naloxone and Dyskinesia--Drug-Induced

The effects of both opiate agonists and the opiate antagonist naloxone were examined in a rodent model of tardive dyskinesia (TD). Chronic (approximately 20 weeks) administration of fluphenazine resulted in the emergence of vacuous chewing mouth movements (VCMs), a response which may be a useful model for this disorder. Fluphenazine-induced VCMs were not affected by a variety of selective opiate agonists administered intracerebroventricularly, but were potently suppressed by subcutaneous administration of the opiate antagonist naloxone. These findings suggest that increased opiate transmission may contribute to the pathogenesis of TD. Further investigation of the role of opiate antagonists in treating this disorder are warranted.

Topics: Animals; Antipsychotic Agents; Dyskinesia, Drug-Induced; Fluphenazine; Locomotion; Male; Mastication; Naloxone; Narcotics; Rats; Rats, Sprague-Dawley

It is suggested that the antipsychotic efficacy of opioids in patients suffering from schizophrenia may result from an interaction of opioids with the dopaminergic system. The modulatory effect of opioids on dopaminergic functions has already been demonstrated in basic experiments: Anatomical and biochemical data reveal an interaction between opioid receptors and dopamine (DA) actions on dopaminergic nerve terminals, cell bodies, and afferent nerve endings. Endogenous enkephalin levels correlate well with the endogenous dopamine content in various brain areas. Systemic or iontophoretic administration of morphine alters the spontaneous activity of ventral tegmental dopaminergic neurons. Morphine and enkephalin effectively enhance pituitary prolactin release, whereas dopamine inhibits it. Opioid agonists effectively alter DA release, DA reuptake, and DA metabolism in the striatum and substantia nigra. In reverse, chronic neuroleptic treatment enhances the synthesis and release of pituitary beta-endorphin. Opioids affect contralateral rotation elicited by dopamine agonists in animals with unilateral lesions of the nigrostriatal pathway. Phencyclidine, a psychotropic drug that shares certain pharmacological characteristics with the putative sigma-opioid receptor ligand SKF 10,047, indirectly mimics the effects of dopamine agonists on prolactin release, release of acetylcholine, etc. It is suggested that an imbalance of opiate-DA interaction might be involved in the pathogenesis of schizophrenia. Consequently, clinical studies on the effects of opioids on psychotic symptoms should also examine opioid influence on dopaminergic functions in these patients.

Topics: Brain; Corpus Striatum; Dopamine; Dyskinesia, Drug-Induced; Endorphins; Humans; Hypothalamo-Hypophyseal System; Hypothalamus; Morphine; Naloxone; Phencyclidine; Prolactin; Receptors, Dopamine; Receptors, Opioid; Schizophrenia; Substantia Nigra; Synaptic Transmission

Topics: Animals; Brain; Cholecystokinin; Dipeptides; Dopamine; Dyskinesia, Drug-Induced; Endorphins; Female; Humans; Morphine; Naloxone; Neuropeptides; Neurotensin; Neurotransmitter Agents; Peptides; Peptides, Cyclic; Rats; Substance P

Opioid peptide transmission is enhanced in the striatum of animal models and Parkinson's disease (PD) patients with levodopa-induced motor complications. Opioid receptor antagonists reduce levodopa-induced dyskinesia in primate models of PD; however, clinical trials to date have been inconclusive. A double-blind, placebo controlled, crossover design study in 14 patients with PD experiencing motor fluctuations was carried out, using the non-subtype-selective opioid receptor antagonist naloxone. Naloxone did not reduce levodopa-induced dyskinesia. The duration of action of levodopa was increased significantly by 17.5%. Non-subtype-selective opioid receptor antagonism may prove useful in the treatment of levodopa-related wearing-off in PD but not in dyskinesia.

Topics: Antiparkinson Agents; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Dyskinesia, Drug-Induced; Follow-Up Studies; Humans; Levodopa; Naloxone; Narcotic Antagonists; Parkinson Disease; Videotape Recording

Tardive dyskinesia (TD) is thought to result from nigrostriatal dopaminergic supersensitivity secondary to prolonged neuroleptic exposure. Preclinical studies have demonstrated that the opiate antagonist naloxone can acutely reverse a haloperidol-induced hyperdopaminergic state. In a trial of high-dose naloxone, 20 patients with TD received i.v. naloxone (20 mg, 40 mg, and placebo) under double-blind conditions. At baseline and at regular postdrug intervals, patients were evaluated using a battery of motor, clinical, and neuropsychological measures to study effects on neurological, behavioral, and cognitive functions. There was a significant improvement in involuntary movements at 30 min postnaloxone, together with improvement in clinical ratings at that time point, as well as some cognitive changes. The implications of these findings for the putative functional relationship between dopaminergic and enkephalinergic systems in the nigrostriatal area are discussed.

