Behavioral Effects Of Haloperidol Research Articles

Lack of cataleptogenic potentiation with non-imidazole H 3 receptor antagonists reveals potential drug–drug interactions between imidazole-based H 3 receptor antagonists and antipsychotic drugs

Since H 3 receptor (H 3R) antagonists/inverse agonists can improve cognitive function in animal models, they may have the potential to be used as add-on therapy in the treatment of schizophrenia, a disease with significant cognitive deficits. However, a recent study showed potentiation of haloperidol-induced catalepsy by ciproxifan, an imidazole-containing H 3R antagonist/inverse agonist, suggesting there is a potential risk of exacerbating extrapyramidal symptoms (EPS) if H 3R antagonists were used as adjunctive treatment [Pillot, C., Ortiz, J., Heron, A., Ridray, S., Schwartz, J.C. and Arrang, J.M., Ciproxifan, a histamine H 3-receptor antagonist/inverse agonist, potentiates neurochemical and behavioral effects of haloperidol in the rat, J Neurosci, 22 (2002) 7272–80]. In order to clarify the basis of this finding, we replicated this result and extended the work with another imidazole and two non-imidazole H 3R antagonists. The results indicate that ciproxifan significantly augmented the effects of haloperidol and risperidone on catalepsy. Another imidazole H 3R antagonist, thioperamide, also potentiated the effect of risperidone on catalepsy. In contrast, no catalepsy-enhancing effects were observed when selective non-imidazole H 3R antagonists, ABT-239 and A-431404, were coadministered with haloperidol and/or risperidone. As ciproxifan and thioperamide are inhibitors of cytochrome P450 enzymes, responsible for metabolizing risperidone and haloperidol, the possibility that the augmentation of antipsychotics by imidazoles resulted from drug–drug interactions was tested. A drug metabolism study revealed that an imidazole, but not a non-imidazole, potently inhibited the metabolism of haloperidol and risperidone. Furthermore, ketoconazole, an imidazole-based CYP 3A4 inhibitor, significantly augmented risperidone-induced catalepsy. Together, these data suggest the potentiation of antipsychotic-induced catalepsy may result from pharmacokinetic drug–drug interactions and support the potential utility of non-imidazole H 3R antagonists in treatment of cognitive impairment in schizophrenia without increased risk of increased EPS in patients.

Ciproxifan, a histamine H3-receptor antagonist/inverse agonist, potentiates neurochemical and behavioral effects of haloperidol in the rat.

By using double in situ hybridization performed with proenkephalin and H3-receptor riboprobes on the same sections from rat brain, we show that histamine H3 receptors are expressed within striatopallidal neurons of the indirect movement pathway. The majority ( approximately 70%) of striatal enkephalin neurons express H3-receptor mRNAs. This important degree of coexpression of proenkephalin and H3-receptor mRNAs prompted us to explore the effect of H3-receptor ligands on the regulation of enkephalin mRNA expression in the striatum. Acute administration of ciproxifan, a H3-receptor antagonist/inverse agonist, did not modify the expression of the neuropeptide by itself but strongly increased the upregulation of its expression induced by haloperidol. This potentiation (1) was suppressed by the administration of (R)-alpha-methylhistamine, a H3-receptor agonist, (2) occurred both in the caudate-putamen and nucleus accumbens, and (3) was also observed with a similar pattern on c-fos and neurotensin mRNA expression. Similarly, whereas it was devoid of any motor effect when used alone, ciproxifan strongly potentiated haloperidol-induced locomotor hypoactivity and catalepsy, two behaviors in which striatal neurons are involved. The strong H3-receptor mRNA expression in enkephalin neurons suggests that the synergistic neurochemical and motor effects of ciproxifan and haloperidol result from direct H3/D2-receptor interactions, leading to an enhanced activation of striatopallidal neurons of the indirect movement pathway. The potentiation of the effects of haloperidol by ciproxifan strengthens the potential interest of H3-receptor antagonists/inverse agonists to improve the symptomatic treatment of schizophrenia.

Acute effects of neuroleptics on unmedicated schizophrenic patients and controls

Acute administration of haloperidol (0.2 mg/kg) produced many more side effects in normal controls than in unmedicated schizophrenic patients. Prior to the neuroleptic challenge, both groups were on the peripheral monoamine oxidase inhibitor, debrisoquin, for at least 1 week, in order to enhance the relative contribution of CNS catecholamine metabolites to those measured in both plasma and urine. The patient group had higher plasma levels of methoxyhydroxyphenylglycol (MHPG) and homovanillic acid (HVA) and higher urinary MHPG output than controls, but there were no effects of haloperidol challenge, compared to placebo challenge. In both groups there were significant declines in plasma HVA levels from 8:30 am to 12 noon. These declines were unaffected by the haloperidol challenge. Explanations for the marked differences in behavioral effects of haloperidol on patients and controls include the possibility that dopamine receptor numbers were increased in the brains of the schizophrenic patients.

