Effects of chronic naloxone administration on vacuous chewing movements and catalepsy in rats treated with long-term haloperidol decanoate

Brain ResearchBulletin,Wol.38, No. 4. pp. 355 363, 1995 1995 ElsevierScienceInc. Printed in the USA.All rightsreserved 0361-9230/95 $950 + .00

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Effects of Chronic Naloxone Administration on Vacuous Chewing Movements and Catalepsy in Rats Treated With Long-Term Haloperidol Decanoate MICHAEL F. EGAN,.1 JENNIFER N. FERGUSON* AND THOMAS M. HYDE1*Neuropsychiatry and ?Clinical Brain Disorders Branches, National Institute of Mental Health, NIMH Neuroscience Research Center at St. Elizabeths, 2700 M.L. King Jr. Ave., S.E., Washington, DC 20032, USA [Received 7 January 1995; Revised and accepted 31 May 1995] dose [231, and association with parkinsonism [29]. This model has been used to investigate potential therapeutic agents for tardive dyskinesia [3,33,59]. The VCM syndrome is associated with increased expression of mRNA for the endogenous opioid peptides enkephalin and dynorphin in striatopallidal and striatonigral neurons, respectively [20]. This suggests that increased neurotransmission involving these opioid peptides may be related to the generation of VCMs and/or catalepsy produced by long-term neuroleptic administration. Previous studies have shown that opioids affect motor activity, oral behavior, and catalepsy. Morphine, a nonspecific agonist, as well as specific delta and mu agonists, produce behavioral activation [13,31, see 16,17 for discussion]. Oral movements, such as stereotyped gnawing and dyskinetic biting, are induced by repeated morphine treatment [2,4], an effect probably mediated by the substantia nigra [45,36]. Catalepsy, on the other hand, can be produced by high doses of morphine [8,24,38,60], or intraventricular dynorphin-(1-13) [27]. These behavioral effects of opioids support the notion [20,36] that increased dynorphin and/ or enkephalin could play an role in the development of the dyskinetic chewing movements of the VCM syndrome and, perhaps, catalepsy during long-term treatment with neuroleptics. Opioids exert complex and at times opposing actions on neuronal systems subserving motor behavior. At least three opiate receptor subtypes, mu, kappa, and delta, mediate these effects through both dopaminergic [39,45] and nondopaminergic mechanisms [5,14a,31,57,48]. The dopamine system is affected in several ways. First, mu and delta agonists increase dopamine release in the nucleus accumbens, leading to motoric activation [32,56, although see 16]. Increased dopamine release is probably due to increased dopamine neuronal firing [25,30,42; see 16 for additional references] from opioid mediated inhibition of GABA intemeurons in the AI0/A9 region [32,35]. Kappa receptor agonists (e.g., endogenous dynorphin), on the other hand, reduce dopamine release. This may be mediated either by receptors in the substantia nigra [50], or inhibitory presynaptic autoreceptors in the nucleus accumbens [28]. Mechanisms underlying the dopamine independent motoric effects of opioids are not as clearly delineated but appear to involve mu and delta receptors in the nucleus accumbens [14a] or kappa receptors [64] in the substantia nigra [44]. The opposing effects of dif-

ABSTRACT: Most antipsychotic medications produce motoric side effects, including parkinsonism and tan:live dyskinesia (TD). Correlates of these behaviors in rats (catalepsy and vacuous chewing movements, respectively) were used as a model to assess the usefulness of chronic naloxone administration in symptom reduction. Previous studies have suggested that increased neurotransmission in the endogenous opioid system modulates neuroleptic-induced motoric side effects. Rats were treated with haloperidol decanoate or vehicle for 27 weeks, and withdrawn for 30 weeks. Subsequently, naloxone (0.5 to 2.0 mg/kg SC twice daily) was given for 5 weeks. Long-term haloperidol treatment produced a syndrome of vacuous chewing movements (VCMs) that persisted during the drug withdrawal period. Catalepsy developed rapidly and also persisted. Naloxone treatment had little effect on VCMs but increased catalepsy scores in both haloperidol and vehicle treated groups. Naloxone reduced rearing and grooming in haloperidol rats while increasing these measures in vehicle treated rats. The results indicate that neuroleptic-induced motoric side effects are not reversed by naloxone in rats. Furthermore, they suggest that increased opioid neurotransmission may not underlie the expression of VCMs. This does not rule out the possibility that endogenous opioid system may be involved in the development of VCMs. To the extent that this animal model is valid, naloxone may not be effective in treating TD and neuroleptic-induced parkinsonism in humans. KEY WORDS: Naloxone, Vacuous chewing movements, Haloperidol, Tardive dyskinesia.

