate systems has recently been accomplished (Frost et al., l?PF;l, and will likely be refined in the future, 4.1

The Use of Opiate Antagonists

in PAT.

A pharmacologic strategy frequently used to assess the role of endogenous npioid systems in humans and animals has been the use of opiate receptor antagonists (Cohen and Pickar, 1981). A variety of antagonists have been developed through rodification of the structure of opioid analogues. Maloxone hydrochloride, a centrally active competitive opiate receptor antagonist, is the best-known and most widely-used. It has heen shown to antagonize almost every pharmacologic action of opiates and opiate peptides (Jaffe and '"artin, lo80). Its effects fin the absence of exopenous opiates) are generally attributed to temporary functional blockade of one or more endogenous opiate systems modulating the affected functions. Wuman studies hegan with naloxone doses of approximately E pg/kg, the dose normally used clinically to precipitate withdrawal from exogenous opiate use. cuhsenuent studies used doses up to 0.3 ng/kg. In normal subjects and patients with a variety of psychiatric disorders, there were no consistent effects of naloxone in this dose range on mood, behavior, cognitive function, or vital signs (functions believed to be modulated at least in part by endogenous opioidsl, although some hormonal channes were reported (,lanowsky et al., l.977; Grevert and Goldstein, lo7R; Watson et al., ln7n; volavka et al., 197"; Willer et al., 1979; navis et al., 1980; Judd et al., 1980; Volavka et al., 19Pn; Film, lonn; File and Silverstone, 1981; Hoehn-Saric and tlasek, lonl; Sethi and nrakash, loPI; Pickar et al., 1982; Liebowitz et al., 1984; Wolkowitz and Tinklenberg, lnnK;!. However, one might inconsistent effects

anticipate that restricted doses of naloxone might have minimal or in view of the number and complexity of distribution of opiaterqic

Opiate agonists

in dementia

615

neurons, as well as the number, variable location, density, and affinity of opioid receptInstead, it might be expected that varyino doses of naloxone would have differential ors. effects, depending on which opioid systems were affected by these different doses. Consistent with the expected differential functional sensitivity of varying doses of naloxone based on these theoretical principles and laboratory findinos, it has heen found that doses in excess of 0.5 mg/kg and up to 8 mg/kg or more were necessary to achieve reliable behavioral and physiologic effects suggestive of blockade of at least some endogenous opioid systems in animals (uoltzman, 1974; Arnsten and Segal 197n; File, ln80; Morley and Levine, 1980; Gorris and van Abeelen, l!W; Gallagher et al., IoR?). nf particular relevance to the symptomatology of Patients with DAT are animal studies of the effects of naloxone on memory and learning. A wide variety of cognitive hehaviors such as step-through inhibitory avoidance, active avoidance, and shuttle avoidance (as well as others) have been reported to be enhanced by peripheral or central administration of naloxone in these higher dose ran9es (Izquieredo, 1980; Izquieredo and craudenz, 1981); JlcCaugh, 1983). Such findings by themselves support consideration for the possihle use of naloxone in nAT (Reishero et al., 1983a1, and underscore the potential importance of variable sensitivity of functional systems to different naloxone doses. Paralleling these animal studies, human studies have shown that J\' administration of naloxone in doses in the milligram-per-kilogram range (up to Q mg/kgl resulted in dosedependent, consistent alterations in a variety of functions. The major effects reported were anxiety, tension, dysphoria, elevated systolic blood pressure and respiratory rate, increased cortisol and growth hormone levels, and impaired cognitive function (specifically, decreased performance on tasks assessing episodic memory, and effortful and automatic 1V3h, loWa, Jnn3h). nemory processes) (Cohen et al., lW1, These changes were generally consistent with those expected during withdrawal from chronic exogenous opiate administration, and hence with dose-dependent, increasing blockade of endogenous opioid systems. These findings also supported a modulating role for endogenous opioid systems in processing memory traces in humans. The threshold for this constellation of effects was approximately 2 ng/kg, suggesting that doses of this magnitude might be necessary to achieve more complete blockade of endogenous opioid systems in humans. In contrast to the reported minimal or inconsistent cognitive and behavioral effects of low doses of naloxone in psychiatric patients and normals, two recent studies, based on the endogenous opiate-GABA hypothesis outlined above, reported clinical and cognitive improvement in patients with pAT after low dose (1 to lo mgl Iv naloxone (Reisberg et al,, 1983a,b). Later open trials using doses from 1 to 5 mg did not confirm these findings @lass et al., 19831, nor did a more recent double-blind trial using doses of 18 mg (Steiger et al., ln85). 5. A riultidose Haloxone 5.1