DISTINGUISHING BETWEEN HALOPERIDOL'S AND DECAMETHONIUM'S DISRUPTIVE EFFECTS ON OPERANT BEHAVIOR IN RATS: USE OF MEASUREMENTS THAT COMPLEMENT RESPONSE RATE

The behavioral effects of haloperidol (0.04 to 0.16 mg/kg) and nonparalytic doses of decamethonium (0.2 to 0.8 mg/kg) were studied with operant methods that permitted the measurement of response rate, peak force of response, duration of response, and duration of the rat's head entry into the reinforcement dipper well. Type of operant response topography (forelimb press or forelimb grasp-and-pull) and peak force (low or high) required for reinforcement delivery were independent variables. The low-force, press-topography condition yielded qualitatively different profiles for the two drugs. Haloperidol increased peak force and duration of operant response, increased maximum head entry duration, and temporally dissociated forelimb and head entry behavior. Decamethonium decreased force and duration of operant response, did not appreciably affect maximum head entry duration, and did not influence the normal temporal coupling of forelimb and head entry responses. The haloperidol effects were seen as reflections of pseudo-Parkinsonism, not muscle weakness, which appeared to be the primary source of decamethonium's behavioral effects.

Striatal homogenates from animals chronically treated with haloperidol stimulate dopamine and GABA uptake in cultures of rostral mesencephalic tegmentum.

The effect of pharmacologic denervation of striatal tissue on the production of growth promoting factors was examined in a cell culture system. Relative to saline-treated controls, rats were rendered behaviorally hypersensitive to a subsequent apomorphine challenge by 2 months of chronic treatment with haloperidol. Four days following chronic treatment, the animals were killed and the striata and cerebella were homogenized in Hank's Balanced Salt solution. The supernatants of these crude homogenates were then added to E-13 rostral mesencephalic tegmentum cultures for 6 days. Within 24 h, the haloperidol-treated striatal supernatants induced an overt increase in culture growth relative to all other supernatants. After 6 days, cultures incubated with haloperidol-treated striatal supernatants exhibited a significant increase in dopamine and GABA uptake relative to cultures incubated with all other supernatants. This effect was observed in the presence and absence of glia. The relative degree of this increased uptake was dependent upon the amount of haloperidol-treated striatal supernatant added. Boiling the supernatant removed the growth promoting effect. These results suggest that pharmacologic denervation of striatal tissue leads to a "target-specific" increase in growth promoting activity that may play a role in the pharmacologic and behavioral effects of haloperidol.

Differential effects of dopamine D 1 and D 2 agonists and antagonists on velocity of movement, rearing and grooming in the mouse : Implications for the roles of D 1 and D 2 receptors

A system combining visual recording of rearing and grooming, with automatic measurement of slow and fast components of locomotion, was examined for its suitability as a means of studying the effects on behaviour of conventional and novel dopaminergic drugs in the mouse. Amphetamine (0.1–10 mg kg ) selectively stimulated fast movements and affected rearing bimodally. Apomorphine (0.01–5 mg kg ) influenced locomotion polyphasically, depressing fast movements and enhancing slow ones, and producing parallel changes in rearing. Both drugs reduced grooming monotonically. A dose of apomorphine (25 μg kg ) which is considered to act presynaptically produced haloperidol-resistant sedation, while a larger dose (0.5 mg kg ; with postsynaptic actions) evoked head-down sniffing and ponderous walking that were partially prevented by pretreatment with 0.05 mg kg haloperidol (D 2 blocker), but not 0.01 mg kg SCH 23390 (D 1 blocker). The behavioural effects of haloperidol (0.2–0.4 mg kg ) and SCH 23390 (0.05 mg kg ) were indistinguishable; both drugs caused sedation and inhibited all forms of motor activity. Small doses of SCH 23390 (2–10 μg kg ) and large doses of the D 1 agonist SKF 38393 (3–10 mg kg ) evoked excessive grooming. The drug SKF 38393 (1–30 mg kg ) had no other effects on motor behaviour, whereas the whole spectrum of pre- and postsynaptic motor responses produced by apomorphine could be duplicated with the D 2 agonist RU24213 (0.05–15 mg kg ). The differential sensitivity of fast and slow components of locomotion to treatment with drug suggests these are qualitatively distinct responses. The results implicate D 2 receptors in the mechanisms of locomotion and rearing, and D 1 receptors in the expression of grooming.

Modification of the behavioural effects of haloperidol and of dopamine receptor regulation by altered thyroid status.