Topics: Adult; Clinical Trials as Topic; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Female; Humans; Male; Mental Recall; Middle Aged; Motor Skills; Naloxone; Problem Solving; Psychological Tests; Random Allocation

Topics: Aged; Clinical Trials as Topic; Double-Blind Method; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Naloxone; Random Allocation

Topics: Clinical Trials as Topic; Double-Blind Method; Dyskinesia, Drug-Induced; Female; Humans; Middle Aged; Naloxone; Time Factors

The subjects were 13 psychiatric inpatients with tardive dyskinesia. Each subject participated in two sessions. Either naloxone (10 mg) or placebo was administered intravenously during each session. In a subset of subjects (n = 7), blood samples for beta-endorphin were drawn before and at 30 and 60 minutes after the injection. The Abnormal Involuntary Movement Scale was administered before and at 10, 20, 40, 60, 120, and 360 minutes after the injection. Double-blind procedures were maintained throughout the experiment. Neither naloxone nor placebo had any appreciable effect on the involuntary movements. Naloxone elicited a significant increase in the plasma beta-endorphin.

Topics: Adult; Affective Disorders, Psychotic; Aged; beta-Endorphin; Dyskinesia, Drug-Induced; Endorphins; Female; Humans; Male; Middle Aged; Naloxone; Psychotic Disorders; Receptors, Dopamine; Schizophrenia

Topics: Animals; Clinical Trials as Topic; Dyskinesia, Drug-Induced; Endorphins; Humans; Mood Disorders; Naloxone; Naltrexone; Rats; Schizophrenia

Eight psychiatric patients with tardive dyskinesia (TD) were treated with single doses of the synthetic met-enkephalin analogue FK 33-824 (1, 2, and 3 mg IM) morphine (10 mg SC) and naloxone, an opiate receptor antagonist (0.8 mg IM). The drug effects were assessed by blind evaluation of randomly sequenced videotapes made before and during treatment. FK 33-824 (1, 2, and 3 mg IM) slightly reduced TD (P < 0.05) and increased preexisting bradykinesia. The effect on TD, however, was pronounced only in patients concurrently treated with neuroleptics in relatively high doses. Morphine had a similar although weaker antihyperkinetic effect, whereas naloxone had no effect. Side effects of FK 33-824 included dizziness, heaviness in the extremities, slurred speech, and dryness of mouth. Morphine caused drowsiness, dizziness, ataxia, and nausea, and naloxone had no side effects. The results do not point to a primary role of enkephalin in the pathophysiology of TD, but enkephalin may interact with dopamine functions and potentiate some of the effects of neuroleptic drugs.

Topics: Aged; Clinical Trials as Topic; D-Ala(2),MePhe(4),Met(0)-ol-enkephalin; Double-Blind Method; Dyskinesia, Drug-Induced; Endorphins; Enkephalins; Female; Humans; Male; Middle Aged; Morphine; Naloxone; Parkinson Disease, Secondary

Repeated exposure to drugs of abuse, such as morphine, elicits a progressive enhancement of drug-induced behavioral responses, a phenomenon termed behavioral sensitization. These changes in behavior may reflect long-lasting changes in some of the important molecules involved in memory processing such as calcium/calmodulin-dependent protein kinase II (CaMKII). In the present study, we investigated the effect of morphine sensitization on mRNA expression of α and β isoforms and activity of CaMKII in the hippocampus of male rats. Animals were treated for 3 days with saline or morphine (20mg/kg) and following a washout period of 5 days, a challenge dose of morphine (5mg/kg) were administered. The results indicate that morphine administration in pre-treated animals produces behavioral sensitization, as determined by significant increase in locomotion and oral stereotypy behavior. In addition, repeated morphine treatment increased mRNA expression of both α and β isoforms of CaMKII in the hippocampus. The present study also showed that induction of morphine sensitization significantly increased both Ca2+/calmodulin-independent and Ca2+/calmodulin-dependent activities of CaMK II in the rat hippocampus. However, acute administration of morphine (5mg/kg) did not alter either α and β CaMKII mRNA expression or CaMKII activity in the hippocampus. The stimulation effects of morphine sensitization on mRNA expression and activity of CaMKII were completely abolished by administration of naloxone, 30min prior to s.c. injections of morphine (20mg/kg/day×3 days). Our data demonstrated that induction of morphine sensitization could effectively modulate the activity and the mRNA expression of CaMKII in the hippocampus and this effect of morphine was exerted by the activation of opioid receptors.

