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PubMed1987

Antagonism of AP-5- and amphetamine-induced behaviour by timelotem as compared with clozapine and haloperidol.

Bilateral intrastriatal injection of DL-2-amino-5-phosphonovaleric acid (AP-5), that blocks glutamatergic transmission at the N-methyl-d-aspartate preferring receptor, induces sniffing and body turns and reduces grooming in rats. Timelotem, a representative of the newly developed chemical class of anellated benzodiazepines antagonized specifically AP-5-induced sniffing and body turns. Classical (haloperidol) as well as atypical (clozapine) neuroleptics had recently been shown to antagonize AP-5-induced sniffing; clozapine, like timelotem, but not haloperidol, additionally antagonized AP-5-induced body turns. Further, timelotem antagonized amphetamine-induced stereotyped behaviour in rats, but was found less active than haloperidol in this test. Comparing the activity of drugs in both paradigms revealed that haloperidol inhibited AP-5-induced sniffing and amphetamine-induced stereotypies within the same dose range, but timelotem and clozapine were found more potent in the AP-5 test than in the amphetamine test. Thus, detailed drug profiles discriminate timelotem and clozapine from haloperidol, linking timelotem again to atypical antipsychotic compounds.

2-Amino-5-phosphonovalerate↗
PubMed1989

Effects of caerulein + haloperidol on amphetamine-induced locomotor stereotypy in rats.

The combination of haloperidol + caerulein has been reported to produce a long-lasting reduction of amphetamine-induced hyperlocomotions in rats. This study was designed to replicate those findings and to determine whether haloperidol + caerulein produce any unique effect on amphetamine-induced locomotor stereotypy. In two experiments, haloperidol + caerulein failed to produce a long-lasting reduction in amphetamine-induced hyperlocomotions. Although haloperidol reduced the locomotor stereotypy produced by higher doses of amphetamine, caerulein had no effect, either alone or combined with haloperidol.

Amphetamine↗
PubMed1991

Effects of cocaine alone and in combination with haloperidol and SCH 23390 on cardiovascular function in squirrel monkeys.

The potential involvement of D1 and D2 dopamine receptors in the effects of cocaine on cardiovascular function in squirrel monkeys was evaluated. A low dose of cocaine (0.1 mg/kg i.v.) produced increases in both blood pressure and heart rate. At the higher doses of cocaine (1.0-3.0 mg/kg) the heart rate response was biphasic, consisting of an early decrease followed by an increase in heart rate 10-20 min following injection. The dopamine D2 antagonist haloperidol (0.1 mg/kg i.m.) attenuated the heart rate increasing effect of cocaine, but doses as high as 0.03 mg/kg did not alter the blood pressure increase. The D1 antagonist SCH 23390 (0.01-0.03 mg/kg i.m.) did not attenuate either the blood pressure or heart rate increasing effects of cocaine. The D2 agonist quinpirole (1.0 mg/kg i.v.) produced increases in heart rate similar to cocaine, with little effect on blood pressure. Although effective against the heart rate increasing effect of cocaine, haloperidol (0.01 mg/kg) did not antagonize the heart rate increasing effects of quinpirole. The D1 agonist SKF 38393 (3.0 mg/kg i.v.) decreased heart rate and increased blood pressure. The blood pressure increasing effect of SKF 38393 was antagonized by 0.01 mg/kg SCH 23390. Haloperidol's ability to partially antagonize the tachycardiac response to cocaine suggests the involvement of D2 receptors in that response. However, the failure of haloperidol to antagonize quinpirole's tachycardiac effect suggests that non-dopaminergic mechanisms may also be involved in haloperidol's antagonism of cocaine's tachycardiac effect. The pressor effects of cocaine do not appear to be controlled by selective dopamine receptors.

Animals↗
PubMed1984

Cytidine(5')diphosphocholine enhances the ability of haloperidol to increase dopamine metabolites in the striatum of the rat and to diminish stereotyped behavior induced by apomorphine.

