During one year's neuroleptic treatment in rats striatal dopamine receptor blockade decreases but serum prolactin levels remain elevated

Rats were treated for one year with either trifluoperazine dihydrochloride (2.5–3.5 mg/kg/day) or thioridazine dihydrochloride (30–40 mg/kg/day) when prolactin levels were measured in comparison to animals treated acutely with a single oral bolus of the same drugs in approximately the same dose. Serum prolactin levels at the end of the year of neuroleptic treatment with either drug remained elevated compared to those in control animals, and the elevation was no different from that obtained by administration of an equivalent acute single oral bolus. In contrast, the inhibition of apomorphine-induced stereotypy produced by the acute administration of either drug disappeared during chronic treatment, to be replaced after a year's neuroleptic administration by a supersensitive response. Similarly, the increase in dopamine turnover produced by acute neuroleptic administration, evidenced by raised striatal 3, 4-dihydroxy-phenylacetic acid (DOPAC) levels, also disappeared at the end of a year's treatment, when specific binding of ³H-spiperone to striatal homogenates indicated an increased number of dopamine receptors. The disappearance of evidence of blockade of striatal dopamine receptors, which appeared to become supersensitive during a year's chronic treatment with either trifluoperazine or thioridazine, contrasts with the persistence of the effect of these drugs on serum prolactin levels.     

Enhanced haloperidol-induced prolactin stimulation with chronic neuroleptic treatment in the rat

Animals were treated either acutely, or chronically for 21 days, with a low dose (0.1 mg/kg) of haloperidol, then sacrificed to obtain trunk blood for radioimmunoassay of prolactin (PRL) level. PRL concentrations on day 21 of chronic treatment were greater than two-fold those produced by acute neuroleptic. Challenge with apomorphine to rats withdrawn for 48 hours revealed similar PRL reductions as a group withdrawn from chronic vehicle injections.     

Correlation of plasma and CSF prolactin with CSF GABA during neuroleptic treatment

We measured serum and CSF prolactin and CSF 5HIAA, HVA and GABA at two time points separated by an average period of 21 days during the beginning of neuroleptic treatment in 26 psychotic patients. Prolactin levels were higher in females at both time points, and there was little evidence of tolerance during the measurement period. The prolactin values showed considerable intercorrelation. CSF GABA tended to be negatively correlated with prolactin values, particularly in male subjects. There were few significant correlations between the prolactin measures and CSF metabolites or clinical ratings.     

Des-tyrosine-γ-endorphin: H-reflex response similar to neuroleptics

In a study of eight schizophrenic patients, des-tyrosine-γ-endorphin was found to significantly reduce secondary facilitation of the H-reflex recovery curve. This result is similar to the effect found after treatment with classical neuroleptic medication. The effect is different from that produced by lithium carbonate or anti-depressants. This suggests that des-tyrosine-γ-endorphin and neuroleptics have a similar pharmacological action in man.     

Changes in the number of benzodiazepine receptors in different parts of the brain of rats after neuroleptic withdrawal

It has been demonstrated in experiments on rats receiving chronic (16 days) treatment with haloperidol (1.0 mg/kg/day), sulpiride (50 mg/kg/day) and clozapine (10 mg/kg/day) that binding of 3H-flunitrazepam in the striatum, limbic system, and cortex is reduced at the 5th day after withdrawal of the neuroleptics. That release was determined by the diminution of the number of receptors without changing in the dissociation constant. The reduction in the density of benzodiazepine receptors (BD-receptors) after withdrawal of the neuroleptics attests to their agonistic effect on BD-receptors. Apparently these changes are not linked with a direct effect of the neuroleptics on BD-receptors, since they displace 3H-flunitrazepam in experiments in vitro only at micromolar concentrations. It is assumed that the reduction in 3H-flunitrazepam binding is mediated via the GABAergic system transsynaptically in response to increase in the number of dopamine (neuroleptic) receptors.     

