The influence of melatonin, epiphysectomy and anaprilin on the cataleptogenic effect of haloperidol and its time dynamics]

The acute administration of the pineal hormone melatonin (1 mg/kg) to rats was shown to increase, and the chronic use to decrease intensity of haloperidol-induced catalepsy with the reorganization of the rhythmic pattern of the neuroleptic effect. The direct opposite shifts were observed after pinealectomy or propranolol chronic administration (1 mg/kg). It is suggested that owing to its own adaptive properties the pineal gland can participate in the formation of drug tolerance.     

The role of the hepatic microsomal electron-transport system in the development of metabolic tolerance from repeated oral methadone administration in mice

The hepatic microsomal cytochromes P-450 and b5, as well as the enzymes of the hepatic microsomal electron-transport system (HMETS), including NADPH oxidase and NAPDH cytochrome c reductase, were monitored in male ICR mice (25 - 30 g) over a six-day period following repeated oral administration of methadone hydrochloride 12.5, 25, or 50 mg/kg per day, or an equivalent volume of water. Cytochrome P-450 content, when expressed per milligram of microsomal protein, was elevated as early as day 1 of administration. This increase in cytochrome P-450, which lasted throughout the period of administration, appeared to correlate with the previously reported increase in the hepatic microsomal enzyme methadone N-demethylase and tolerance to methadone lethality. The activities of the enzymes NADPH cytochrome c reductase and NADPH oxidase were both elevated significantly by day 2 of administration. However, these increases returned to control levels by day 6 of treatment. The only other cytochrome in the HMETS, cytochrome b5, showed no significant change following repeated oral methadone administration. Further, methadone administration depressed the hepatic microsomal protein content following two days of treatment and no elevation above control values was noted. The significance of these findings with respect to the role of the HMETS in the development of tolerance is discussed in some detail for methadone, as well as the findings previously reported by this laboratory for its acetylated congener, l-alpha-acetylmethadol.     

Circadian rhythm-dependent development of melatonin effects and tolerance to PHNO in rats

Male Sprague-Dawley rats were given 12 days of continuous infusions of (+)-4-propyl-9-hyroxynapthoxazine (PHNO, 5microg/h), a highly selective dopamine D(2) receptor agonist, via subcutaneous ALZET((R)) osmotic pumps. Motor stimulant effects (locomotion and rearing) were monitored throughout the treatment period, including after the animals were injected with 2-iodo-melatonin (0.5 mg/kg) on days 8-10 and 13 after initiation of PHNO infusions. The rats (maintained on 12 L:12 D cycle) developed tolerance to the motor stimulant effects of PHNO during the day, and behavioral sensitization to PHNO during the night. Arousing rats with a vehicle injection transiently blocked the daytime tolerance. A more sustained environmental noise without handling of animals, which had a stronger effect on increasing motor activity of control rats, reversed tolerance to sensitization. Therefore, graded levels of arousal produce graded increases in motor activity in rats otherwise tolerant to the effects of PHNO. Daytime tolerance to PHNO was reversed to sensitization by 2-iodo-melatonin. This effect was more than an additive effect of drug + injection procedure stress. The differential development of nocturnal sensitization and diurnal tolerance to PHNO effects on motor activity may depend upon circadian rhythms in melatonin release, as well as on state of arousal.     

Chronic administration of haloperidol during development: Behavioral and psychopharmacological effects

Chronic haloperidol treatment during prenatal and postnatal development was found to induce long-term behavioral and psychopharmacological effects. Rats tested shortly after termination of the chronic treatment at weaning or as young adults were hyperactive in the open field and exhibited an attenuated behavioral response to amphetamine and an accentuated cataleptic response to later doses of haloperidol, when compared with control offspring of the same age. Tests at an intermediate interval (adolescence period) showed no significant difference from control offspring on any of these behavioral measures. Adult rats administered haloperidol chronically for the same duration were also hyperactive after termination of treatment. In contrast to the effects of haloperidol during development, these adults exhibited an accentuated behavioral response to amphetamine and an attenuated cataleptic response to a later dose of haloperidol. Compensatory mechanisms in response to chronic haloperidol treatment during development thus appear to be different from those in adulthood.Work completed by this author prior to 1977 was published under the name of Linda Patia Lanier     

