Melatonin treatment for tardive dyskinesia: a double-blind, placebo-controlled, crossover study.

BACKGROUND: Antipsychotics remain the mainstay of drug intervention in the management of schizophrenia. However, long-term treatment with antipsychotics is associated with a variety of movement disorders, the most disabling of which is tardive dyskinesia (TD), which occurs in up to 50% of patients hospitalized with chronic schizophrenia. The pathophysiology of TD is still unclear and no definite treatment exists. Both dopamine receptor supersensitivity and oxidative stress-induced neurotoxicity in the nigrostriatal system are apparently implicated. The pineal hormone melatonin is a potent antioxidant and attenuates dopaminergic activity in the striatum and dopamine release from the hypothalamus. Thus, it may have a beneficial effect for both the treatment and prevention of TD. METHODS: Using a double-blind, placebo-controlled, crossover study, we evaluated the efficacy of 10 mg/d of melatonin for 6 weeks in 22 patients with schizophrenia and TD. The primary outcome measure was the change from baseline in Abnormal Involuntary Movement Scale (AIMS) score. RESULTS: The decrease (mean +/- SD) in AIMS score was 2.45 +/- 1.92 for the melatonin and 0.77 +/- 1.11 for the placebo treatment groups (P<.001). No adverse events or side effects were noted. CONCLUSION: This is the first clinical evidence for efficacy of melatonin in the treatment of TD.

The latent inhibition model of schizophrenia: further validation using the atypical neuroleptic, clozapine.

Latent inhibition (LI) refers to retarded conditioning to a stimulus that has been repeatedly presented without reinforcement. LI is impaired in schizophrenia patients and in rats treated with amphetamine. Neuroleptic drugs produce two effects in this test paradigm: antagonism of amphetamine-induced disruption of LI, and enhancement of LI when administered on their own. The present experiments tested the effects of the atypical neuroleptic, clozapine, on LI. The experiments used a conditioned emotional response procedure in rats licking for water, consisting of three stages: preexposure, in which the to-be-conditioned stimulus (tone) was repeatedly presented without reinforcement; conditioning, in which the preexposed stimulus was paired with reinforcement (foot shock); and test, in which LI was indexed by animals' degree of suppression of licking during tone presentation. In experiments 1 and 2, the effects of 5.0 and 10.0 mg/kg clozapine on LI were assessed following 20 or 10 tone preexposures, respectively. Experiments 3 and 4 used 40 preexposures and investigated antagonism of amphetamine-induced disruption of LI by 5.0 and 10.0 mg/kg clozapine, respectively. The results demonstrated that clozapine possesses a neuroleptic profile in the LI model, namely, it facilitates the development of LI and antagonizes amphetamine-induced disruption of LI.

Basolateral amygdala lesions do not disrupt latent inhibition.

Latent inhibition (LI) is a measure of retarded conditioning to a previously presented non-reinforced stimulus that is impaired in schizophrenic patients and in rats treated with amphetamine, and is restored in both by neuroleptic drugs. In terms of neural substrates, LI depends on the integrity of the nucleus accumbens (NAC) and the inputs to this structure from the hippocampal formation and adjacent cortical areas. The present experiments investigated the effects of electrolytic lesions to the basolateral amygdala (BLA), which is another major source of input to the NAC, on the LI effect. LI was assessed in a conditioned emotional response (CER) procedure in rats licking for water, consisting of three stages: pre-exposure, in which the to-be-conditioned stimulus (a tone) was repeatedly presented without being followed by reinforcement; conditioning, in which the pre-exposed stimulus was paired with reinforcement (a foot shock); and test, in which LI was indexed by the animal's degree of suppression of licking during tone presentation. In Expt. 1, which used a lesion at a more posterior location, no effect on either LI or CER conditioning was seen. In Expt. 2, lesion at a more anterior location reduced the magnitude of CER conditioning in both the pre-exposed and the non-pre-exposed animals, but left the LI effect intact. The latter lesion did not affect spontaneous and amphetamine-induced activity (Expt. 3). These results suggest that the development of LI is not dependent on the amygdalar input to the NAC, but that the input from the anterior aspects of BLA to the NAC is involved in the establishment of stimulus-reinforcement associations.