Experiments were performed to determine whether exogenous cytidine(5')diphosphocholine (CDP-choline) could modify release of dopamine in the striatum and behavior dependent on dopamine, perhaps by providing supplemental choline for synthesis of acetylcholine. Rats received water (control) or CDP-choline orally (100 mg/kg per day, for 5 days), either alone or before injection with haloperidol (1 mg/kg, i.p.), apomorphine (0.15 mg/kg, s.c.), or both. Stereotyped behavior was measured during the hour after administration of apomorphine; levels of the dopamine metabolites, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum were assessed at the end of this period (2 hr after administration of haloperidol). In rats receiving the CDP-choline, the stereotyped behavior observed after injection of apomorphine alone (P less than 0.01), or after haloperidol plus apomorphine (P less than 0.01), was attenuated. The pretreatment with CDP-choline also significantly increased levels of HVA (by 24%) and DOPAC (by 23%) in the striatum over appropriate controls in animals receiving haloperidol, or by 29 and 59% (averaging data for all time points), respectively, in animals receiving haloperidol plus apomorphine. One mechanism by which CDP-choline may affect behavior involves contributing choline to enhance synthesis of acetylcholine.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1984

Effects of treatments with apomorphine, haloperidol and ethanol on apomorphine-induced changes in body temperature in the rat.

In previous research, we discovered two DA-related thermoregulatory mechanisms in the rat: a haloperidol-sensitive, hypothermia-inducing mechanism and a haloperidol-nonsensitive, hyperthermia-inducing mechanism. The latter mechanism must also involve serotonin, since its activity can be blocked by serotonin antagonists. We have now found that the responsiveness of these mechanisms to apomorphine could be selectively affected by acute pretreatments with apomorphine, haloperidol and ethanol. The hypothermia-inducing mechanism was supersensitized by pretreatment with either haloperidol (0.25 mg/kg, administered 5 days earlier) or ethanol (3 g/kg, 15 h), but was not affected by pretreatment with apomorphine (1 mg/kg, 15h). In contrast, the hyperthermia-inducing mechanism was supersensitized and desensitized by similar pretreatments with apomorphine and ethanol, respectively, but was not affected by pretreatment with haloperidol.

Animals↗
PubMed1987

Modification of the function of D1 and D2 dopamine receptors in striatum and nucleus accumbens of rats chronically treated with haloperidol.

With the aim of evaluating the possible functional modifications of both D1 and D2 dopamine receptor subpopulations after repeated administration of neuroleptics, the ability of selective D1 and D2 dopamine agonists to stimulate or inhibit, respectively, the activity of adenylate cyclase in the striatum and nucleus accumbens of rats treated with either saline or haloperidol for 21 days, was studied. It was found that stimulation of the activity of adenylate cyclase elicited by the selective D1 receptor agonist SKF 38393 was significantly greater in homogenates of striatum in rats treated with haloperidol, than in those of saline-treated rats. Similarly, the inhibitory effect on the activity of the enzyme elicited by the selective D2 agonist bromocriptine was much more evident in homogenates of the striatum from rats treated with neuroleptic than in those from saline-treated rats. When dopamine, sodium fluoride (NaF), or 5-guanylyl imidodiphosphate (Gpp(NH)p), were used as agonists to stimulate the activity of adenylate cyclase, the amount of cyclic AMP formed appeared the same in rats treated with haloperidol or saline. Dopamine receptors in nucleus accumbens behaved like those in the striatum in the pattern of modifications after repeated administration of haloperidol. Indeed, the inhibitory effect elicited by bromocriptine, as well as the stimulatory effect elicited by SKF 38393, was much more evident in nucleus accumbens from rats treated with haloperidol than in that from controls, whereas activation of adenylate cyclase induced by dopamine and sodium fluoride was similar in both experimental groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1988

8-Hydroxy-2-(di-n-propylamino) tetralin, a selective serotonin1A receptor agonist, blocks haloperidol-induced catalepsy by an action on raphe nuclei medianus and dorsalis.

The selective serotonin1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) was studied for its ability to reverse haloperidol-induced catalepsy in rats. Given subcutaneously 8-OH-DPAT (0.06-0.5 mg/kg), dose-dependently antagonized the catalepsy induced by 1 mg/kg of haloperidol. Intraventricular injection of the serotonin (5-HT) neurotoxin 5,7-dihydroxytryptamine (5,7-DHT), which caused marked depletion of 5-HT in brain, did not change haloperidol-induced catalepsy per se, but completely antagonized the anticataleptic effect of subcutaneously administered 8-OH-DPAT. When injected directly into the median or dorsal raphe nucleus, 8-OH-DPAT, in doses ranging from 0.2 to 5 micrograms/0.5 microliter, reduced the catalepsy induced by haloperidol. The results suggest that the activation of 5-HT1A receptors, probably those located presynaptically on 5-HT-containing cell bodies, reduces the catalepsy induced by haloperidol.