The effect of the acute and chronic administration of melatonin on the relearning of rats in a Y maze and their sensitivity to haloperidol

After acute (10 mg/kg) and chronic (1 mg/kg, 10 days) administration melatonin facilitated parameters of rats relearning in the Y-maze. A simultaneous shortening of latency avoidance reaction was observed. Haloperidol (0.1 mg/kg) against the background of chronic melatonin administration more strongly optimized the animals' relearning. The hormonal action is supposed to depend on its sedative properties.     

Characteristics of oral movements in rats during and after chronic haloperidol and fluphenazine administration

Rats were chronically administered either haloperidol (HAL) or fluphenazine (FLU) via depot injections for 8 months, given these same drugs in their drinking water for the next 2 months, and then withdrawn from the drugs. Throughout the experiment the animals were tested repeatedly in an enclosed tube using a computerized device which measured computer-scored movelets (CSMs) and, in the latter half of the experiment, were also scored by a human observer in the tube, as well as in an open cage, for observed oral movements (OMs). In the tube, the animals in both neuroleptic-treated groups showed initial decreases in the number of CSMs and made sluggish CSMs; these effects were generally larger in the FLU animals. After 6 months of chronic neuroleptics, the HAL-treated animals showed increased oral movements, both as reported by the human observer and in CSMs of all amplitudes, and this effect increased upon drug withdrawal. FLU-treated animals showed a more persistent depression of both OMs and CSMs of large amplitudes. However, the behavior most characteristic of both neuroleptic-treated groups was the gradual development of increases in CSMs of the smallest amplitudes measurable.A different pattern was observed in the open cage test, where both neuroleptic groups showed significant increases in vacuous OMs during drug administration which rapidly became attenuated upon drug withdrawal. These results indicate a complex syndrome of oral activity in the drugged animals which changed over time. The measure of oral activity which most clearly showed the time-course for late-onset changes in oral activity was CSMs of the smallest amplitudes.     

The analgesic effects of peripheral and central administration of melatonin in rats

To explore the site and mechanism of the analgesic action of melatonin, the present study was designed to evaluate the analgesic effects of intraperitoneal (i.p.) and intracerebroventricular (i.c.v. ) administration of melatonin, and to investigate the effect of i.c. v. naloxone on the analgesic effect induced by i.p. melatonin in rats. Antinociception was determined by tail-flick latency to hot water at 50 degrees C. On i.p. administration, melatonin (30, 60 and 120 mg/kg) produced the antinociceptive effect in a dose-dependent manner, with an A(50) of 72.8 mg/kg. Administered i.c.v., melatonin (0.25, 0.5 and 1 mg/kg) also resulted in dose-dependent antinociception, with an A(50) of only 0.693 mg/kg. Injected i.c.v. to rats, 10 microg of naloxone antagonized significantly the antinociceptive effect induced by i.p. melatonin. It is concluded that melatonin has an analgesic effect in rats and the central nervous system (CNS) may be the primary site for melatonin to elicit the response, and the effect of melatonin is related to the central opioid system.     

Chronic administration of haloperidol during development: Later psychopharmacological responses to apomorphine and arecoline

Offspring of pregnant rats injected with 0.25 mg/kg of haloperidol or saline throughout gestation and until weaning were psychopharmacologically tested for their responsiveness to arecoline and apomorphine. On postnatal day 50, offspring of such chronic treatments were tested in the open field after administration of 0, 0.05, 0.1, 1.0 or 3.0 mg/kg apomorphine, a dopamine agonist. The two chronic treatment groups did not differ in response to high doses of apomorphine which induced stereotyped sniffing and a depression of matrix crossing behavior. However, while control offspring exhibited a low dose (0.05 mg/kg apomorphine) suppression of matrix crossings and rearing behavior, haloperidol treated offspring did not, which may indicate a functional hyposensitivity of dopaminergic autoreceptors in these treated animals. When tested at postnatal day 65 for their cataleptic responses to the cholinergic agonist arecoline, haloperidol treated offspring were more cataleptic to 2 and 5 mg/kg arecoline than control offspring. This suggests that chronic dopamine receptor blockade during development may have long-term indirect effects on the sensitivity of the cholinergic system.     