Fimbria-fornix cut affects spontaneous activity, two-way avoidance and delayed non matching to sample, but not latent inhibition.

Latent inhibition (LI) consists of a decrement in conditioning to a stimulus as a result of its prior nonreinforced preexposure. Based on evidence pointing to the involvement of the hippocampus and the nucleus accumbens (NAC) in LI disruption, it has been proposed that LI depends on the integrity of the subicular input to the NAC. Since fibers originating in the subiculum and destined for the NAC run through the fimbria-fornix, we assessed the effects of fimbria-fornix lesion, made using a knife cut, on LI. In addition, we assessed the effects of the fimbria-fornix cut in three tests known to be sensitive to lesions to the hippocampal region, namely, spontaneous activity, two-way active avoidance and delayed-non-matching-to-sample. In accord with previously documented effects of lesions to the hippocampus and related structures, the fimbria-fornix cut increased spontaneous activity (Experiment 1), facilitated the acquisition of two-way active avoidance (Experiment 3), and produced a delay-dependent deficit in the delayed-non-match-to-sample task (Experiment 4), demonstrating that it disrupted hippocampal functioning. In contrast, LI remained unaffected by the fimbria-fornix cut (Experiment 2), indicating that disruption of subicular input to the NAC is not responsible for the attenuation of LI following non-selective hippocampal lesions. The implications of these results for the neural circuitry of LI are discussed.

Effects of electrolytic lesions of the medial prefrontal cortex or its subfields on 4-arm baited, 8-arm radial maze, two-way active avoidance and conditioned fear tasks in the rat.

The present study tested the effects of electrolytic lesions in two mPFC subregions, the dorsal anterior cingulate area (dACA) and prelimbic cortex, as well as the effects of a larger medial prefrontal cortex (mPFC) lesion which included both subregions, on 4-arm baited, 4-arm unbaited, 8-arm radial maze task and its reversal (Experiments 1 and 4), two-way active avoidance (Experiments 2 and 5) and conditioned emotional response (Experiments 3 and 6). Rats with large or small lesions of the mPFC learned the location of the 4 baited arms in the training and reversal stages of the radial maze task similarly to sham rats, indicating that these lesions did not affect animals' capacity to process and remember spatial information. dACA and mPFC lesions produced a transient deficit in the acquisition of the radial maze task, suggestive of an involvement of these regions in mnemonic processes. However, in view of the normal performance of these groups by the end of training and during reversal, this deficit is better interpreted as stemming from a difficulty to learn the memory-based strategy used to solve the task. Only mPFC lesion led to better avoidance performance at the beginning of training and tended to increase response during the presentation of a stimulus previously paired with shock, compared to sham rats. Both effects can be taken as an indication of reduced emotionality following mPFC lesion. The results are discussed in relation to known behavioral functions of the mPFC and the suggested functional specialization within this region.

Electrolytic lesion of globus pallidus ameliorates the behavioral and neurodegenerative effects of quinolinic acid lesion of the striatum: a potential novel treatment in a rat model of Huntington's disease.

Bilateral electrolytic pallidal lesion ameliorated the deleterious effects of bilateral quinolinic acid (QA) lesion to the striatum on post-surgery weight, activity level, and performance in a water maze task, and reduced the extent of striatal damage. Given that the neurodegenerative and behavioral effects of QA striatal lesion are thought to mimic those seen in Huntington's disease, these results may point to a potential novel treatment for this disease.

Compliance to naltrexone treatment after ultra-rapid opiate detoxification: an open label naturalistic study.

