Oral Dyskinesias and striatal lesions in rats after long-term co-treatment with haloperidol and 3-nitropropionic acid

The pathophysiologic basis of tardive dyskinesia remains unclear. It has been proposed that tardive dyskinesia may be a result of excitotoxic neurodegeneration in the striatum caused by a neuroleptic-induced increase in striatal glutamate release and impaired energy metabolism. To investigate this hypothesis, haloperidol decanoate (38 mg/kg/four weeks intramuscularly) and the succinate dehydrogenase inhibitor 3-nitropropionic acid (8 mg/kg/day via subcutaneous osmotic mini-pumps), were administered alone or together for 16 weeks to four-months-old rats. Control rats received sesame oil intramuscularly and had empty plastic tubes subcutaneously. Vacuous chewing movements, a putative analogue to human tardive dyskinesia, were recorded during and after drug treatment. Haloperidol alone, 3-nitropropionic acid alone, and 3-nitropropionic acid+haloperidol treatments induced an increase in vacuous chewing movements. However, vacuous chewing movements were more pronounced and appeared earlier in rats treated with 3-nitropropionic acid+haloperidol. After drug withdrawal, increases in vacuous chewing movements persisted for 16 weeks in the haloperidol alone and 3-nitropropionic acid+haloperidol group and for four weeks in the 3-nitropropionic acid alone group. Brains from each group were analysed for histopathological alterations. Bilateral striatal lesions were present only in rats with high levels of vacuous chewing movements in the 3-nitropropionic acid+haloperidol-treated rats. Nerve cell depletion and astrogliosis were prominent histopathologic features. There was selective neuronal sparing of both large- and medium-sized aspiny striatal neurons. These results suggest that mild mitochondrial impairment in combination with neuroleptics results in striatal excitotoxic neurodegeneration which may underlie the development of persistent vacuous chewing movements in rats and possibly irreversible tardive dyskinesia in humans.     

Reduction of stereotyped behavior in profoundly retarded individuals

High-frequency, stereotyped behavior may interfere with the acquisition of appropriate behavior. Through the use of a procedure involving access to vibratory stimulation and its response-contingent withdrawal, stereotyped behavior of two profoundly retarded students was virtually eliminated. A reversal design, employed in Experiment 1, demonstrated that the nonoccurrence and the occurrence of stereotypic hyperventilation was a function of the presence or absence of the intervention procedure. In Experiment 2, a multiple-baseline design provided evidence that the procedure repeatedly produced suppression of stereotyped mouthing across three settings in which it was employed. The observed level of suppression was similar to that typically achieved by contingent application of aversive stimulus procedures. In addition, the procedures seemed to be learned quickly by teachers and administered effectively by public school personnel.     

The effect of aging on the response of striatal preproenkephalin and preprotachykinin mRNA contents to chronic haloperidol treatment in rats: measurement by solution-hybridization RNase protection assay

In this retrospective study on Kienb?ck's disease, a comparison was made between 21 cases operated on by various techniques and 22 cases treated conservatively, with a mean follow-up of 65 months. Operative management of the disease did not show any superiority over conservative treatment. Moreover, surgery was responsible for a loss of mobility of 24%, and for a change in social activities in about a quarter of the patients, while grip strength was only slightly improved. Surgical indications for Kienb?ck's disease should be carefully considered, keeping in mind their side-effects, and the relative benignity in some cases of the natural course of the disease.     

Effect of chronic haloperidol treatment on synaptic protein mRNAs in the rat brain

Chronic haloperidol treatment caused significant decreases in the levels of synaptotagmin I and IV, synaptobrevin II, syntaxin 1A and Rab 3A mRNAs in the nucleus accumbens but not in the prefrontal cortex medial field, striatum, substantia nigra and ventral tegmental area. No significant changes in SNAP 25 and synaptophysin mRNA levels were observed in any brain region examined. The reduced expression of synaptic proteins may be related to haloperidol-induced depolarization block of mesolimbic dopamine neurons.     