Differential tolerance to cataleptic effects of SCH 23390 and haloperidol after repeated administration

The development of tolerance to the cataleptic effect of the selective D-1 antagonist SCH 23390 (0.5 mg/kg/day SC or 0.1 mg/kg/day SC) and haloperidol (1 mg/kg/day SC) during repeated administration was investigated. Catalepsy in rats was measured using the horizontal bar method. SCH 23390 induced a dose-related cataleptic effect of short duration, whereas the cataleptic effect of haloperidol appeared more slowly and lasted longer.Marked tolerance to the cataleptic effect of haloperidol developed already 6 days from the beginning of the treatment. The cataleptic effect of the higher dose regimen of SCH 23390 was also significantly reduced after 6 days' treatment. However, unlike haloperidol, this subacute tolerance was gradually reversed and was no longer significant after 12 and 18 days. The cataleptic response to the lower dose of SCH 23390 (0.1 mg/kg/day) was not significantly altered during the treatment and no initial catalepsy tolerance was observed with this dose regimen. These results suggest that different mechanisms are involved in the expression of cataleptic behaviour during chronic treatment with SCH 23390 and classical antipsychotics, such as haloperidol.     

Chronic administration of S-(-)-pentobarbital in pigeons and rats: tolerance development

The development of tolerance to pentobarbital and cross-tolerance to other barbiturates has been documented in both laboratory animals and man. This study was undertaken to determine the extent of tolerance development to S-(-)-pentobarbital in rats and pigeons receiving 10 mg/kg/day S-(-)-pentobarbital, PO. In addition, the extent of cross-tolerance was determined to R-(+)-pentobarbital and both isomers of secobarbital. Rats were trained to respond under a variable-interval 60-sec (V160) schedule of food presentation while pigeons were trained to respond under a multiple fixed-ratio 30, fixed-interval 600-sec schedule of food presentation. After responding had stabilized, dose-response curves were determined for R-(+)-pentobarbital, S-(-)-pentobarbital, R-(+)-secobarbital, and S-(-)-secobarbital in both species. Upon the completion of the acute dose-response curves, both rats and pigeons were given 10 mg/kg/day S-(-)-pentobarbital, PO for 30 consecutive days prior to the redetermination of all four dose-response curves. Upon the completion of this second determination of each curve, the daily administration of the S-(-)-pentobarbital was discontinued, and the rats and pigeons remained drug free for 30 days. Following this 30-day drug free period, dose-response curves for the isomers of both pentobarbital and secobarbital were redetermined for a third time.(ABSTRACT TRUNCATED AT 250 WORDS)     

Treatment schedule as a determinant of the development of tolerance to haloperidol

Three groups of rats received haloperidol 0.5 mg/kg IP twice daily for 20 days, twice daily for 10 days, or every other day for 40 days. The rats in control groups received saline injections according to the same schedules as the experimental groups. During the chronic treatments, spontaneous motor activity was measured as an indicator of behavioral tolerance, and at the completion of treatments, limbic and striatal homovanillic acid (HVA) levels were determined in order to provide a biochemical indication of tolerance. Both of the haloperidol groups on twice-daily injection schedules exhibited a trend towards recovery of spontaneous motor activity during treatment, indicative of behavioral tolerance, as well as reduced HVA levels indicative of near complete biochemical tolerance. The group receiving haloperidol every other day exhibited a trend toward behavioral intolerance to haloperidol, along with elevated HVA levels that indicated a complete absence of tolerance. The suggested importance of treatment schedule rather than cumulative drug dosage in the development of tolerance to haloperidol may have significance to long-term side effects of chronic neuroleptic treatment such as tardive dyskinesia and clinical issues such as drug holidays.     