Studies have found that naltrexone, a long-acting opiate antagonist, owing to poor patient compliance, is of limited value in preventing relapse. The current study investigates compliance with a 9-month course of naltrexone (25-50 mg daily) given with counseling after ultra-rapid opiate detoxification which uses clonidine and naltrexone under general anesthesia. Eighty-three of 113 randomly selected patients (out of 640), who were detoxified more than 1 year prior (average 1.5 years), responded to phone interviews. Phone questionnaire asked about patients' compliance with naltrexone, counseling and drug use since detoxification. Similar interviews were also conducted with patients' significant other. Non-relapse patients (n = 47, 57%) took naltrexone an average of 2 months longer than did relapse patients (n = 36, 43%). About half of the non-relapse patients completed at least 5 months of naltrexone, 30% completed at least 7 months and about 20% completed 9 months. Fifty-five percent of the relapse patients stopped using naltrexone by the end of the 3rd month, and by the end of 7th month 10% continued to take it. After the first 2 months the decline in naltrexone compliance was about the same for relapse and non-relapse patients. These results are more encouraging about the use of naltrexone for relapse prevention than previous studies. This method of using naltrexone should be further tested in prospective random assignment controlled studies.

Epileptogenic activity in the amygdala is not affected by the amidine steroid, R 5135.

The synthetic steroid amidine 3-alpha-hydroxy-16-imino-5-beta-17aza androstan-11-one (R 5135) is known to elicit long-lasting spiking in the cortex in the presence of neocortical damage. R 5135 administered to amygdaloid-kindled and naive rats resulted in regular, high-amplitude spiking in the cortex but only occasionally elicited small-amplitude spikes in the amygdala (AMY) and hippocampus (HPC). Interictal spikes from the AMY of kindled rats were not synchronized with cortical spikes induced by the steroid. Given that R 5135 is known to be a GABAA receptor antagonist, these findings suggest that GABAA receptors in AMY and HPC may have lower affinity for 3 alpha-hydroxysteroids.

The effects of the new antipsychotic, sertindole, on latent inhibition in rats.

Latent inhibition (LI) is a measure of retarded conditioning to a previously presented non-reinforced stimulus, that is impaired in schizophrenic patients and in rats treated with amphetamine. Neuroleptic drugs are known to produce two effects in this paradigm: to antagonize amphetamine-induced disruption of LI, and to facilitate the development of LI when administered on their own. The present experiments tested the effects on LI of the new neuroleptic, sertindole. The experiments used a conditioned emotional response procedure in rats licking for water, consisting of three stages: pre-exposure, in which the to-be-conditioned stimulus (a tone) was repeatedly presented without being followed by reinforcement; conditioning, in which the pre-exposed stimulus was paired with reinforcement (a foot shock); and test, in which LI was indexed by degree of suppression of licking during tone presentation. In Experiment 1 the effects of 0.31, 1.3 and 5.0mg/kg sertindole were assessed following pre-exposure to 40 non-reinforced tones. Experiment 2 tested the effects of 5mg/kg on LI following pre-exposure to 10 non-reinforced tones. Experiment 3 investigated antagonism of amphetamine-induced disruption of LI by 5.0mg/kg sertindole. The results demonstrated that sertindole (5.0mg/kg) possesses a neuroleptic-like profile in the LI model: it facilitates the development of LI and antagonizes amphetamine-induced disruption of LI.

The effects of chronic administration of ceronapril on the partial reinforcement extinction effect and latent inhibition in rats.

Previous experiments showed that acute administration of the angiotensin converting enzyme (ACE) inhibitor, ceronapril, shares with neuroleptic drugs an ability to enhance latent inhibition (LI), which consists of retardation in conditioning to a stimulus as a consequence of its prior non-reinforced pre-exposure. Experiment 1 tested whether ceronapril would produce a neuroleptic-like effect in the partial reinforcement extinction effect (PREE) at one trial a day. The PREE refers to the increased resistance to extinction observed in animals trained on a partial reinforcement (PRF) schedule compared with those trained on a schedule of continuous reinforcement (CRF). Two groups of rats were trained to run in a straight alley. The CRF group received food reward on every trial. The PRF group was rewarded on a quasi-random 50% schedule. All animals were then tested in extinction in which no reward was given. Ceronapril at a dose of 0.05mg/kg was administered in a 2 x 2 design, with drug or no drug in acquisition and drug or no drug in extinction. Rats receiving vehicle in acquisition showed a PREE, regardless of their drug treatment in extinction. In contrast, ceronapril administered in acquisition attenuated the PREE irrespective of drug treatment in extinction, by both increasing resistance to extinction in CRF animals and decreasing resistance to extinction in PRF animals. This pattern of results does not resemble that produced by neuroleptics. The PREE procedure necessitated repeated administration of ceronapril whereas the previous demonstrations of neuroleptic-like enhancement of LI have been obtained with acute administration. Experiment 2 therefore tested the effects of chronic ceronapril administration on LI. Under these conditions, ceronapril abolished LI. The results are discussed in relation to the antipsychotic, anti-anxiety and cognitive-enhancing effects formerly attributed to ACE inhibitors.