Study

in DAT

Rationale.

Since functional blockade of at lease some endogenous opioid systems does not appear to be achieved in animals or young normal human subjects until high doses (2 mg/kg, or approximately 120 ng) are used, it is possible that the use of low-dose naloxone in pAT achieved incomplete pharmacologic blockade of endogenous opiate systems modulating the behaviors of In order to more fully assess central endogenous opioid systems in PAT using interest. naloxone as a challenge agent, we designed a study in which the cognitive and behavioral effects of "very low" (5 ug/kg, the dose needed to produce morphine withdrawal), "low" (0.1 mg/kg, the dose analogous to those used in prior pAT-naloxone studies), and "high" (2 ng/kg, the dose that may be necessary to achieve more complete blockade of endogenous opiate systems) doses of naloxone would he compared to the effects of placebo. 5.2 Design. Pharmacokinetics and Phannacodynamics. One issue to be considered in the design is the timing of dependent measures after naloxone administration. After an initial rapiddistribution phase, the half-life of naloxone is approximately 60 minutes (Fishman et al., Measurement of behavioral and cognitive changes to be 1973; Rerkowitz et al., 1975). attributed to acute changes in the physiology of central opioid systems should therefore be

616

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made in the period anproximately 30 to On minutes after naloxone infusion. nynamic effects of high dose naloxone have largely been reported at these times (Cohen et al., 1983hl. Specificity. Another issue is the specificity of naloxone in this dose range. At very high doses, naloxone is believed to be neither completely selective nor a pure opiate antagonist (Sawynok et al., 197"). With an approximate volume of distribution of 2On liters in man (Berkowitz et al., 1976; Fishman et al., 1973) and a brain/plasma naloxone concentration ratio of approxinately 1.5 at maximum plasma concentrations, administration of naloxone 2 mg/kg over 2 minutes would result in a peak brain naloxone concentration of less than 6 umole/liter. This is within the known in vitro limits of naloxone's specificity as an opiate receptor antagonist (ningledine et aT;,m, Sawynok et al., ln79. To the extent that in vitro findings can be related to in vivo events, it seems unlikely that nonspecific or non-opiate receptor mediated effects o~n?XZone would occur. nependent Heasures. Ideally, hehaviors known to occur in OAT (Feohs et al., lo821 and likely to be affected by naloxone administration (Cohen et al., 1983a,h) would be targeted for quantitative observation. A modified Rrief Psychiatric Patinp Scale (RPRS) (Guy, 1076) It is observer-rated, and several items and subscales target was selected as one instrument. behaviors potentially relevant both to manifestations of nAT (e.g., conceptual disorganization, depression, disorientation, psychosis, motor activity, loss of functioning, impairment) and to previously reported effects of naloxone administration (e.g., anxiety, tension, hostility, suspiciousness, retardation, motor activity). It has the added advantage of having been used in a variety of other naloxone studies (Janowsky,et al., lo77; F!atson et al., 1978; Davis et al., 1980; Sethi and Prakash, 1981; Pickar et al., lW7; Cohen et al., Iq83b), allowing a basis for comparison. A visual analog scale was also developed, consisting of 100 rnn lines for the observer's glohal assessment of selected behaviors based on the above considerations. Since, in our experience, nA? patients have difficulty reportino symptoms on self rating forms, the physician observer assisted the patient in completing the FIIHH self-rating form (van kanen and Murphy, 1975) by reading the ouestions aloud and marking the responses. Cognitive functions known to he affected in DAT, likely to show change if any improvement occurred, likely to be affected by naloxone, and comparable to those measured in other naloxone trials in nAT were selected for assessment. Attentional capacities were assessed by digit span and performance on one aspect of a vigilance task (Cohen et al., 1983a); motor performance was assessed by finger tapping speed and measures of sustained motor effort (Cohen et al., lq82a); episodic learning and memory (generally for recent events) was evaluated by a serial reminding task (Ruschke, ln73) and vigilance task; knowledge memory was assessed by category retrieval (Battig and Montague, 1969) and identification of degraded figures (fiollin, 1960); and recognition was assessed by the vigilance task (Cohen et In some cases, partially redundant measures were chosen in an effort to al., 1983a). investigate possible determinants of the variable expressions of cognitive failure in nAT. Maloxone was administered in a double-blind, placebo-controlled, Summary of Design. randomized fashion to 12 subjects with clinically diagnosed nAT. There were 2 infusions separated by 60 minutes on each of 3 test days; placebo-placebo, naloxone 5 ug/kg-naloxone Measures were obtained as shown in Fig 1. 8.1 mglkg, naloxone 5 ug/kg-naloxone 2.0 mg/kg. In nearly every case the only changes recorded occurred within 60 minutes of the second inStatistical analysis was performed by repeated measures analysis of variance. The fusion. full design, description of patients, method of analysis, and results are described in detail elsewhere (Tariot et al., 1985a,bl. Previously unpublished data are included in this paper. 6. Results