5,7-Dihydroxytryptamine↗
PubMed1982

Haloperidol-induced hyperactivity in neonatal rats: effect of lithium and stimulants.

The effect of chronic subcutaneous administration of haloperidol directly into neonatal rats was investigated as a possible model for the hyperkinetic syndrome in human children in terms of its onset, duration and offset of hyperactivity. In addition, the ability of chronically-administered lithium in the diet of nursing mothers to attenuate the haloperidol-induced hyperactivity was investigated. Experiments with acute administration of the clinically-effective stimulants, amphetamine and methylphenidate, to the pups were also conducted to determine the adequacy of this behavioral model vis-a-vis the human condition. The results indicate that, although chronic haloperidol (2.5 mg/kg) produced hyperactivity relative to controls on the 25th day of life, this hyperactive behavior does not return to control levels at 30 days of age. Moreover, neither the stimulants nor lithium attenuates this hyperactivity and, indeed, lithium, by itself, produces increased activity. Thus, chronic haloperidol administered directly into neonatal rat pups produces hyperactivity possibly by the production of dopaminergic supersensitivity, yet this effect does not model the temporal course seen in hyperkinetic humans. In addition, the administration of drugs that are clinically-useful in treating childhood hyperactivity were unable to decrease the hyperactivity produced by haloperidol in neonatal rats. Taken together, these observations cast doubt upon the usefulness of this animal model to mimic the human condition.

Animals↗
PubMed1982

Estrogen and haloperidol-induced versus handling-related catalepsy in male rats.

A single injection of 17 beta-estradiol valerate produces, 6-7 days later, potentiation of neuroleptic catalepsy. Multiple behavioral measures demonstrate that this effect occurs with an acute dose of haloperidol of 0.25 mg/kg IP. An even lower dose of haloperidol (0.10 mg/kg), which fails to make control rats cataleptic, produces catalepsy in estrogen-treated animals. Thus, estrogen lowers the threshold of haloperidol-induced catalepsy. Repeated testing alone induces cataleptic reactions in control rats. Estrogen suppresses such handling-related catalepsy in animals that subsequently show potentiation of catalepsy at a dose of haloperidol (0.10 mg/kg), which has virtually no effect on control rats. Thus, in these behavioral paradigms, estrogen by itself does not produce cataleptic effects, and estrogen-induced potentiation of haloperidol catalepsy is not merely additive to an antecedent, neuroleptic-like effect of this hormone. We interpret our results in terms of (1) the relationship of cataleptic reactions in normal rats to drug-induced cataleptic states; (2) the possible relevance of our behavioral results to basal ganglia disorders; and (3) the relationship of neuroleptic catalepsy to striatal DA receptors and their modulation by estrogen.

Animals↗
PubMed1983

The effects of chronic haloperidol administration on GABA receptor binding.

The effect of chronic administration of haloperidol for 30 days and its subsequent withdrawal for 0, 4 and 8 days on the binding of [3H]-GABA and [3H]-muscimol to GABA binding sites in rat brain membranes obtained from six discrete regions of the brain and spinal cord was investigated. The chronic administration of haloperidol resulted in a marked increase in the number of GABA binding sites within the substantia nigra, but did not affect GABA binding sites in other regions of rat brain or spinal cord. The increase in GABA binding sites in the substantia nigra was evident for at least 4 days following termination of haloperidol treatment; however, 8 days following withdrawal from haloperidol, when dopaminergic supersensitivity had become maximally expressed, the number of GABA binding sites in the substantia nigra had declined and was the same as that observed in the control rats. These observations suggest that blockade of dopamine receptors in the striatum by haloperidol results in a compensatory decrease in the activity of the GABAergic strionigral system that leads to an increase in the number of GABA binding sites within the substantia nigra. This increase in the number of GABA binding sites is gradually reversed when dopamine is again allowed to interact with its receptors.

Animals↗
PubMed1983

Drug discrimination in rats: evidence for amphetamine-like cue state following chronic haloperidol.