Effects of haloperidol on morphine-induced antinociception morphine tolerance and withdrawal in hyperprolactinaemic rats

Male rats with hyperprolactinaemia, induced by adenohypophyseal homografts under the kidney capsule, were injected with haloperidol for 3 days and then subjected to treatment with morphine, administered twice in a day at increasing doses for 12 days. At the first treatment, morphine induced an antinociceptive effect that was more prolonged in homografted rats than in sham-operated controls. The pretreatment with haloperidol did not change the prolongation of morphine-induced antinociception in homografted rats. After 12 days of treatment with morphine, all animals were tested for the development of tolerance to the antinociceptive effect of morphine. Pituitary homografts resulted in an inhibition of the development of tolerance, while this effect was absent in homografted rats pretreated with haloperidol. At the end of the treatment with morphine, the naloxone-precipitated abstinence syndrome was studied. Homografted rats shown an attenuation of the withdrawal syndrome and pretreatment with haloperidol did not change this response.These results suggest an involvement of dopaminergic transmission in prolactin-induced changes in the development of tolerance to morphine, but not in the antinociceptive effect following an acute injection of morphine and in naloxone-precipitated withdrawal syndrome of the rat.     

Chronic haloperidol and clozapine administration increases the number of cortical NMDA receptors in rats

The aim of the present study was to examine the influence of 3-month administration of haloperidol (1 mg/kg per day) and clozapine (30 mg/kg per day) in drinking water on cortical NMDA (N-methyl-d-aspartate) receptors in rats. On day 5 of withdrawal, the animals were killed and their brains were removed. The binding of [³H]MK-801 ([³H](5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine) and [³H]CGP 39653 ([³H]d,l-(E)-2-amino-4-propyl-5-phosphono-3-pentenoic acid) to NMDA receptors in different cortical areas, as well as the binding of [³H]spiperone to dopamine D₂ receptors in the striatum, were analysed by quantitative autoradiography. Haloperidol increased the binding of [³H]CGP 39653 in frontal, insular and parietal cortices. Clozapine increased the binding of [³H]CGP 39653 in insular and parietal cortices. Haloperidol, but not clozapine, increased the binding of [³H]spiperone in the striatum. None of the neuroleptics influenced the binding of [³H]MK-801 to cortical NMDA receptors. An additional assay revealed an increase in the B _max value, with no significant changes in the K _D of [³H]CGP 39653 binding in parieto-insular cortical homo-genates as a result of haloperidol and clozapine administration. The present results suggest that long-term treatments with haloperidol and clozapine increase the number of NMDA receptors in different cortical regions. Received: 15 September 1998 / Accepted: 25 January 1999     

The development of tolerance to antilipolytic agents in rats

The development of tolerance to the action of certain antilipolytic agents has been investigated in vivo in rats. Tolerance to oral nicotinic acid developed during twice daily dosing for 4 days at 100 and 250 mg/kg but not at 10, 25 or 50 mg/kg. Tolerance induced by high doses of nicotinic acid was no longer detectable after a further week without treatment. Tolerance developed to a dose of 10 mg/kg nicotinic acid when dosing was repeated at hourly intervals for up to 6 hr. Rats made tolerant to nicotinic acid also became tolerant to both 5-methylpyrazole-3-carboxylic acid and to pyridyl-3-tetrazole and rats made tolerant to these antilipolytic agents were also tolerant to nicotinic acid. Rats made tolerant to nicotinic acid still responded to the antilipolytic activity of the prostaglandin analogue, sulprostone. These results suggest that nicotinic acid, pyridyl-3-tetrazole and 5-methylpyrazole-3-carboxylic acid act through a common mechanism or receptor and that the development of tolerance is associated with this receptor or the mechanism by which it is linked to adenylate cyclase.     