and niscussion

Some considerations in the design of this study are relevant for its interpretation. Several of the behaviors targeted for double-blind observation did in fact change after drug administration, generally at the anticipated times. In addition, there was a differential dose-responsiveness which supported the general rationale for using a range of doses. The cognitive and hehavioral findings can be compared both to reports of the effects of naloxone in young normals (a group which has received high dose naloxone) and in OAT patients (who previously had received low dose only).

Opiate agonists in dema~tia

III

617

616

P. N. Tariot et al.

fi.l Cognitive

rffects.

MO cognitive measures improved after naloxone administration, and in fact there were no reliable changes in any cognitive realm, despite the use of overlapping measures of cognitive function. Ve noted that the production of appropriate responses to specific verbal stimuli (category retrieval) decreased while inappropriate responses increased after the low (0.1 mg/kg) dose of naloxone. This finding is consistent with iwo prior reports suggesting no cognitive improvement after naloxone in DAT patients (Mass et al., 1983; Steiger et al., 19Rn;). It also suggests that the altered category retrieval performance observed after low dose naloxone might be a nonspecific finding, since no other measure of semantic menory \4as affected. The absence of changes in measures of cognitive function in IlAT patients receiving high dose naloxone differs from the findings in young normal subjects, where statistically significant and relatively specific changes in coonitive function were reported (Cohen et al., 1983al. In whatever manner endogenous opioid systems may normally function to modulate memory and learning processes, they do not appear to be sensitive to acute functional blockade in DAT patients. Alternative explanations for the lack of consistent changes in this study might be that the cognitive measures were not valid for the population (who have significantly impaired baseline performance on many of these tasks), or for measuring naloxone effects. For example, Arnsten et al. (1983) reported that naloxone in doses of approximately 0.03 mg/kg augmented electrophysiologic indices of attention in normal subiects in the absence of However, the measures used in the current study were chosen for their global arousal. general relevance to the symptoms of nAT: it remains to he seen whether other measures, perhaps of more fundamental aspects of cognitive function, will change in a discernible and clinically helpful fashion. 6.2

Behavioral

Effects.