INTRODUCTION Neuroleptic medications produce a variety of unwanted motoric side effects, including tardive dyskinesia and parkinsonism. Treatments for tardive dyskinesia are largely unsuccessful [1]. Long-term administration of haloperidol in rats produces vacuous chewing movements (VCMs) [65]. The VCM syndrome, although controversial [66], is similar to tardive dyskinesia in several important respects, including delayed onset after initiation of treatment [65], persistence following neuroleptic withdrawal [66 for review], suppression with increased neuroleptic To whom requests for reprints should be addressed. 355

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Rating Session (Weeks) FIG. 1. VCM ratings (_+ SE) for haloperidol and vehicle treated groups prior to admanistration of naloxone. Rats were injected with haloperidol decanoate or vehicle every 3 weeks for 27 weeks and then withdrawn for 30 weeks. VCM ratings are significantly increased in haloperidol treated rats compared to controls by Week 12 and remain elevated during the withdrawal period. *p < .05, **p < .005. ferent receptor subtypes in different brain regions may explain why opioid agonists can produce increased motor behavior or catalepsy, depending on factors such as dose, receptor affinity, site of infusion, and duration of treatment. Naloxone, an antagonist for mu, delta, and kappa opioid receptors, reduces both hyperactivity and catalepsy produced by alterations in dopamine and opioid neurotransmission. For example, ldopa and amphetamine induced rotation in unilateral dopamine depleted rats can be blocked by low (0.3 to 3.0 mg/kg SC), but not high (10 to 30 mg/kg) doses of naloxone [10,15]. More relevant to this study, supersensitivity to mu and delta agonists following chronic neuroleptic treatment produces hyperactivity that is blocked by low doses (1.5 mg/kg SC) of naloxone [581. Similarly, oral stereotypies induced by dopamine agonists after chronic haloperidol treatment is blocked by naloxone [49]. Naloxone treatment can also block morphine-induced catalepsy [8,18,27,11]. Other opioid agonists (e.g., levorphanol) increase haloperidol-induced catalepsy, an effect blocked by 2.0 mg/kg of naloxone [55]. Finally, in humans, several reports suggest that naloxone reduces/-dopa induced dyskinesias (2.4 mg IV) [53] and tardive dyskinesia (0.4 mg IV) [9, also see 37]. The seemingly paradoxical effects of naloxone in reducing both hyperactivity and catalepsy may be due to blockade of different receptor subpopulations. Increased dynorphin and enkephalin neurotransmission in striatonigral and striatopallidal neurons, respectively, may play a role in the induction or expression of VCMs and/or catalepsy [20,29,36]. To test this hypothesis, we attempted to reduce these behaviors by administering naloxone to rats following very longterm treatment with haloperidol decanoate.

MATERIALS AND METHODS Animals and Drug Treatment Fifty-eight male Sprague-Dawley rats initially weighing 140-160 g were housed in groups of two with free access to