Gestational exposure to cocaine or pharmacologically related compounds: effects on behavior and striatal dopamine receptors

Gestational cocaine (COC) exposure has been reported to alter behavior and possibly dopamine (DA) receptors. In this paper, we further examined the effects of prenatal COC (40 mg/kg, s.c.) on DA receptor binding and the behavioral response to quinpirole, a DA D2 receptor agonist. In an attempt to elucidate possible mechanisms of such effects, we exposed pregnant dams to specific reuptake blockers; fluoxetine 12.5 mg/kg, a serotonin reuptake blocker; desipramine 10 mg/kg, a norepinephrine reuptake blocker; GBR-12909 10 mg/kg, a DA reuptake blocker; or to a local anesthetic, lidocaine 40 mg/kg. Drugs were administered once daily over gestational days 8-20. Control dams were injected with saline (SAL) or pair-fed to the COC group. Quinpirole challenge was performed in the offspring on post natal day 19. Two pups per litter were injected (s.c.) with 0.03 or 0.09 mg/kg quinpirole-HCl on post-natal day 19. The remaining pups in each litter were sacrificed for analysis of striatal DA receptors. Results showed that only COC exposure altered the behavioral response to the quinpirole challenge by increasing quinpirole-induced stereotypy and motor activity relative to SAL controls. DA receptor analysis showed no alteration in K(D) or B(MAX) for striatal D1 or D2 sites in any group. These results suggest that prenatal COC exposure produces alterations in function of the D2 receptor complex which are not reflected in K(D) or B(MAX) and that these effects are not fully mimicked by exposure to specific monoamine reuptake blockers or a local anesthetic.     

Different effects of subchronic clozapine and haloperidol on dye-coupling between neurons in the rat striatal complex

Atypical antipsychotic drugs, such as clozapine, are distinguished from classical antipsychotics (e.g. haloperidol) by their lower liability for producing motor side-effects. Although initial studies suggested that the clinical efficacy of antipsychotic drugs is related to their affinity for the D2 dopamine receptor, the delayed onset of both the therapeutic effects and the extrapyramidal symptoms associated with these drugs implicates a more complex mechanism of action. In this study, we found that continuous (but not acute) treatment of rats with either drug caused an increase in dye coupling between neurons in the limbic component of the rat striatal complex (i.e. the shell region of the nucleus accumbens) after withdrawal of the drugs. Furthermore, continuous treatment with haloperidol, but not clozapine, also increased dye coupling in the motor-related part of the striatal complex (i.e. the dorsal striatum). Thus, both therapeutically effective drugs show a delayed effect on dye coupling between neurons in the accumbens shell, whereas only the drug associated with motor side effects altered coupling between cells in the dorsal striatum. Antipsychotic drugs may therefore alleviate the profound disturbances in cognitive function of schizophrenics by producing sustained alterations in the way signals from the cortex are integrated within these brain regions.     

Effect of dopamine-depleting brain lesions in rat pups: Role of striatal serotonergic neurons in behavior.

Previous results from our laboratory have demonstrated that 3-day-old rats given dopamine (DA) -depleting brain lesions are spared the severe behavioral dysfunctions seen after comparable brain damage in adults. This behavioral sparing is accompanied by a sprouting of serotonin (5-HT) -containing neurons in the striatum. The present results extend these observations by demonstrating that rats given the brain lesions as 15- or 27-day-olds continue to suckle, wean, and grow into adulthood without exhibiting any obvious behavioral dysfunctions, yet striatal 5-HT levels do not increase. Moreover, combined destruction of DA- and 5-HT-containing neurons in 3-day-old rat pups also produced no obvious behavioral dysfunctions. These and other results indicate that increases in striatal 5-HT are not necessary for the behavioral sparing observed after DA-depleting brain lesions in neonatal rats. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Inhibition by memantine of the development of persistent oral dyskinesias induced by long-term haloperidol treatment of rats

The effects of ginsenoside-Rh1 and Rh2 in the induction of nitric oxide (NO) synthesis by IFN-gamma plus LPS were investigated using murine peritoneal macrophages. The NO production from rIFN gamma plus LPS-treated macrophages was markedly reduced by ginsenoside-Rh1 or Rh2 in a dose dependent manner, but had no inhibitory effects by ginsenoside-Rb1, Rc or Re. In addition, treatment of the cells with ginsenoside-Rh2 6 hr before the stimulation with IFN-gamma plus LPS showed more inhibitory effect than the treatment with ginsenoside-Rh2 6 hr after or simultaneously with the stimulation with IFN-gamma plus LPS in the NO production. Ginsenoside-Rh2 also effectively inhibited IFN-gamma induced NO production when the cells were treated with IFN-gamma 6 hr after the treatment with ginsenoside-Rh2. Our findings suggest that this phenomenon might be caused by inhibition of priming signal such as IFN-gamma for the synergistic induction of NO synthesis.     