Topics: Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Dyskinesia, Drug-Induced; Hippocampus; Isoenzymes; Male; Morphine; Motor Activity; Naloxone; Narcotic Antagonists; Narcotics; Rats, Wistar; RNA, Messenger; Stereotyped Behavior

Blocking dopamine (DA) receptors in the basal ganglia can cause parkinsonian symptoms, acute dystonia, akathisia, tardive dyskinesia (TD), and neuroleptic malignant syndrome. TD is characterized by abnormal, involuntary, irregular motor movements involving muscles of the head, limbs, or trunk. Many drug therapies have been tried for TD, but none are approved by the U.S. Food and Drug Administration. The second-generation antipsychotic drugs should be considered as a treatment of first choice for clinically significant TD, because they will also be potentially effective as a primary treatment for the underlying disorder. Dopamine-depleting drugs are effective for TD, but their practical use is severely limited because of tolerability and safety concerns. Various DA-modulating drugs have been tried; clinical evidence of efficacy suggests that amantadine (Symmetrel®) and naloxone (Narcan®) are worthwhile to try. Although efficacy evidence for buspirone (Buspar®) in TD is limited, this drug is safe and well tolerated and would be reasonable to try. Bromocriptine (Parlodel®), selegiline (Deprenyl®), and cholinergic-modulating drugs are not considered effective for TD.

Topics: Amantadine; Antipsychotic Agents; Buspirone; Dopamine Agents; Dyskinesia, Drug-Induced; Humans; Movement Disorders; Naloxone; Narcotic Antagonists; Serotonin Receptor Agonists

Although oral administration of L-Dopa remains the best therapy for Parkinson disease, its long-term administration causes the appearance of abnormal involuntary movements such as dyskinesia. Although persistent striatal induction of some genes has already been associated with such pathologic profiles in hemiparkinsonian rats, molecular and cellular mechanisms underlying such long-term adaptations remain to be elucidated. In this study, using a rat model of L-Dopa-induced dyskinesia, we report that activity regulated cytoskeletal (Arc)-associated protein is strongly upregulated in the lesioned striatum and that the extent of its induction further varies according to the occurrence or absence of locomotor sensitization. Moreover, Arc is preferentially induced, along with FosB, nur77, and homer-1a, in striatonigral neurons, which express mRNA encoding the precursor of dynorphin. Given the likely importance of Arc in the regulation of cytoskeleton during synaptic plasticity, its upregulation supports the hypothesis that a relationship exists between cytoskeletal modifications and the longlasting action of chronically administrated L-Dopa.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Adrenergic Agents; AIDS-Related Complex; Amphetamine; Analgesics, Non-Narcotic; Animals; Antiparkinson Agents; Behavior, Animal; Carrier Proteins; Central Nervous System Stimulants; Corpus Striatum; Disease Models, Animal; Drug Interactions; Dynorphins; Dyskinesia, Drug-Induced; Functional Laterality; Homer Scaffolding Proteins; Immunohistochemistry; In Situ Hybridization; Levodopa; Male; Motor Activity; Naloxone; Naltrexone; Narcotic Antagonists; Neurons; Oxidopamine; Protein Precursors; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Stereotyped Behavior; Substantia Nigra; Time Factors; Tyrosine 3-Monooxygenase; Up-Regulation