LONG-TERM EFFECTS OF TEFLUTIXOL ON THE SYNTHESIS AND ENDOGENOUS LEVELS OF MOUSE BRAIN CATECHOLAMINES

—The long term effects on accumulation of ¹⁴C-labelled dopamine and noradrenaline after [¹⁴C]tyrosine administration and on the endogenous levels of catecholamines in mouse brain were studied after treatment with a new potent thioxanthene neuroleptic, teflutixol. The drug was given as a single dose (5 mg/kg i.p.), as repeated daily doses (1·25 mg/kg p.o.), or as a single dose of the palmitic ester in Viscoleo® (20 mg/kg s.c). After a single dose, teflutixol increased catecholamine synthesis (100%). Noradrenaline synthesis rapidly returned to normal, whereas decreased dopamine synthesis was seen from the third to sixth day, after which it was normal. When the receptors were continuously exposed to teflutixol, either by daily dosage or by the depot preparation, catecholamine synthesis was increased for the first few days but then returned to normal, indicating development of tolerance. Endogenous concentrations of catecholamines were only decreased during the first few days, when the increase in synthesis was greatest. The findings are in accordance with results obtained by Møller Nielsen & Christensen (1975), who found that receptor blockade was followed by receptor supersensitivity after treatment with a neuroleptic compound. The receptor blockade may activate a feedback mechanism that induces increased nervous firing with increased amine synthesis as a consequence. The resulting supersensitivity, if sufficiently great, may lead to reduced nervous firing, followed by slowing of dopamine synthesis.     

Changes in the sensitivity of brain dopamine and serotonin receptors during the prolonged administration of carbidine

Male Wistar rats were treated chronically with either carbidine (10 mg/kg/day) or haloperidol (1 mg/kg/day) for 23 consecutive days. On days 4-5 after the treatment discontinuation the animals were challenged with apomorphine HCl (0.5 mg/kg) or 5-OTP (150 mg/kg i. p) in combination with pargiline (40 mg/kg i. p) and stereotype responses were scored. In carbidine-treated rats the intensity of stereotype sniffings was increased after apomorphine treatment. In contrast, animals treated with haloperidol exhibited more intensive gnawing after apomorphine in comparison to vehicle-treated rats. 5-OTP-induced head twitches were increased only in carbidine-treated rats. Prolonged carbidine treatment in contrast to haloperidol induced a decrease in 5H-spiperone and 3H-LSD binding in the frontal cortex, with the density of D-2 receptors in the striatum practically unchanged. It is concluded that neuroleptic carbidine in contrast to classical neuroleptics has a more selective effect in serotonin (S-2) receptors and antidepressive properties of this compound may be due to the down-regulation of S-2 receptors in the brain.     

Effect of increased dairy consumption on appetitive ratings and food intake

Objective: The influence of dairy product consumption on food intake and appetitive sensations was explored in a cross‐over design study with individuals who were habitually low (<1 serving/d) or high (>3 servings/d) dairy consumers. Research Methods and Procedures: Fifty‐eight participants were required to eat one portion of dairy each day (low dairy) or three portions of dairy each day (high dairy) for 7 days. After a 7‐day washout period, the opposite treatment condition was completed. Food intake and appetitive ratings were measured on each day of the treatment periods. Results: During the high‐dairy period, participants consumed 209 kcal/d more than during the low dairy period (p < 0.05). There were no significant differences in subjective appetite ratings. Habitual dairy use did not influence either the appetitive or dietary findings. Discussion: These data indicate that increasing dairy consumption may lead to increased energy intake, which could potentially cause weight gain.     