GM1 ganglioside attenuates the development of vacuous chewing movements induced by long-term haloperidol treatment of rats

Tardive dyskinesia (TD) is a serious side-effect of long-term treatment with neuroleptics. To investigate if TD may be a result of neuroleptic-induced excessive stimulation of striatal glutamate receptors, the effect of the anti-excitotoxic GM1 ganglioside was studied in a rat model of TD. In an acute experiment each of four groups of rats was treated with GM1 20 mg/kg SC+saline IP, saline SC+haloperidol 1.2 mg/kg IP, GM1 SC+haloperidol IP, or saline SC+saline IP. In a subsequent long-term experiment lasting 16 weeks, each of the four groups was treated as in the acute experiment, with the exception that haloperidol was injected IM as decanoate 38 mg/kg every 4 weeks, and the controls received vehicle injections. The behavior was videotaped and scored at intervals during both experiments, including 16 weeks after cessation of the long-term treatment. Haloperidol induced a significant increase in vacuous chewing movements (VCM) and immobility both in the acute and in the long-term experiment. Other categories of behaviour (rearing, moving, sitting) were significantly affected only in the acute experiment. GM1 did not affect any of the acute behavioural effects of haloperidol, but significantly reduced VCM in the long-term experiment. The effects on VCM of haloperidol and GM1 persisted for at least 8 weeks after cessation of the long-term treatment. These results suggest that long-lasting changes in striatal function induced by excessive glutamate receptor stimulation may be a mechanism for the development of VCM in rats and perhaps also for TD in humans.     

Effects of amphetamine and haloperidol on avoidance behavior and exploratory activity

The effect of graded doses of D-amphetamine and haloperidol were tested on retention of a one trial learning passive avoidance response, on extinction of pole-jumping active avoidance behavior and on open-field activity. Low doses of amphetamine (10 microgram/animal) increased passive avoidance latency when given s.c. 1 h prior to the retention test. Higher doses (20 and 1000 microgram/animal) caused a bimodal distribution of avoidance latencies. Haloperidol (0.03 or 1.0 microgram/animal) significantly attenuated passive avoidance behavior. Amphetamine caused a delay of extinction of pole-jumping avoidance behavior in a dose-dependent manner (10, 30 or 90 microgram per rat). Conversely, haloperidol induced a dose-dependent facilitation of extinction (0.03 or 0.1 microgram per rat). Open-field activity was not significantly affected by 30 microgram amphetamine or 0.03 microgram haloperidol; 90 microgram amphetamine significantly increased rearing activity and 0.1 microgram haloperidol decreased ambulation. The data show that passive and active avoidance behavior are sensitive measures to test the activity of psychomotor stimulant and neuroleptic drugs. Exploratory behavior allows more specific behavioral effects to be dissociated from locomotor influences.     

A mechanistic account of striatal dopamine function in human cognition: Psychopharmacological studies with cabergoline and haloperidol.

The authors test a neurocomputational model of dopamine function in cognition by administering to healthy participants low doses of D? agents cabergoline and haloperidol. The model suggests that DA dynamically modulates the balance of Go and No-Go basal ganglia pathways during cognitive learning and performance. Cabergoline impaired, while haloperidol enhanced, Go learning from positive reinforcement, consistent with presynaptic drug effects. Cabergoline also caused an overall bias toward Go responding, consistent with postsynaptic action. These same effects extended to working memory and attentional domains, supporting the idea that the basal ganglia/dopamine system modulates the updating of prefrontal representations. Drug effects interacted with baseline working memory span in all tasks. Taken together, the results support a unified account of the role of dopamine in modulating cognitive processes that depend on the basal ganglia. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Bancroftian filariasis in Tanzania: specific antibody responses in relation to long-term observations on microfilaremia