A patient underwent repair of a thoracoabdominal aortic aneurysm. Epidural morphine, 4 mg, was given for pain relief. After anesthesia, the patient displayed lower extremity paraparesis. This effect was reversed by naloxone. The authors sought to confirm these observations using a rat spinal ischemia model to define the effects of intrathecal morphine administered at various times after reflow on behavior and spinal histopathology.. Spinal cord ischemia was induced for 6 min using an intraaortic balloon. Morphine or saline, 30 microg, was injected intrathecally at 0.5, 2, or 24 h after reflow. In a separate group, spinal cord temperature was decreased to 27 degrees C before ischemia. After ischemia, recovery of motor function was assessed periodically using the motor deficit index (0 = complete recovery; 6 = complete paraplegia).. After ischemia, all rats showed near-complete recovery of function by 4-6 h. Intrathecal injection of morphine at 0.5 or 2 h of reflow (but not at 24 h) but not saline caused a development of hind limb dysfunction and lasted for 4.5 h (motor deficit index score = 4-6). This effect was reversed by intrathecal naloxone (30 microg). Intrathecal morphine administered after hypothermic ischemia was without effect. Histopathological analysis in animals that received intrathecal morphine at 0.5 or 2 h after ischemia (but not at 24 h) revealed dark-staining alpha motoneurons and interneurons. Intrathecal saline or spinal hypothermia plus morphine was without effect.. These data indicate that during the immediate reflow following a noninjurious interval of spinal ischemia, intrathecal morphine potentiates motor dysfunction. Reversal by naloxone suggests that this effect results from an opioid receptor-mediated potentiation of a transient block of inhibitory neurons initiated by spinal ischemia.

Topics: Aged; Analgesics, Opioid; Animals; Aortic Aneurysm, Abdominal; Aortic Valve Stenosis; Constriction; Dyskinesia, Drug-Induced; Female; Humans; Hypothermia, Induced; Injections, Spinal; Male; Morphine; Naloxone; Narcotic Antagonists; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Spinal Cord; Spinal Cord Ischemia; Tissue Fixation; Vascular Surgical Procedures

The pathogenesis of levodopa-induced dyskinesias (LID) still remains obscure. It has been suggested that enhanced opioidergic transmission in striatal output pathways may play a role in the induction of LID. To test this hypothesis, we have investigated the effect of different doses of the opioid receptor antagonists, naloxone and naltrexone on the dyskinetic response to a D1 agonist SKF 82958, a D2 agonist quinpirole and L-3,4-dihydroxyphenylalanine (L-Dopa). We have used six female cynomolgus monkeys rendered parkinsonian by the toxin MPTP and presenting a stable parkinsonian syndrome. All responded to L-Dopa and had developed dyskinesias which were manifested with each dose. The parkinsonian syndrome and dyskinesias were evaluated for each animal and scored after the treatments. Locomotor activity was measured by an electronic motility monitoring system. Our results show that coadministration of naloxone or naltrexone with dopaminergic agents leads to a significant increase in the severity of dyskinesias without noticeable effect on the antiparkinsonian efficacy of the treatment. These results suggest that increased opioidergic transmission in the two major striatal output pathways in monkeys or humans with LID might be an attempt to dampen the effect of abnormal dopaminergic stimulation rather than the cause of dyskinesias.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Benzazepines; Dopamine; Dopamine Agents; Dopamine Agonists; Dyskinesia, Drug-Induced; Endorphins; Female; Levodopa; Macaca fascicularis; Motor Activity; Naloxone; Naltrexone; Narcotic Antagonists; Parkinson Disease, Secondary; Quinpirole; Receptors, Dopamine D1; Receptors, Dopamine D2; Synaptic Transmission

Using in situ hybridization, it was found that subchronic treatment with levodopa/benserazide increased preproenkephalin-A and preproenkephalin-B mRNAs in the dopamine-depleted striatum. In order to examine whether dysfunction of the endogenous opioid system may underlie the development of levodopa-induced dyskinesias, the effect of naloxone, an opioid antagonist, on dyskinesias was investigated in two models of parkinsonism in the common marmoset. MPTP-treated monkeys were administered a daily oral dose of levodopa/benserazide which relieved the parkinsonian symptoms but induced severe and reproducible dyskinetic movements. Naloxone (0.1, 0.2 or 0.5 mg/kg) was given subcutaneously (s.c.) during peak-dose dyskinesia, which reduced the dyskinesias significantly using the highest dose, normalized the motor activity, but did not modify the antiparkinson effect. Unilaterally 6-OHDA -lesioned marmosets received apomorphine s.c., which caused a contralateral turning behavior that could be reduced up to 35 percent by concomitant administration of naloxone. Taken together the present results suggest a possible role for the endogenous opioid system in the pathogenesis of levodopa-induced dyskinesia in primates.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Benserazide; Callithrix; Dopamine; Dopamine Agents; Dopamine Antagonists; Dyskinesia, Drug-Induced; Enkephalins; Female; In Situ Hybridization; Levodopa; Male; Motor Activity; Naloxone; Narcotic Antagonists; Oxidopamine; Parkinson Disease, Secondary; Protein Precursors; RNA; Rotation; Stereotyped Behavior; Sympathectomy, Chemical