Relationship Between Dopamine Receptor Occupation by Spiperone and Acetylcholine Levels in the Rat Striatum After Long-Term Haloperidol Treatment Depends on Dopamine Innervation

The effect of chronic neuroleptic treatment on the relationship between the blockade of dopamine (DA) receptors by the neuroleptic drug spiperone and the decline in acetylcholine (ACh) levels was determined in the rat striatum in vivo. In rats, a unilateral lesion of the nigrostriatal pathway was produced with 6-hydroxydopamine. The rats were treated for 6 weeks with haloperidol (twice a day at 1 mg kg-1). Partial and complete receptor occupation was determined with radioactive spiperone (a D2 antagonist), given in various doses of different specific activity 2 h before death. ACh, choline, and radioactivity contents were measured in the same striatum. Following long-term haloperidol treatment, an increase in the maximal number of binding sites for spiperone was found. Virtually identical negative (linear) correlations between striatal ACh content and the number of receptors occupied by spiperone were found in saline- or subchronic haloperidol-treated rats when DA innervation was intact. The slope of the line describing the decrease in ACh content per occupied receptor, however, was much lower in haloperidol-treated rats than in saline-treated animals. After lesioning of the dopaminergic pathway, there was no longer a correlation between the receptor occupation and ACh levels in the striatum. These results show that receptor occupation by a neuroleptic correlates highly with function only when dopaminergic innervation is intact. Also, it appears that there is no fixed number of striatal ACh molecules per DA receptor, and, finally, that in vivo receptor detection methods distinguish differences in receptor density (as do in vitro techniques).     

Hydrocortisone induces an increase of amylase content in individual zymogen granules from rat pancreas

This study was performed to evaluate the effects of different doses of hydrocortisone (1, 10 and 25 mg/kg/day) administered for 1, 3 and 8 days on pancreatic enzyme storage in rats. The enzyme content in both pancreas homogenates and in individual isolated zymogen granules (ZGs) was measured using standard biochemical assays and flow cytometry, respectively. Hydrocortisone did not alter the total amount of pancreatic DNA but increased the pancreas enzyme content in a time-dose-dependent way. Amylase activity was significantly increased after hydrocortisone administration at day +8 when 10 mg/kg/day was used, and from the first day of treatment when 25 mg/kg/day was administered. A significant increase in trypsin activity was also observed in response to 25 mg/kg/day of hydrocortisone but only from the third day of treatment onwards. As compared with control rats, chronic administration of either 1 or 10 mg/kg/day of hydrocortisone did not alter significantly either the size or the percentage of the two ZG subpopulations (Z1 and Z2) identified in the pancreas by flow cytometry; in addition, no significant changes were observed in the mean amylase content per individual granule, although its mean concentration increased in rats treated with 10 mg/kg/day for 3 and 8 days. Nevertheless, when 25 mg/kg/day of hydrocortisone were administered for 1 and 3 days, a significant increase in the proportion of Z1 ZGs was observed, which may be related to the formation of new and smaller ZGs. When a very high dose of hydrocortisone (25 mg/kg/day) was used, an overall increase in the pancreatic enzyme content related to an increase in the mean amylase content per individual ZG was observed; this effect was apparent from the first day of treatment in the Z1 subset of ZGs and from day +3 in the Z2 subpopulation. Only a high concentration of hydrocortisone was able to alter the enzyme storage process in individual zymogen granules, but they maintain a normal enzyme load at lower hydrocortisone doses.     

Enhanced striatal 3H-spiroperidol binding induced by chronic haloperidol treatment inhibited by peptides administered during the withdrawal phase

Chronic intragastric administration of haloperidol (1.5 mg/kg/day) for 21 days followed by a 3-day withdrawal period resulted in the development of enhanced locomotor activity response to apomorphine, and an increase in the number of binding sites for 3H-spiroperidol in the striatal membranes of the rat brain. Subcutaneous administration of Pro-Leu-Gly-NH2 or cyclo(Leu-Gly) in doses of 2 mg/kg/day given for 3-days after termination of haloperidol treatment inhibited the enhanced response to apomorphine, as well as the increases in the number of 3H-spiroperidol binding sites in the striatum. If indeed, the supersensitivity of striatal dopamine receptors is one of the mechanisms in the development of tardive dyskinesia symptoms, the present results suggest that the above peptides may be helpful in ameliorating some of the symptoms of tardive dyskinesia induced by neuroleptic drugs.     