food and water, a 12-h light-dark cycle (with lights on at 7 a.m. and off at 7 p.m.), and constant temperature (25°C). Animals were initially divided into two groups. The control group (n = 18) received vehicle (provided by McNeil Pharmaceuticals, Spring House, PA), whereas the haloperidol group (n = 40) received intramuscular haloperidol decanoate 28.5 mg/kg (McNeil Pharmaceuticals), the equivalent of 1.0 mg/kg/day of unconjugated haloperidol. Treatments were administered by intramuscular injection (IM) every 3 weeks. After nine injections over 27 weeks, treatment was discontinued. Eight rats in the haloperidol group and seven in the vehicle group died before completion of the study. Data from these animals were not included in the statistical analysis. Thirty weeks after the final injection, rats were divided into two groups. One group received naloxone (0.5 mg/kg SC), whereas the second received vehicle twice daily for 21 days. Following this 3-week treatment period, the naloxone dose was increased on Days 22 to 28 (Week 4) to 1.0 mg/kg, and on Days 29 to 35 (Week 5) to 2.0 mg/kg, twice daily. Of animals receiving naloxone, 16 had previously received chronic haloperidol decanoate (hal/nalox group), whereas 8 had received vehicle injections (veh/nalox group). In the animals receiving vehicle injections, 17 had received chronic haloperidol decanoate (hal/veh group), whereas 7 had received chronic vehicle (veh/veh group). Behavioral Measures For assessment of VCMs, 2-min rating sessions were held from 10 a.m. to 12 noon in the same room in which animals were housed. Rats were transferred from their home cages to uncovered 20 x 30x 40 cm plastic cages located on a rotating platform, allowing raters to observe mouth movements at all times. Habituation periods were not employed because ratings before and after habituation periods are highly correlated. In particular, VCM frequency during a 2-rain period without habituation is similar to that after a l-h habituation period, despite increased

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injection) FIG. 2. Effects of naloxone or vehicle injections on VCM scores (__+SE) in four groups: (a) hal/nalox and hal/veh; (b) veh/nalox and veh/veh. Naloxone treated groups (hal/nalox and veh/nalox) are shown with solid lines, whereas respective vehicle treated control groups (hal/veh and veh/veh) are shown with dashed lines. There were no differences in ratings between hal/nalox and hal/veh, or veh/nalox and veh/veh groups before initiation of naloxone treatment. No significant effect of naloxone treatment was seen over the entire 5-week period. In separate analyses, no effect of naloxone was seen during the first 3 weeks treatment with 0.5 mg/kg or in Week 4 (1.0 mg/kg). In Week 5, however, there is a significant increase in VCM scores in naloxone treated groups.

rearing and exploratory b e h a v i o r seen during the former [21]. During the initial 2 7 - w e e k treatment period, V C M rating sessions (N = 9) were assessed 1 day before injections. Additional rating sessions were held 6, 12, 18, 24, and 30 w e e k s after treatment was discontinued. All V C M ratings were p e r f o r m e d by raters blind to treatment and previous ratings. Interrater reliability, using the intraclass correlation coefficient (ICC) [6], based on 32 joint ratings (n =

3 to 4 per rating period for 10 rating periods), was highly significant ( F = 12.1, df = 31,32, ICC = 0.85, p < .0001). A s previously noted, several types o f vacuous c h e w i n g m o v e m e n t s were o b s e r v e d [23]. Intermittent c h e w i n g m o v e m e n t s that were not directed toward an object and were unrelated to grooming, gnaw ing, or mouthing food were each c o u n t e d as one m o v e m e n t . A s:-cont, type o f j a w m o v e m e n t , bursts o f c h e w i n g often prec e d e d by tremors, was also counted. Each separate c h e w i n g

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FIG. 3. Catalepsy ratings (_+ SE) for haloperidol and vehicle treated groups prior to administration of naloxone. Catalepsy is significantlyincreased in haloperidol treated rats compared to controls by the second rating session, **p < .005. movement in a burst was counted as one VCM. Number of bursts was not included in the data analysis due to the low frequency. Tongue protrusions were occasionally observed but were not rated separately. In addition to VCMs, episodes of rearing and grooming were counted during the 2-min observation periods. These behaviors are elicited by dopamine agonists, particularly D~ agonists, and have been associated with VCMs (14b). For the 5-week naloxone study, all VCM ratings were performed 30 min after injections. Rating sessions were held on Days 1, 7, 14, 21, 28, and 35. Ratings were also obtained on Days 22 (following increase in dose from 0.5 to 1.0 mg/kg) and 29 (following increase in dose to 2.0 mg/kg). In addition, on Days 21, 22, 28, 29, and 35, total number of rearing movements and grooming episodes were counted during the 2 min VCM rating sessions. We looked for, but did not observe, evidence of opioid withdrawal, such as wet dog shakes, teeth chattering, irritability to touch, or diarrhea [7,41]. Catalepsy was assessed six times during the haloperidol decanoate treatment period in the same room in which animals were housed. Rats were rated in their ability to sustain the following paw positions on an elevated platform: both front paws (rated twice), right front paw, left front paw, right rear paw, left rear paw, right front and rear paws together, left front and rear paws together, and both rear paws (rated twice). One point was given for each position maintained for the full 15 s for a maximum total score of 10 [29]. The first rating was held 1 week after the second injection of haloperidol decanoate, corresponding to the second rating session. Subsequent ratings were held 1 week after the next six decanoate injections, during Rating Sessions 3 through 7. One additional rating was performed during the withdrawal period, 3 days before ,the beginning of the naloxone study. During the 5week naloxone study, catalepsy was assessed 30 min after the third injection (Day 2) and again on Days 8, 15, 21, 23, 28, 31, and 34. On days where both VCMs and catalepsy were assessed (i.e., Days 21 and 28), the latter was performed 30 min after the second injection.