The purpose of this study was to compare core body and brain temperatures after complete but intermittent occlusions of the umbilical cord. Thermocouple probes were placed in the parasagittal parietal cortex, ascending aorta, and jugular vein of eight near-term fetal sheep and in the maternal descending aorta. Three days later, after an initial control period, the umbilical cord was occluded for 5 min, followed by a 30-min recovery period, and this cycle was repeated 4 times. Temperature changes, blood gases, and plasma glucose, lactate and adenosine were measured. In the first occlusion period, body core temperature increased 0.12 degreesC over control, and then declined to baseline after cord release, and this pattern was repeated with subsequent occlusions. Brain temperature, however, did not increase in response to any of the cord occlusions. Plasma adenosine increased 2.4-fold during the first occlusion, but not during subsequent occlusions, despite a continuing pattern of constant brain temperature, a result which minimizes adenosine's importance as a continuing regulator of cerebral metabolism. We conclude that brain temperature fails to increase because of diminished heat production by the brain and increases in cerebral blood flow, responses which delay complete depletion of adenosine 5'-triphosphate stores in brain tissue.     

Effect of inositol treatment on the behavior of rhesus monkeys: preliminary results

In the present report, the peptides arginine vasopressin (AVP), oxytocin (OXT) or their respective antagonists were infused bilaterally into the olfactory bulb to assess their effects upon recognition responses. Recognition responses were determined in a social discrimination paradigm and consisted of measuring the amount of investigation directed to either the same (previously exposed) or novel juvenile rats under conditions in which clear recognition responses are either present as tested with a 30 min inter-exposure interval or absent as tested with a 120 min inter-exposure interval. Infusion of AVP or OXT resulted in preserved recognition responses, as tested with a 120 min inter-exposure interval, compared with that observed in vehicle-infused controls. When animals were infused with the AVP or OXT antagonists using two different doses and tested for the display of recognition as tested with the 30 min inter-exposure interval, no effects of these antagonists were obtained with either dose. These results demonstrate that the olfactory bulb represents an additional important central nervous system target site where these peptides can act to preserve social recognition responses. Moreover, our results suggest that the underlying mechanisms by which peptides function within the olfactory bulb differ as a function of whether they are involved with the display versus preservation of recognition responses.     

Neurometabolic and behavioural effects of haloperidol in relation to drug levels in serum and brain

A method has been developed for the quantitative determination of haloperidol in brain and other tissues. Such determinations have been made after acute and chronic administration of haloperidol to Sprague-Dawley rats. Different regions of the brain including the striatum, the limbic forebrain and the cerebellum have been analyzed separately. The haloperidol effects on Dopa formation have been studied in the same tissue samples. The stimulation of prolactin secretion via blockade of hypothalamic dopaminergic mechanisms and behavioural effects of the drug have been evaluated in parallel experiments. The elimination of haloperidol from brain tissue is a multiphasic process. The fourth phase of elimination is the slowest with a half life of 4 days. No strict correlation was found between serum and brain concentrations of haloperidol. Both after acute and chronic administration there exists apparently a saturating dose above which the brain concentration of the drug increases very little. The dose seems to coincide with that beyond which little increase in Dopa formation is observed. A pharmacokinetic analysis suggests an element of saturable binding or transfer of haloperidol to brain tissue. This mechanism is not preferentially localized to areas of brain rich in dopaminergic synapses. A good correlation was found between the haloperidol concentration in the brain on the one hand and its effects on behaviour, on serum prolactin values and on Dopa formation on the other.     

Effect of processing and heat treatment on behavior of Cu-Cr-Zr alloys to railway contact wire

A new series of Cu-Cr-Zr alloys to be used as railway contact wire, Cu-0.26 wt pct Cr-0.15 wt pct Zr, Cu-0.13 wt pct Cr-0.41 wt pct Zr, and Cu-0.34 wt pct Cr-0.41 wt pct Zr, were studied. The results indicated that processing and aging treatment had an effect on the microstructure, tensile strength, and electrical conductivity behavior of the Cu-Cr-Zr alloys. Process I (solution treatment + cold work + aging) was superior to process II (cold work + solution treatment + aging), because precipitation can occur heterogeneously at the dislocations and subcells. An appropriate processing and aging treatment may improve the properties of the alloys due to the formation of fine, dispersive, and coherent precipitates within the matrix. It is demonstrated that the best combination of tensile strength and electrical conducitivity, on the order of 599 MPa and 82 pct IACS (International Annealed Copper Standard), respectively, can be obtained in alloy Cu-0.34 wt pct Cr-0.41 wt pct Zr in the solution-heat-treated, cold-worked, and aged condition. The mechanism of tensile and conductive properties of Cu-Cr-Zr alloy is also discussed.     