rloderately significant behavioral changes resulted from administration of low and high doses of naloxone with no effects of the very low dose. These changes were more robust after the low dose, and consisted primarily of a syndrome of "irritahle activation" (Table I). The behavioral arousal may account for the altered category retrieval performance (increased inappropriate responses and decreased appropriate responses), with the response score simply providing a nonspecific measure of verbal output. In contrast, the activation was less evident after the high dose, while psychomotor retardation was more prominent, and drowsiness became evident several hours later. A consideration in the interpretation of the behavioral changes observed in this study is the possible non-specificity of effects resulting from any pharmacologic challenge in this nAT patients could conceivably be more susceptible to any disrupting stimulus population. with attendant behavioral arousal; such changes would not be specifically attributable to alterations of particular neurotransmitter systems. However, in this study, the general similarity of the observed effects to those ohserved during exogenous opiate withdrawal argue for a more specific opiate systems effect. A behavioral comparison to prior reports of naloxone in CAT patients is not possible because behavioral changes were not described in detail, nor were high doses of naloxone However, using somewhat different but related measures, comparison to young normal used. subjects receiving high dose naloxone is possible (Table 1, which includes previously unpublished data regarding changes in RRRS scores). As a group, the normals experienced physical symptoms (dizziness, flushing, stomachache, etc.) that peaked within minutes and were followed by tension, irritability, and dysphoria (Cohen et al., 1983b). These responses were similar to those observed in our IJAT patients, suggesting a very similar pharmacologic effect. Furthermore, the qeneral consistency of these responses with those expected following withdrawal from long-tern opiate administration supports a role for endogenous opioid systems in behavior nodulation in both groups, and suggests that the effects were due to partial blockade of these systems.

or Placebo

from ?as~line

after ~Ja~oxo~e

Patientsb

Rattles

and MT

ia ~eha~~o~al

r'n~o~~~ Fformal Subjectsa

(A SE!11 Change

1

values represent ~xi~u~ change in measures W-W ~~~~tes after the secolrrfof txlro~aloxo~e i~~~si~n~, n=7 cloven et al, l9lt3b) \faltresrepresent cb~~9e in WastIres W ninutes after the second of two naloxane iflfusions, n-l? ffariot et a?., l~~~a~b~ ~P~o~s~ness~ score retained elevated ~p<*~~) F hours later P~e~~~us~y u~publ~sbed data ~ta~u~~ indicate the probability that differences in scores between doses could have occupied by chance alone based on repeated 17easures analysis of variance

Mean

Table

P. N. Tariot et al.

*RETARDATION

btem)

scores (2 SEfq) after naloxone and placeho Fig. 2. Chanqe from baseiine in mean WRS 12 PAT patients. **p<.O5 compared to placebo by AW'AR with paired comnarisons using Tukey's Honestly S
in

~laloxone Effects in ~~t~~~ts. Two apparent d~s~r~~a~c~es emerge in these behavioral The first is the apparently mixed activating and updating effects of naloxone in our patients with relatively more activation after the lower dose, and mre prominent and longer-lasting sedatSon after the high dose. This is depicted graphically in Fig 2, which compares change from baseline in WRS ratings of activation and retardation as a function fine aspect of the behavioral data in the high dose study of young of dose Sn MT patients. Specifically, %he vigor-activity subscale normals is suggestive of this type of response. of the Profile of Mood States (PnIIS) was found te be increased only at an intermediate dose (Table I). There is some support for this dose-dependent behavioral effect in the animal Arnsten and Segal (1970) found that lower doses (0.5 mg/kg) of nalaxone in mice literature. tended to enhance interaction with environmental stimuli, while high doses (up to 25 mg/kg) Similar dose-response profiles have been reported generally suppressed behavioral activity. fine speculative explanation for such in other animal studies (Arnsten and Seqal, lP79). apparently opposing behavioral effects is that they resulted from variable blockade of For exa~Fle, it may be that the different opioid receptor subclasses at different doses. subclass of kappa receptors (in which normal receptor-~p~oid ligand interaction produces Wxed

data.