analysis of variance (rmANOVA; SuperAnova, Abacus Concepts). To test the hypothesis that naloxone reduced severity of VCMs and catalepsy, a rmANOVA was employed including data from all 5 weeks. Effects of haloperidol and naloxone treatments (main effects) were assessed using repeated rating sessions as the within group measures. Additional analyses using rmANOVAs were performed for each separate drug dose and treatment period alone. Weeks 1-3 included ratings on Days 1-21, Week 4 included ratings from Days 22 and 28, and Week 5 included ratings from Days 29 and 35. Post hoc t-tests (Fisher's protected LSD) were used to compare hal/veh with hal/nalox and veh/veh with veh/nalox groups for ratings within a treatment period. Comparisons between groups for individual rating sessions were made using separate ANOVAs with group as the main effect followed by Fisher's protected LSD. RESULTS

VCMs Over the initial 27-week treatment period, haloperidol administration resulted in a gradual increase in VCMs compared with vehicle treatment that persisted during the withdrawal period (see Fig. 1). Significant effects are present for drug, time, and drug x time interaction (drug treatment effect, /:(1,45) = 23.49, p < .0001; time effect, F(13) = 7.65, df = 13, p < .0001, drug x time interaction, F(13,585) = 2.34, p < .005). Before naloxone treatment, there were no differences in VCM scores between the hal/nalox and hal/veh groups, nor between veh/nalox and veh/ veh groups (Fig. 2a, b). Considering VCM ratings from the entire 35-day study, naloxone treatment had no effect (F(I) = .39, p = .53, see Fig. 2a,b). In separate analyses for each dose, 0.5 mg/kg of naloxone did not affect VCM scores during the initial 3-week treatment period, nor did the 1.0 mg/kg dose during Week 4. VCM ratings during Week 5 (2.0 mg/kg), however, were higher in the naloxone treated groups (F(1) = 4.2, p < .05, Fig. 2a,b).

Statistics

Catalepsy

Effects of haloperidol on VCMs and catalepsy were analyzed for the prenaloxone treatment period using a repeated measures

Haloperidol treatment increased catalepsy scores compared to vehicle prior to naloxone administration (Fig. 3). Significant el-

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FIG. 4. Effects of naloxone or vehicle injections on catalepsy scores (2 SE) in four groups: (a) hal/nalox and hal/veh; (b) veh/nalox and veh/veh. There were no differences in ratings between hal/nalox and hal/veh, or veh/nalox and veh/veh groups at baseline. Considering ratings for the entire 5 weeks, naloxone treatment increased catalepsy scores. In separate analyses, no effect of naloxone was seen in the first 3 weeks during treatment with 0.5 mg/kg. In Weeks 4 (1.0 mg/kg) and 5 (2.0 mg/kg), however, naloxone increased catalepsy scores. *p < .05, **p < .005 for naloxone treated groups compared to appropriate control groups (i.e., hal/veh or veh/veh).

fects are seen for drug treatment, time, and the interaction between drug treatment and time (drug treatment effect, F(1,45) = 50.27, p < .0001; time effect, F(5) = 16.95, p < .0001, drug × time interaction, F(5,225) = 5.04, p < .0002). Prior to beginning naloxone treatment, there were no differences in catalepsy scores between the hal/nalox and hai/veh groups, nor between veh/nalox and vebJveh groups, suggesting that the groups were well matched (Fig. 4a,b). Considering all ratings from Weeks 1 through 5, catalepsy was significantly elevated in groups treated with naloxone (hal/nalox and veh/nalox) (F(1) = 7.14, p = .01). Additional analyses revealed that catalepsy was increased only

in Weeks 4 and 5 (F(1) = 14.78, p < .0004; F(1) = l l . 1 7 , p < .002, respectively), but not during Weeks 1 through 3 (Fig. 4a,b).