Inhibition of mitochondrial complex I by haloperidol: the role of thiol oxidation

We have examined the effects of a variety of classical and atypical neuroleptic drugs on mitochondrial NADH ubiquinone oxido-reductase (complex I) activity. Sagittal slices of mouse brain incubated in vitro with haloperidol (10 nM) showed time- and concentration-dependent inhibition of complex I. Similar concentrations of the pyridinium metabolite of haloperidol (HPP+) failed to inhibit complex I activity in this model; indeed, comparable inhibition was obtained only at a 10000-fold higher concentration of HPP+ (100 microM). Treatment of brain slices with haloperidol resulted in a loss of glutathione (GSH), while pretreatment of slices with GSH and alpha-lipoic acid abolished haloperidol-induced loss of complex I activity. Incubation of mitochondria from haloperidol treated brain slices with the thiol reductant, dithiothreitol, completely regenerated complex I activity demonstrating thiol oxidation as a feasible mechanism of inhibition. In a comparison of different neuroleptic drugs, haloperidol was the most potent inhibitor of complex I, followed by chlorpromazine, fluphenazine and risperidone while the atypical neuroleptic, clozapine (100 microM) did not inhibit complex I activity in mouse brain slices. The present studies support the view that classical neuroleptics such as haloperidol inhibit mitochondrial complex I through oxidative modification of the enzyme complex.     

Distinct endocrine effects of chronic haloperidol or risperidone administration in male rats

Antipsychotic drugs have been used effectively for the treatment of schizophrenia symptoms, but they are often associated with metabolic side effects such as weight gain and endocrine disruptions. To investigate the possible mechanisms of antipsychotic-induced metabolic effects, we studied the impact of chronic administration of a typical antipsychotic drug (haloperidol) and an atypical antipsychotic (risperidone) to male rats on food intake, body weight, adiposity, and the circulating concentrations of hormones and metabolites that can influence energy homeostasis. Chronic (28 days) haloperidol administration had no effect on food intake, weight gain or adiposity in male rats, whereas risperidone treatment resulted in a transient reduction in food intake and significantly reduced body weight gain compared to vehicle-treated control rats. Whereas neither antipsychotic had any effect on serum lipid profiles, glucose tolerance or the circulating concentrations of hormones controlled by the hypothalamo-pituitary-thyroid (free T4), -adrenal (corticosterone), -somatotropic (IGF-1), or -gonadotropic axes (testosterone), haloperidol increased circulating insulin levels and risperidone increased serum glucagon levels. This finding suggests that haloperidol or risperidone induce distinct metabolic effects. Since metabolic disorders such as obesity and type 2 diabetes mellitus represent serious health issues, understanding antipsychotic-induced endocrine and metabolic effects may ultimately allow better control of these side effects.     

Oral dyskinesias and morphological changes in rat striatum during long-term haloperidol administration

RATIONALE: Neuroleptic-induced oral dyskinesias in rats, a putative analogue to human tardive dyskinesia, may be due to increased glutamate release within the striatum. This may lead to excitotoxic degeneration and, as a consequence, persistent motor side effects. OBJECTIVES: To investigate whether alterations in glutamatergic synapses within the striatum are associated with the development of neuroleptic-induced oral dyskinesia. METHODS: Haloperidol was administered for 20 weeks, and rats with high and low levels of vacuous chewing movements (VCM) were analyzed for morphological changes with electron microscopy at three time points. RESULTS: At week 8, the high VCM rats had a larger nerve terminal area and lower density of nerve terminal glutamate immunoreactivity than the other groups. After 18 weeks of treatment, the nerve terminal area was increased relative to controls in both the high and low VCM groups. After discontinuation of treatment, there were no significant morphological differences between the groups, but the level of VCM was still significantly increased in the high VCM group. CONCLUSIONS: These results show that striatal glutamatergic transmission is affected during haloperidol treatment and the nerve terminal area and the density of nerve terminal glutamate immunoreactivity are important in determining the VCM response to haloperidol treatment. This indicates that increased glutamatergic synaptic activity in the striatum contributes to the development of human tardive dyskinesia.