Two groups of male Sprague-Dawley rats were trained to discriminate which of two levers to press for milk reinforcement on a VI-20 sec schedule of reinforcement on the basis of whether they were injected intraperitoneally with d-amphetamine (0.50 mg/kg or 1.50 mg/kg) or saline 15 min prior to daily 30 min training sessions. Following acquisition of the discrimination, dose-response functions were generated for both training-dose groups during 5 min test sessions. All subjects were then injected with 1.0 mg/kg of haloperidol for ten consecutive days and retested on either saline or intermediate doses of amphetamine on days 1, 2, 4 and 7 following the final haloperidol injection. The results indicated that chronic haloperidol enhanced the discriminative stimulus properties of amphetamine in both training groups. More importantly, when tested on saline, subjects in both training groups made significantly more responses on the d-amphetamine lever than observed prior to chronic haloperidol. On the basis of linear regression analysis of the dose-response curves it was shown that rats in both groups responded as though they had been injected with 0.18 mg/kg of d-amphetamine. In a second experiment this increase in amphetamine-lever responding when animals were tested with saline following chronic haloperidol was replicated and in addition it was observed that chronic amphetamine had the opposite effect on this measure.

Amphetamines↗
PubMed1985

Amphetamine-haloperidol discrimination: effects of chronic drug treatment.

Rats responding for food reinforcement were trained in a 2-lever drug discrimination task. Groups of rats were trained to discriminate one of four doses of amphetamine (0.0, 0.1, 0.3, or 0.5 mg/kg) from haloperidol (0.02 mg/kg). Both the rate of acquisition and level of discrimination at asymptote were a function of amphetamine training dose. Following acquisition of this discrimination, choice behavior was assessed in the absence of drug during two test sessions. Twenty-four hours following the second drug-free test session, chronic drug treatment commenced. Half of the animals received 10 mg/kg amphetamine for 10 consecutive days while the other half received 1 mg/kg haloperidol during the same period. Choice behavior was assessed during three 2.5-minute unreinforced drug-free test sessions 24, 48, and 72 hours following the chronic drug regimen. Following chronic haloperidol, animals responded as though a small dose of amphetamine had been administered, while following chronic amphetamine, they responded as though a small dose of haloperidol had been administered. Collectively, these results suggest that animals trained to discriminate amphetamine from haloperidol respond on the basis of a continuum of dopaminergic function. Further, this continuum can be used to elucidate the net effect of pharmacologically-induced alterations in dopaminergic function, as well as the effect of nonpharmacological manipulations that may result in dopaminergic changes.

Amphetamine↗
PubMed1985

Haloperidol and nonreinforcement produce different patterns of response slowing in a food reinforced runway task.

Rats were trained to traverse a runway for food reward and speeds were measured in the start, run and goal segments of the alley. After eight days of acquisition training, subjects were tested for four days under conditions of either extinction or haloperidol pretreatment. Although both haloperidol and extinction produced a suppression of the running response, the pattern of this suppression in the three alley segments was quite different for the two conditions. Haloperidol tended to be more effective than extinction in slowing start speeds but less effective than extinction in reducing run and goal speeds. This differential effect of haloperidol and extinction on speeds in different alley segments provides further evidence that haloperidol-induced impairments in performance cannot result entirely from a blunting of primary reinforcement.

Animals↗
PubMed1989

Functional supersensitivity of the hippocampal dopaminergic system after prolonged treatment with haloperidol.

The effect of acute and prolonged (21 days) treatment with haloperidol (1 or 5 mg/kg SC) on the dopamine-, apomorphine- and LY 171555-induced changes in the firing rate of CA1 layer neurons was studied in a hippocampal slice preparation. Dopamine and apomorphine administration evoked either an excitatory or inhibitory reaction, while the selective D2 receptor agonist LY 171555 increased the firing rate of hippocampal neurons. The excitatory effects of dopamine and LY 171555 were blocked by sulpiride and haloperidol. Prolonged administration of haloperidol potentiated the excitatory reaction of dopamine and apomorphine; however, even a single dose of the neuroleptic enhanced the dopamine-induced effect. The reaction evoked by LY 171555 was not significantly affected by either acute or chronic treatment with haloperidol. The present findings indicate that long-term administration of haloperidol results in an increased sensitivity of hippocampal neurons to the mixed dopamine agonists, dopamine and apomorphine, but not to selective stimulation of the D2 receptor.

Animals↗
PubMed1990

Sensitization versus tolerance to haloperidol-induced catalepsy: multiple determinants.