Rearing and Grooming Naloxone appeared to reduce episodes of rearing in haloperidol treated rats while increasing them in vehicle treated rats (Fig. 5a,b). Haloperidol and naloxone both tended to affect rearing scores ( F ( I ) = 3.8, p = .06; F(1) = 3.3, p = .08, respectively). A significant interaction between these main effects was seen (F(I) = 14.0, p = .0006). Individual A N O V A s for each day show

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Days of Naloxone T r e a t m e n t FIG. 5. Effects of naloxone or vehicle injections on episodes of rearing (+__SE) in tour groups: (a) hal/nalox and hal/veh; (b) veh/nalox and veh/veh. Naloxone reduced rearing in haloperidol treated animals while increasing them in controls. Group differences were significant for Days 22, 29, and 35. *p < .05 for veh/nalox compared to veh/veh).

group differences for Days 22, 29, and 35 (F(3) = 6.86, p = .0008; F(3) =- 9.25, p = .0001 ; F(3) = 3.1, p =.04, respectively). Naloxone had a similar effect on grooming, reducing counts in haloperidol treated animals while increasing them in controls. Although no effect was found for haloperidol or naloxone treatment alone, a significant interaction was seen (F(1) = 5.0, p = .03). Individual A N O V A s for each day show group differences for Days 22, 28, and 29 (F(3) = 4.52, p = .008; F(3) = 3.3, p = .03; F(3) = 6.4, p = .001, respectively, data not shown). DISCUSSION The results suggest that naloxone does not reduce the motoric side effects of long-term neuroleptic administration. To the con-

trary, catalepsy was increased in the last 2 weeks of naloxone treatment. V C M scores were not reduced. In fact, separate analysis of V C M scores during treatment with 2.0 mg/kg indicate that, if anything, naloxone increased VCMs. It is unclear whether these delayed effects were due to time or increased dose. Naloxone also reduced rearing and grooming in haloperidol treated rats while increasing scores in vehicle treated rats. This interaction effect supports the notion that long-term treatment with neuroleptics alters opioid neurotransmission. It is unlikely that the naloxone-induced increase in catalepsy were due to elevations of haloperidol brain levels. Catalepsy was increased in the vehicle/nalox group compared to the veh/veh group. Furthermore, V C M s are suppressed, not worsened, by in-