Ultrasonic vocalization in rat pups: effects of early postnatal exposure to haloperidol

The effects of prolonged postnatal administration of haloperidol (H) on ultrasonic vocalization elicited by the removal of rat pups from their nest were investigated. The results show that the number of ultrasonic calls was significantly reduced by H exposure from the 8th until the 14th day after birth. Conversely, this neuroleptic significantly increased the duration of ultrasound from the 4th up to the 16th day of age. Moreover, changes in the frequency of calls were produced by early postnatal treatment with H. These alterations could be due to an impaired functional maturation of the dopaminergic system produced by neonatal exposure to H. Furthermore, the present data suggest that ultrasonic vocalization may be considered as an early sensitive indicator of subtle changes elicited by the postnatal treatment with a dopamine receptor blocking agent at dose levels below those associated with overt signs of neurotoxicity.     

Adaptive changes in sigma and phencyclidine receptors during the long-term use of haloperidol and raclopride in rats

The experiments on male albino rats have shown that 15 days haloperidol (0.5 mg/kg) and raclopride (1 mg/kg) treatment, but not acute administration, causes the increase of density of sigma receptors in the brain. The number of phencyclidine receptors was also elevated, but this increase was not statistically evident. The behavioral effects of ketamine (5 mg/kg) were evidently decreased after long-term haloperidol and raclopride treatment. The motor stimulation and stereotyped behavior induced by apomorphine (0.15 mg/kg) were increased only after treatment of haloperidol, but not raclopride. It seems probable that repeated neuroleptic (haloperidol and raclopride) treatment causes the hyposensitivity of sigma and phencyclidine receptors, despite the increase of their number. It is possible that this change is related to the depolarization inactivation of dopamine neurons caused by repeated neuroleptic administration.     

Electric convulsive therapy (ECT) increases plasma and red blood cell haloperidol neuroleptic activities

In nine schizophrenic patients (five males and four females) on haloperidol treatment, plasma and red blood cell (RBC) haloperidol neuroleptic activities were measured before and after ECT by radioreceptor assay. Five patients randomly selected from these patients also served as controls on another occasion and neuroleptic activities in plasma and RBC were examined before and after the premedication only. All patients given ECT showed a considerable increase in plasma and RBC haloperidol neuroleptic activities after ECT (% increase in plasma neuroleptic activity, 28–409%; mean + SD, 136 ± 155%, P<0.005, Wilcoxon test; % increase in RBC neuroleptic activity, 11–121%; mean + SD, 59 ± 40%, P<0.005). However, no significant increase was observed for either plasma or RBC haloperidol neuroleptic activity, when patients were examined after premedication only. It was suggested that ECT induced a transient redistribution of haloperidol. It remains to be studied whether this phenomenon is causally related to the previous observation that the combination therapy of ECT and neuroleptics is more effective in the treatment of schizophrenia than ECT alone.     

Induction of c-fos mRNA Expression in Rat Striatum by Neuroleptic Drugs

The effect of selective dopamine D2 receptor-acting drugs on striatal c-fos mRNA expression in the rat has been investigated by Northern hybridization and autoradiography to determine a possible role for c-fos in the initiation of adaptive changes in D2 receptor number by neuroleptic drugs. The neuroleptic drug haloperidol, a D2 receptor antagonist, was found to produce a rapid and transient induction of c-fos mRNA expression as compared with the expression in animals treated with saline. This induction by haloperidol was found to be dose dependent and D2 receptor mediated, inasmuch as a D2 agonist completely reversed the induction and the inactive isomer of the neuroleptic butaclamol, which does not produce an increase in D2 receptors, had no effect on c-fos mRNA expression. From these data, it can be concluded that c-fos expression in striatum is under dopamine D2 receptor-mediated inhibitory control. It is suggested that c-fos may play a role in the initiation of the increase in D2 receptor number produced by chronic neuroleptic drug treatment.     