A steroid derivative (RU 5135) exhibits epileptogenicity in the presence of deficient blood-brain barrier.

A hypothesis was tested that epileptic spiking, induced by systemic administration of a steroid derivative (RU 5135), may be associated with surgery-related cortical damage rather than epileptogenicity of the agent. Cumulative doses of the drug were given to rats and rabbits. The lasting quasi-periodic seizure discharges were always seen initially only under an epicortical electrode implant. Brain damage in inflicted by such an electrode was confirmed anatomically (by assessing the area of lesion) and noninvasively (by showing contrast-induced enhancement of CT brain images in the hemisphere homolateral to epicortical electrodes). The threshold of epileptic spiking varied inversely with the area of cortical damage inflicted by the electrode. In a number of cases no spiking was obtained from the hemisphere with nonpenetrating (intraosteal) electrodes. We caution that a breach of the BBB caused by conventional surgery in rodents can make a benign drug appear as excessively toxic thereby discrediting potentially useful compounds.

Amphetamine-induced disruption of latent inhibition is not reinforcer-mediated.

Latent inhibition (LI) refers to retarded conditioning to a stimulus that had been repeatedly preexposed without consequences, as compared with a nonpreexposed stimulus. Amphetamine disrupts LI, and this effect was suggested to result from enhanced switching to respond according to the stimulus-reinforcer contingency. Recently, it has been argued that amphetamine disrupts LI by increasing the impact of the reinforcer. This implies that amphetamine should produce stronger conditioning in the nonpreexposed group and that its influence on LI can be modified only by changing reinforcer parameters. We report two studies, using an off-baseline conditioned emotional response procedure in rats licking for water, that question both predictions. In the first study, a meta-analysis based on 23 replications of the effect of amphetamine on LI, using tone as the preexposed stimulus, showed that LI is significantly attenuated due to drug-induced increased suppression in the preexposed groups only. The second study included two experiments, each using two shock intensities but different preexposed stimuli. Amphetamine disrupted LI at both shock intensities when the stimulus was a steady light, but this effect disappeared when the stimulus was three flashing lights. Thus, the effect of amphetamine could not be modified by manipulating shock intensity, but was modifiable by manipulating the nature of the preexposed stimulus. The results are inconsistent with the hypothesis that amphetamine-induced disruption of LI is solely mediated by drug-induced changes in the effects of reinforcers.

Factors associated with self-evaluated severity of illness and quality of life in male Israeli asthmatic soldiers.

OBJECTIVE: To evaluate whether the asthmatic condition and quality of life of male asthmatic Israeli soldiers deteriorate during army service. METHOD: We retrospectively assessed 178 asthmatic soldiers during service using an adapted version of the Mini Asthma Quality of Life Questionnaire, and compared it to their condition before service. The participants responded additionally to questionnaires assessing psychosocial resources and adjustment to illness. RESULTS: The self-evaluated degree of asthma disease severity (SEDOAD) of the participants deteriorated in the army compared to before service. Soldiers with mild SEDOAD during service, compared to soldiers with severe (and in most cases also moderate) SEDOAD, had less severe medically evaluated and self-evaluated asthma before service. Mild SEDOAD participants showed, additionally, lower inclination towards active seeking of asthma-related information, more favorable health care-related attitudes, less unfavorable effects of their illness on military and extra-military functioning, greater reported pre-enlistment optimism, and a greater belief in their ability to cope successfully with their asthma during service. CONCLUSION: SEDOAD and the quality of life during service are associated not only with pre-enlistment asthma severity, but also with the manner in which the soldier perceives the influence of the illness on his health condition, and the manner in which he copes with this influence.