Chronic neuroleptic treatment leads to the development of tardive dyskinesia in 20-30% of patients. While the pathogenesis of tardive dyskinesia remains elusive, altered opioid peptide function in striatal projection pathways of the basal ganglia has been implicated. Using a rodent model of vacuous chewing movements induced by chronic neuroleptic administration, we investigated regional involvement of opioid transmission in tardive dyskinesia. We examined the role of dynorphin in the direct striatonigral pathway by infusing nor-binaltorphimine, a selective kappa opioid receptor antagonist, into the substantia nigra pars reticulata. As well, infusions of naloxone (a non-specific opioid receptor antagonist), D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr amide (CTOP; a mu opioid receptor antagonist) or naltrindole (a delta opioid receptor antagonist) into the globus pallidus were used to establish the contribution of the striatopallidal pathway. Chronic fluphenazine treatment (25 mg/kg i.m. every 3 weeks for 18 weeks) resulted in a robust increase in vacuous chewing movements. Infusion of nor-binaltorphimine (5.0 nmol) into the substantia nigra pars reticulata significantly attenuated vacuous chewing movements. Infusion of naloxone (0.5 and 2.0 nmol) into the globus pallidus also significantly attenuated vacuous chewing. Infusion of naltrindole into the globus pallidus blocked vacuous chewing at all doses administered (0.5, 1.0, 2.0 nmol) while CTOP was only effective at the two higher doses. From these results we suggest that increases in dynorphin in the direct striatonigral pathway and enkephalin in the indirect striatopallidal pathway following chronic neuroleptic administration are both likely to contribute to tardive dyskinesia.

Topics: Animals; Dose-Response Relationship, Drug; Dynorphins; Dyskinesia, Drug-Induced; Fluphenazine; Globus Pallidus; Male; Mastication; Naloxone; Naltrexone; Narcotic Antagonists; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Somatostatin; Substantia Nigra

The endomorphins are recently discovered endogenous agonists for the mu-opioid receptor (Zadina et al., 1997). Endomorphins produce analgesia; however, their role in other brain functions has not been elucidated. We have investigated the behavioral effects of endomorphin-1 in the globus pallidus, a brain region that is rich in mu-opioid receptors and involved in motor control. Bilateral administration of endomorphin-1 in the globus pallidus of rats induced orofacial dyskinesia. This effect was dose-dependent and at the highest dose tested (18 pmol per side) was sustained during the 60 min of observation, indicating that endomorphin-1 does not induce rapid desensitization of this motor response. In agreement with a lack of desensitization of mu-opioid receptors, 3 hr of continuous exposure of the cloned mu receptor to endomorphin-1 did not diminish the subsequent ability of the agonist to inhibit adenylate cyclase activity in cells expressing the cloned mu-opioid receptor. Confirming the involvement of mu-opioid receptors, the behavioral effect of endomorphin-1 in the globus pallidus was blocked by the opioid antagonist naloxone and the mu-selective peptide antagonist Cys(2)-Tyr(3)-Orn(5)-Pen(7) amide (CTOP). Furthermore, the selective mu receptor agonist [d-Ala(2)-N-Me-Phe(4)-Glycol(5)]-enkephalin (DAMGO) also stimulated orofacial dyskinesia when infused into the globus pallidus, albeit transiently. Our findings suggest that endogenous mu agonists may play a role in hyperkinetic movement disorders by inducing sustained activation of pallidal opioid receptors.