Opiate

agonists

in dementia

67.1

sedation) was more completely affected at the low dose of naloxone, while the subclass of sigma receptors (in which normal lioand-receptor interaction normally nroduces stimulation) was more affected at the high dose (Zukin and 7ukin, 1%). This hypothesis could be evaluated more fully by use of specific agonists and antagonists (e.g., for kappa receptors). Altered Sensitivity and nose-Responsiveness. The other apsarent discrepancy in these data is that, despite the similarity between nAT patients and young normal subjects in terms of general behavioral response to naloxone, the two qrouns differ in their behavioral sensitivity and dose-responsiveness to the drug. The threshold dose for analagous behavioral responses was 7o-fold lower in nAT patients (n.I mq/ka versus 7 mg/kq) (Cohen et al., lQQ1, 1983h). The psychomotor activation increased cnnsistently with increasing naloxone dose in young normals, whereas these behaviors decreased somewhat with increasinq dose in PAT natients. This is reoresented in Fiq 3. comoarinq chanqe from baseline in total QPRS scores (as a global estimate'of behavioral effect) as a function of dose in the 3 qroups. 'The mean total BPRS at haseline was 24 for the normals and a4 for the patients; note that the normals did not receive placebo (Cohen et al., lnQ3bJ.l Furthermore, nAT patients experienced fatigue that became more persistent, whereas fatioue was not prominent in the young normal subjects (Table Il.

u

DAT

cF--o

YOUNG

PATIENTS NORMALS

Fig. 3. Change from baseline in mean total QPRS scores (+ SEW) after placebo or naloxone in 12 DAT patients and 7 young normal subjects. **p<.Ol, *~<.I35 comparted to placebo, +p<.nF compared to 0.3 ng/kg dose by AHOYAR with paired comparisons using tukey's Honestly significant llifference.

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The behavioral (as well as cognitive) differences between these 2 groups might be partly It is possible accounted for by differences in age alone, the presence of DAT, or both. that one or more endogenous opioid systems could change in terms of receptor density, location, affinity, or in ligand characteristics, with attendant differential effects of Fxtendinq the receptor postulate above, for example, one could functional blockade. speculate that both kappa as well as sigma receptors become more susceptible to functional blockade in nAT patients, accounting for the increased sensitivity, combined with a relative shift in affinity for sigma receptors, accounting for the sedative effects of naloxone. (This would he supnorted by the finding of sedation in young normal subjects at extremely hiqh doses.) It is also possihle that there are changes in the pharmacokinetics of naloxone with aqe or disease, accounting in part for these croup differences; perhaps even resulting in nonspecificity of effects (i.e., other than opiate blockade1 as a result of hiqher systems levels. Likewise, alterations with ape and/or disease in other neurotransmitter of linked to endoqenous opioid systems may occur, resulting in different manifestations opiate blockade. Reasons for the differential naloxone responsiveness hetween young normal subjects and D9T patients might hecome clearer with studies of aqe-matched controls, which are currently Other pharmacologic studies of the endoqenous opiate systems, under way at our institution. Comparing and contrasting the such as using more selective agents, have been suggested. effects of blockade and enhancement of other neurotransmitter systems to those resulting from manipulation of opioid systems in DAT patients and controls would also be of interest in defining the specificity of behavioral response to selective neurotransmitter modulation, as well as in further delineating the role of opiate-modulating systems in the pathophysiology and symptoms of nAT.

7. Summary In SUPI, the design of this study incorporated features derived from basic considerations The results susqest that the nAT patients studied derived no of endoaenous ooioid svstens. Ne clinical or cognitive ‘benefit from acute naloxone administration'in this dose range. found the apparent paradox of generally activating effects of naloxone at low doses, and In addition, the patients appear to generally more retarding effects at higher doses. differ from young normal subjects (a comparison group which has received high dose naloxone) in their increased sensitivity to naloxone administration, as well as the complex dose The results are consistent with the dependency of their hehavioral response just outlined. general concept of differential sensitivity and dose-responsiveness of different endogennus .Such considerations may he opiate systems within a population and across populations. important in the design and interpretation of other peptidergic studies in PAT. This is For example, Cutler et al. (1085) reported particularly true for dose-finding strateqies. lack of effect of somatostatin in DAT patients but pointed out the limitations of having used a single dose. The possibility remains that the use of different doses might yield different results for this or other peptides.

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