EFFECTS OF NALOXONE ON CHEWING MOVEMENTS

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creased haloperidol levels [21,23]. Haloperidol suppression was also found in the current group of rats (data not shown). Thus, at least some of naloxone's effects were probably related to opiate receptor blockade. Nevertheless, we cannot exclude the possibility that increased catalepsy in the hal/nalox group is due to alterations in brain haloperidol levels, even though these levels are very low following a 6-month withdrawal [21]. Although opioid and haloperidol-mediated catalepsy can be distinguished with electromyographic analysis [19] and response to challenge with anticholinergic agents [22], such data was not available in this study. The increased catalepsy scores in veh/nalox and hal/nalox groups appear paradoxical. Prior studies have shown that opioid agonists induce catalepsy, an effect blocked by acute naloxone treatment [8,11,18,27]. The naloxone induced increase in catalepsy observed in this study may be analogous to another paradoxical response mediated by the opioid system, the phenomenon of opioid antagonist-inducedanalgesia. Although acute naloxone lowers pain thresholds, chronic naloxone treatment (e.g., 0.5 rag/ kg/h for 7 days) increases these thresholds [43]. Naloxone's paradoxical analgesic effect is most likely due to an upregulation of mu opioid receptors during long-term blockade [34,46,63]. Mu receptor upregulation may also play a role in the increased cataleptic effect of morphine following chronic naloxone treatment [46]. A similar mechanism could account for increased catalepsy scores in this study. Although we selected doses lower than those that typically produce mu receptor upregulation [43], the duration of treatment was relatively long and could have contributed to delayed supersensitivity. On measures of rearing and grooming, naloxone affected vehicle and haloperidol treated rats differently. These behaviors were reduced in haloperidol treated rats but increased in vehicle treated rats. Earlier studies reported that acute naloxone reduces rearing following injections of dopaminergic or enkephalinergic agonists [26,32]. The differential effects in haloperidol and vehicle treated groups on these measures contrasts markedly with the similar effects on catalepsy scores. This suggests, at the very least, that some aspect of opioid transmission is altered by chronic haloperidol treatment [58] and implies, more specifically, that rearing, grooming, and catalepsy involve different opioid components (see introduction). The failure of naloxone to suppress VCMs suggests that nonspecific opioid antagonists do not reduce neuroleptic induced dyskinesias. Similar to increased catalepsy, the trend toward increased VCM scores during the fifth week was unexpected. The mechanisms underlying this response are unclear, and could involve either opioid or nonopioid systems [e.g., see 40,46,52 for discussion]. It could be argued that the doses of naloxone selected for this study may have been too low to block VCMs. These doses, however, have been shown previously to antagonize a variety of hypermotoric behavioral states associated with increased opioid [31,45,47,55] and dopaminergic neurotransmission [ 10,12,15,17,51,57,58]. This includes apomorphine-induced stereotypies [12], l-dopa and amphetamine induced rotation in unilateral dopamine depleted rats [10,15], gnawing behavior following mu receptor agonist infusion into the substantia nigra [45], and hyperactivity from enkephalin infusion into either the nucleus accumbens or ventral tegmental area [31,47]. Higher doses, on the other hand, may be less effective in blocking amphetamine and apomorphine induced hyperactivity and turning behavior (following unilateral dopamine depletion) [15,26]. A relatively narrow range for naloxone's antagonistic effects on dopamine mediated behaviors has been reported previously [51, although see 17]. Thus, although it is possible that higher doses

would have reduced VCM scores, previous studies suggest that they would not. The failure of naloxone to suppress VCMs raises questions about the role of elevated striatal and nucleus accumbens' dynorphin and enkephalin mRNA in the VCM syndrome [20]. Increased mRNA of these endogenous opioids may be an epiphenomena unrelated to the pathophysiology of the VCM syndrome. Alternatively, the nonspecificity of SC naloxone could account for these results. Selective mu or kappa antagonists applied to a specific region, such as the substantia nigra, might exert greater behavioral effects than nonselective blockade alone. Thus, we cannot exclude the possibility that the generation of VCMs is directly mediated by mu or kappa neurotransmission in a specific region of the basal ganglia. If endogenous opioids do not play a role in the generation of VCMs, they could play a role in the initiation of this syndrome. This process might involve long-term effects that are not easily reversed by short-term treatment with opioid antagonists. The neurobiological feasibility of this notion is supported by a variety of studies. For example, chronic administrationof opioid agonists produces behavioral sensitization. That is, increasing behavioral activation is elicited in rats with repeated administration of opioids (or stimulants). Behavioral sensitization appears to be initiated at the level of the dopamine cell body and is mediated by both Dj receptors and endogenous opioids [32]. Interestingly, opioid antagonists can prevent the development, but not the expression, of behavioral sensitization [32]. A similar process could occur during chronic neuroleptic treatment. Persistent elevations in dopamine release during neuroleptic treatment could increase activity of the Drmediated striatonigral pathway [20], resulting in changes analogous to those seen with behavioral sensitization, These changes would not, then, be normalized with short-term treatment with naloxone. If this model is correct, it may be possible to block the development of VCMs by the concurrent administration of D~ or opioid antagonists. In summary, we have investigated the behavioral effects of chronic naloxone treatment in rats administered long-term haloperidol decanoate or vehicle. We attempted to block VCMs and catalepsy induced by neuroleptic exposure. A number of previous studies have suggested that opiates play a role in regulating oral behavior and catalepsy in rats. The results show that naloxone does not reduce VCM scores and increased catalepsy. These findings, in part paradoxical, may be due to naloxone-induced opiate receptor supersensitivity. The results imply that naloxone may not be effective in treating tardive dyskinesia in humans.

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