The effects of dose, administration frequency, and behavioral testing conditions on the development of tolerance versus sensitization to haloperidol-induced catalepsy were tested in rats. Animals received daily or weekly injections of haloperidol (0.05-5.00 mg/kg SC) for up to 22 days. Catalepsy assessments were made either once or repeatedly using two tests: the horizontal bar and the inclined screen. Tolerance was found only in animals treated daily with haloperidol (1.5 mg/kg) and tested repeatedly on the horizontal bar. In contrast, sensitization was observed with various haloperidol doses, daily or weekly administration schedules (for most doses), either horizontal bar or inclined screen catalepsy tests, and repeated or single testing. Sensitization developed most strongly following weekly drug administration and repeated testing on the horizontal bar. No single experimental variable produced a definitive pattern of change in catalepsy over time. Dose, drug administration schedule, and behavioral test conditions all influenced the evolution of catalepsy during chronic haloperidol treatment.

Animals↗
PubMed1993

Effects of haloperidol, lithium, and valproate on phosphoinositide turnover in rat brain.

The effects of acute, subacute, and chronic treatment with haloperidol, lithium, and valproate on inositol phosphate (IP) formation were examined. Acute treatment with haloperidol or the combination of haloperidol and lithium significantly reduced IP basal cortical levels. Subacute (three days) treatment with lithium decreased the IP basal level in the frontal cortex. Chronic treatment with haloperidol (14 and 28 days) caused a significant attenuation of carbachol-sensitive IP accumulation in the frontal cortex and striatum and a significant decrease in norepinephrine (NE)-induced IP formation in the frontal cortex (14 and 28 days) and striatum (28 days). Lithium treatment for 14 days produced a significant reduction in the IP basal cortical value, and a significant reduction in cortical carbachol- and NE-induced IP formation was found after 28 days of lithium treatment. The combination of haloperidol and lithium for 28 days decreased the striatal carbachol- and cortical NE-induced IP accumulation and caused a significant increase in NE-sensitive IP formation in the striatum at 14 days. Valproate treatment for 28 days was associated with a significant attenuation in striatal agonist-stimulated IP formation. Therefore, three drugs with different specificities for primary neurotransmitters may have common effects on second-messenger systems.

Animals↗
PubMed1995

Gender differences in the effects of haloperidol on avoidance conditioning in mice.

Gender differences in the effects of haloperidol (0.075 mg/kg per day for 5 days) on avoidance conditioning were evaluated. We also studied performance of the subjects free of the drug and the acute effects of haloperidol in animals trained without drug 48 h after the last haloperidol administration. Latencies of escape and avoidance responses, number of nonresponses, escapes, avoidances, crossings during the adaptation period, crossings during intertrial intervals, and total crossings per minute were analyzed. This dosage impaired conditioning of the male animals but did not attain the same effects on females. Haloperidol did not deteriorate performance of the task when it had been learned previously without drug. The results confirm the existence of gender differences in haloperidol effects on avoidance conditioning in mice and suggest that these differences are related to the learning process and not only to the impairment of motor behavior characteristic of neuroleptic drugs.

Animals↗
PubMed1994

In vivo dopamine-D2 and serotonin-5-HT2 receptor binding study of risperidone and haloperidol.

An in vivo receptor binding technique was applied to evaluate the affinities of risperidone and haloperidol for dopamine-D2 receptors (D2) and serotonin-5-HT2 receptors (5-HT2) in rat brain with [3H]YM-09151-2 and [3H]ketanserin as selective ligands. Radioactivities were obtained in the striatum frontal cortex, and cerebellum of the rats treated with the ligands. Time course study of receptor occupancy at 25 to 250 min after single doses of the drugs (1 mg/kg, IP) showed higher 5-HT2 occupancy in the frontal cortex and lower D2 occupancy in the striatum by risperidone than by haloperidol. Dose-response analysis of receptor occupancy revealed risperidone demonstrated higher binding affinity for 5-HT2 than for D2, while the reverse was observed with haloperidol. It appeared that risperidone (1 mg/kg, IP), but not haloperidol (1 mg/kg, IP), demonstrated regional selectivity in D2 occupancy favouring frontal cortex more than the striatum. That risperidone displayed a higher ratio of 5-HT2 to D2 in occupancy than haloperidol is in agreement with the previous findings obtained in vitro.

Animals↗