Heroin addiction: Its relation to sexual behavior and sexual experience.

Describes a study in which 31 17-60 yr. old male drug-free heroin addicts, residents of a therapeutic community, were questioned individually by a nonaddict male interviewer as to 7 sexual variables. Results show that during addiction periods, "sexuality" was suppressed; most Ss reported decreased frequencies of intercourse, masturbation, and nocturnal emissions. Proportion of orgasm dropped, ratings of desire and the quality of orgasm were low, and all Ss reported that time to ejaculation was long. In the postaddiction residential phase in the program, sexuality recovered and resembled or was higher than that reported for preaddiction periods. A relationship between changes in sexuality and heroin addiction appears firmly established. A reinforcement hypothesis is discussed. (21 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of prenatal haloperidol administration on anxiety patterns in rats

Haloperidol (0.1 mg/kg, i.p.) treatment was given from day 12 to 20 of gestation to pregnant rats, this being the critical period for neural development in this species. The pups born were subjected to open-field exploratory behaviour, tunnel-board exploratory behaviour, elevated zero-maze and elevated plus maze behaviour tests at 7-8 weeks of age. The results indicate that prenatal haloperidol treatment induces a significant increase in open-field ambulations and rearings, decrease in scratching and licking/washing behaviours whereas grooming and faecal droppings remain unchanged. Significantly reduced activity in the centre and increased activity in the periphery of the tunnel board was noted. These suggest presence of anxiety in these animals. Significant anxiogenic behavioural patterns were also observed on elevated zero-maze and plus-maze in the prenatally haloperidol treated offsprings. The results suggest that prenatal exposure of haloperidol leaves a lasting effect on offsprings resulting in hyper-emotional responsiveness and anxiety state.     

COPD: results of long-term treatment

During the last decades the life expectation of patients with COPD increased continually. Today the life expectation of these patients reach that of the normal general population. Most important for this effect is the improvement of the therapeutical possibilities. Following the experience over nearly 3 decades the treatment regime is described. Glucocorticosteroids are at first line as much as necessary and as less as possible, starting with the inhalative forms adjusted at the clinical course stabilizes the situation. Bronchodilatation around the clock and as good as possible is a further important step. These effects have to be functionally-analytically controlled. It is not enough to follow only the clinical impression. beta 2-sympathicomimetics are the overall dilators with strongest effects and increase even the clearing mechanisms of the bronchopulmonary system. Short- as long-acting medicaments are available, but the duration of the action at each of the different forms is sometimes clearly shorter as the mean values describe. Anticholinergics and theophyllines have weaker bronchodilatation power, but they show additive effects, which could be used at special situations. Combinations as Berodual (beta 2-sympathicomimetics and anticholinergics) can decrease the dosage of the beta 2-sympathicomimetics and therefore increase the therapeutic range. At the situation of exacerbation antibiotics can be very helpful, but sometimes an increase of the dosage of glucocorticosteroids is necessary and sometimes the increase of this dosage alone can control the situation. It is very important to detect the deterioration which can end with a severe life threatening exacerbation as early as possible and to control the situation already at this stage. It is shown at examples of 56 patients functionally-analytically controlled over 5 years that the function values do not deteriorate during the constant treatment regime any more. Even in spite of the constant treatment with beta 2-sympathicomimetics no signs of any kind of down regulation or of tachyphylaxis of the bronchodilatation power could be detected. A bronchodilatation test after 4.2 years of constant bronchodilatation treatment together with beta 2-sympathicomimetics showed at 25 patients the same effect as normally at acute tests without pre-treatment seen. Because after the start of this treatment regime to-day a further deterioration does not take place, it is important to detect signs of the disease as early as possible. This can be achieved as the basis of lung function values measure over a long time. The best basis for this is the individual norm known from measurement at healthy days.