An experimental model of tardive dyskinesias

Rats treated continually and chronically with trifluoperazine (ca 3 mg/kg/day) for six months initially developed mild catalepsy and an inhibition of spontaneous locomotor activity; both effects disappeared by three months. An initial increase in dopamine turnover (as measured by levels of homovanillic acid and dihydroxyphenylacetic acid) also disappeared by three months. Apomorphine-induced stereotypy was completely inhibited in drug-treated animals at two weeks, but progressively returned to normal after three months of drug intake. An exaggerated response to apomorphine developed in animals after six months of drug administration. Inhibition of striatal dopamine-stimulated adenylate cyclase found during the first month of drug intake was reversed at three months, a trend exaggerated after continuous drug administration for six months. Specific striatal ³H-spiperone binding affinity decreased acutely, but was increased after six months drug intake; no change in number of receptor sites occurred.These changes suggest that at least striatal dopamine receptors may become “supersensitive” during chronic neuroleptic treatment.     

Exposure-dependent accumulation of N-(2-hydroxypropyl)valine in hemoglobin of F344 rats exposed to propylene oxide by the inhalation route

The detection of hemoglobin adducts by mass spectrometry is a very sensitive and specific measurement of the extent of covalent binding of electrophilic chemicals. The exposure-dependent accumulation of N-(2-hydroxypropyl)valine (N-HPVal) in globin of rats exposed to propylene oxide (PO) (0, 5, 25, 50, 300 or 500 ppm) by the inhalation route was measured to assess the utility of Hb adducts as biomarkers of exposure. Analysis of N-HPVal by gas-chromatography tandem mass spectrometry showed a linear exposure-dependent response for adduct accumulation in globin of rats exposed to PO for 3 days (6 h/day). After 20 days of exposure (6 h/day; 5 days/week), the exposure-response curve was slightly sub-linear. DNA adducts had been measured in several organs of the same animals in a companion study. The dose-response for accumulation of DNA adducts was similar to that obtained for Hb adducts. However, the number of DNA adducts varied by 17-fold between different tissues. The highest number of DNA adducts was found in respiratory nasal tissue, followed by lung and then liver. These data demonstrate that hemoglobin adducts provide a sensitive dosimeter for systemic exposure, but cannot be used to predict the extent of DNA binding in individual tissues. Furthermore, the exposure-response curve for both hemoglobin and DNA adduct accumulation does not reflect the tumor incidence curve for PO, providing evidence that the assessment of risk to cancer is more complex than simple biomarker measurements. When the present rat data were compared with recent N-HPVal measurements in humans, similar binding was found.     

Neuroleptic malignant syndrome: occurrence in a child after reconstructive surgery

The occurrence of the rare but potentially fatal neuroleptic malignant syndrome must be considered by the surgeon treating a patient who develops hyperthermia, mental abnormalities, autonomic instability, and muscle rigidity after exposure to phenothiazines or other neuroleptic drugs. The dopamine agonist bromocriptine appears to be the treatment of choice in adults and seemed to be effective and well tolerated in our patient. Although the syndrome cannot be prevented, recognition is crucial, since effective general and specific therapy is available. Differentiating neuroleptic malignant syndrome from malignant hyperthermia allows early appropriate treatment with bromocriptine.     

Individual differences in the amount and timing of salivary melatonin secretion

The aim of this study was to examine individual differences in a large sample of complete melatonin profiles not suppressed by light and search for possible associations between the amount and timing of melatonin secretion and a multitude of lifestyle variables. The melatonin profiles were derived from saliva samples collected every 30 minutes in dim light from 85 healthy women and 85 healthy men aged 18-45 years. There was a large individual variability in the amount of melatonin secreted with peak values ranging from 2 to 84 pg/ml. The onset of melatonin secretion ranged from 18:13 to 00:26 hours. The use of hormonal birth control, reduced levels of employment, a smaller number of days on a fixed sleep schedule, increased day length and lower weight were associated with an increased amplitude of melatonin secretion. The use of hormonal birth control, contact lenses, a younger age, and lower ratings of mania and paranoia were associated with a longer duration of melatonin secretion. An earlier occurrence of the onset of melatonin secretion was associated with an earlier wake time, more morningness and the absence of a bed partner. Lifestyle and behavioral variables were only able to explain about 15% of the individual variability in the amount of melatonin secretion, which is likely because of a substantial genetic influence on the levels of melatonin secretion.