Topics: Animals; Behavior, Animal; Catalepsy; Cell Line; Colforsin; Cyclic AMP; Dose-Response Relationship, Drug; Drug Administration Routes; Dyskinesia, Drug-Induced; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Globus Pallidus; Humans; Male; Mice; Motor Activity; Naloxone; Narcotic Antagonists; Oligopeptides; Protein Binding; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Somatostatin; Transfection

The opioid antagonist naloxone is widely used in the emergency treatment of nontraumatic coma. Although it is uncommon for serious side effects to result from administration of opiate antagonists, we report that naloxone can have epileptogenic effects in the context of encephalitis. In an experimental model of viral encephalitis, rats infected with Borna disease virus developed myoclonic, generalized clonic, or atonic seizures; behavior arrest; and staring spells when treated with naloxone. These findings suggest a novel neuropharmacologic link, through opioid peptide systems, between epilepsy and encephalitis and disclose a potential contraindication to use of opioid antagonists in nontraumatic coma.

Topics: Animals; Borna Disease; Contraindications; Dyskinesia, Drug-Induced; Encephalitis, Viral; Male; Naloxone; Rats; Rats, Inbred Lew; Seizures

Current treatments for Parkinson's disease (PD) rely on dopamine-replacing strategies, and centre around dopamine precursors (e.g. levodopa) or directly acting dopamine agonists. With long-term therapy these agents lose much of their clinical utility due to the appearance of adverse effects such as dyskinesias and/or a wearing off of efficacy. Although dyskinesias in Huntington's disease, hemiballism and experimental animals are thought to be associated with reductions in amino acid transmission within the lateral and medial segments of the globus pallidus, the neural mechanisms underlying treatment-related dyskinesias in PD are poorly understood. Recent evidence suggests that, within these regions of the brain, the opioid peptides enkephalin and dynorphin, acting at delta and kappa opioid receptors, respectively, can reduce the release of amino acid transmitters. Furthermore, the synthesis of these peptides appears to be enhanced in neurons projecting to the pallidal complex in animal models of PD following repeated treatment with dopamine-replacing agents that also cause dyskinetic adverse effects (e.g. levodopa and apomorphine). In contrast, dopamine receptor agonists such as bromocriptine and lisuride do not cause dyskinetic adverse effects following long-term treatment, and do not elevate peptide synthesis when given de novo. These data, together with recent data on the behavioural effects of opioid antagonists in a rodent model of levodopa-induced dyskinesia in PD, suggest the possibility that antagonists of opioid receptors may prove useful as adjuncts to levodopa. By limiting the severity of dyskinetic adverse effects, these drugs may help extend the time for which the antiparkinsonian effects of such compounds can be usefully exploited.

Topics: Animals; Antiparkinson Agents; Dyskinesia, Drug-Induced; Humans; Levodopa; Naloxone; Narcotic Antagonists; Parkinson Disease

Most antipsychotic medications produce motoric side effects, including parkinsonism and tardive 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.

Topics: Animals; Anti-Dyskinesia Agents; Catalepsy; Dyskinesia, Drug-Induced; Grooming; Haloperidol; Male; Naloxone; Narcotic Antagonists; Rats; Rats, Sprague-Dawley; Stereotyped Behavior; Substance Withdrawal Syndrome

A commonly used animal model for tardive dyskinesia is the oral stereotypy that is expressed by a challenge dose of a dopamine agonist after daily administration of dopamine antagonists (neuroleptics). In the first of two experiments the expression of this dopamine agonist-induced oral stereotypy was prevented by the concomitant administration of the opiate antagonist naloxone. In a second experiment, if the stereotypy was allowed to be expressed, it could be blocked by the administration of naloxone. To the extent that the effects of chronic neuroleptic treatment in rats is a model for tardive dyskinesia, the results suggest that administration of naloxone can both prevent and block the dyskinetic syndrome associated with neuroleptic use.

Topics: Animals; Antipsychotic Agents; Dextroamphetamine; Dyskinesia, Drug-Induced; Haloperidol; Male; Nalidixic Acid; Naloxone; Naphthyridines; Rats; Rats, Inbred F344; Stereotyped Behavior

Chronic L-DOPA treatment of Parkinson's disease frequently leads to the development of motoric overstimulation and hyperkinetic movements. To investigate this problem in the laboratory, rats surgically altered by unilateral 6-hydroxydopamine lesions (6-OHDA) were chronically treated with one L-DOPA (10 mg/kg i.p.) injection per day for 20 days. In this 6-OHDA rotation model, the unilateral dopamine denervation results in a profound contralateral sensory-motor neglect and the animals spontaneously rotate in a direction ipsilateral to the dopamine depleted hemisphere. Initially, the L-DOPA treatment did not alter the response bias but after several weeks, the response bias was reversed and the animals rotated in the formerly akinetic direction, contralaterally, at a significantly higher level. Using this overstimulation effect as an analogue of the clinically observed L-DOPA overstimulation, animals were given naloxone in conjunction with the L-DOPA treatment. Naloxone (0.10, 0.25 and 0.50 mg/kg i.p.) produced a dose related decrease in the L-DOPA induced contralateral rotation. Consistent with an expected selective effect on the L-DOPA induced rotation, a dose related increase in ipsilateral rotation was observed. These results suggest that naloxone can attenuate the overstimulation effect of L-DOPA and that this effect is not attributable to non-specific response suppression effects.

Topics: Animals; Carbidopa; Chromatography, High Pressure Liquid; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Drug Administration Schedule; Dyskinesia, Drug-Induced; Hydroxydopamines; Levodopa; Male; Mesencephalon; Naloxone; Oxidopamine; Parkinson Disease; Rats; Rats, Inbred Strains; Time Factors

Topics: Animals; Dyskinesia, Drug-Induced; Male; Melatonin; Naloxone; Rats; Rats, Inbred Strains

Topics: Aged; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Female; Humans; Naloxone

Topics: Dyskinesia, Drug-Induced; Humans; Levodopa; Male; Middle Aged; Naloxone; Parkinson Disease; Receptors, Opioid

The unilateral microinjection of ACTH 1-24 (20 nmol) into the locus coeruleus (LC) produced a long lasting (2-3 hr) posture asymmetry and movement disorder in all rats tested. This response was readily suppressed by the subsequent local microinjection of an equimolar dose of beta-endorphin or morphine or by the intraperitoneal injection of morphine sulphate (50 mg/kg). Microinjection of naloxone (20 nmol) into the LC produced the above syndrome in a lower percentage of animals. The results support the hypothesis that ACTH peptides and opioids play opposite roles in the control of different brain functions.

Topics: Adrenocorticotropic Hormone; Animals; beta-Endorphin; Cosyntropin; Dyskinesia, Drug-Induced; Endorphins; Locus Coeruleus; Male; Microinjections; Morphine; Naloxone; Posture; Rats; Rats, Inbred Strains

Topics: Adult; Dyskinesia, Drug-Induced; Hallucinations; Humans; Male; Naloxone; Schizophrenia, Paranoid

A woman with a schizophreniform syndrome, drug-induced dyskinetic movements, and partial adrenocortical 21-hydroxylase deficiency was given short-term treatment with naloxone, which ameliorated the psychiatric symptoms and eliminated the dyskinetic movements.

Topics: Adrenal Hyperplasia, Congenital; Adult; Dyskinesia, Drug-Induced; Female; Humans; Naloxone; Psychiatric Status Rating Scales; Psychotic Disorders; Steroid 21-Hydroxylase; Steroid Hydroxylases

Rhesus monkeys with a history of drinking methadone, but presently drug-free, were injected with low doses of methamphetamine (MA). They immediately developed oral dyskinesias resembling the symptoms of tardive dyskinesia in humans, a condition resulting from chronic blockade of striatal dopamine receptors by neuroleptics. Nine of 11 control monkeys failed to develop dyskinesias during prolonged MA administration. A stressful stimulus intensified the MA-elicited oral dyskinesias, an effect analogous to exacerbation of tardive dyskinesias by emotional stress. Control monkeys were then injected with methadone, chlorpromazine, haloperidol, or saline for 45 days. Ten days following this chronic treatment, MA immediately elicted oral dyskinesias in the methadone and chlorpromazine monkeys. Acute administration of the dopaminergic blocking agents chlorpromazine, spiroperidol, and clozapine eliminated MA-elicited dyskinesias, whereas the alpha-adrenergic blocker phentolamine was ineffective. Physostigmine blocked the dyskinesias in 1 of 2 cases. Sedative doses of phenobarbital and diazepam had no effect on oral dyskinesias. These data indicate that chronic treatment with methadone or other dopamine receptor blocking agents leads to receptor supersensitivity to the actions of MA.

Topics: Animals; Chlorpromazine; Clozapine; Diazepam; Dyskinesia, Drug-Induced; Haloperidol; Haplorhini; Humans; Macaca mulatta; Male; Methadone; Methamphetamine; Naloxone; Phenobarbital; Phentolamine; Physostigmine; Spiperone; Stereotyped Behavior