Rats made hypothyroid by the chronic oral administration of 200 mg/kg propylthiouracil were less sensitive to the cataleptic effects of haloperidol (0.1 mg/kg) treatment than were euthyroid rats chronically treated with isotonic saline. However, rats made hyperthyroid by the chronic injection of 200 micrograms/kg thyroxine were not more sensitive to the cataleptic suppressant effects of haloperidol (0.1 mg/kg). Higher doses of haloperidol (1 and 5 mg/kg) produced significantly greater catalepsy in the hyperthyroid rats and significantly reduced catalepsy in the hypothyroid rats. Receptor binding studies carried out on the striata from rats sacrificed 48 h after a 6-day course of chronic haloperidol (0.1 mg/kg once daily) treatment revealed a significant upregulation (increase) of dopamine receptors in the hypothyroid rats only. These findings are consistent with the hypothesis that altered thyroid status can modify the sensitivity of dopamine receptors.

Circadian changes in behavioral effects of haloperidol in rats.

Circadian changes in behavioral responses to haloperidol were evaluated in rats under normal and altered lighting cycles. There was a 5.5-fold change in ED50 between the maximum (4 PM) and minimum (4 AM) cataleptic response to the drug under normal lighting (lights of 7 AM- 7 PM). The rhythm was present whether the same rats were tested repeatedly, or fresh rats were used at each time to avoid drug effects which persist for at least several days. Under normal lighting, the maximum cataleptic effect of haloperidol corresponded closely to the light-phase minimum of spontaneous motor activity in untreated rats. Measures of sedation (ptosis and motor inhibition) induced by haloperidol yielded small circadian rhythms under normal lighting and were highly dependent on the baseline level of arousal. A month of constant light or dark, or reversed dark-light cycles had small effects on the sedative actions of haloperidol, although inhibition of locomotion tended to phase-shift with general arousal; these changes did not alter the catalepsy rhythm. While the circadian rhythm of spontaneous activity underwent a complete reversal within 1 month (t 1/2 =17 days) of reversed lighting cycles, the catalepsy rhythm changed very gradually (t 1/2 = 82 days) and required nearly 6 months for complete reversal. Thus, catalepsy is a robust endogenously regulated circadian response that is only slowly influenced by altered lighting conditions which dissociate this rhythm of neuroleptic response from that of spontaneous general arousal. Endogenous neurobiologic and pharmacokinetic factors may contribute to circadian changes in neuroleptic responses.

Tissue levels of haloperidol by radioreceptor assay and behavioral effects of haloperidol in the rat

A radioreceptor assay verified by independent biochemical methods was used to evaluate tissue levels of neuroleptic activity in serum and brain extracts after injections of haloperidol in the rat. The assay detected activity between doses of 0.1 and 10 mg/kg at times between 0.25 and 12 hrs. Tissue levels in blood and brain were highly correlated and corresponded well with a behavioral test of catalepsy at one hour after drug administration. This relationship between brain levels and behavior persisted but changed quantitatively over time.

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.

An operant counting scale for children: A preliminary methodological psychoactive-drug case study.

This pilot study is the first attempt at objective measurement of well-defined molecular behaviors through covert field observation. Though the main thrust is the development of a methodology for the clinical investigation of drug effects on children, a method that minimizes or overcomes many of the special problems that have plagued child drug research in the past, some preliminary data on the behavioral effects of haloperidol and imipramine were obtained. The technique developed is called an operant counting scale, and it promises to be useful in future full-drug studies.

Effect of aminooxyacetic acid, thiosemicarbazide and haloperidol on the metabolism and half-lives of glutamate and GABA in rat brain

The activity of the enzymes glutamate decarboxylase (GAD) and GABA-2-oxoglutarate transaminase (GABA-T), the endogenous GABA and glutamate levels and the half-lives ( t 1 2 values) of radioactive GABA and glutamate have been measured in the brains of untreated rats and in those injected with aminooxyacetic acid (AOAA), thiosemicarbazide (TSC) and haloperidol. The effect of the drugs in vitro on a purified preparation of glutamate dehydrogenase (GDH) was also measured. AOAA profoundly inhibited GABA-T, did not inhibit GAD and in in vitro experiments activated GDH. Brain glutamate levels were unaffected by the drug as was the half-life for glutamate. Brain GABA levels were elevated after AOAA and the rate of disappearance of radioactive GABA slowed. TSC did not significantly alter either GABA or glutamate brain levels but did significantly inhibit GAD and GDH activities. In addition, TSC had no effect on the half-life of either GABA or glutamate. Haloperidol was an effective inhibitor of GDH in vitro and reduced brain glutamate concentrations in vivo. Moreover, the rate of disappearance of radioactive GABA was increased whereas that of glutamate was decreased. The drug had no effect on GAD and GABA-T activities or on brain levels of GABA. It is suggested that the behavioural effects of haloperidol might in part be due to actions on the metabolism of GABA and glutamate. Interaction of TSC with glutamate metabolism might be a factor in seizure-provoking activity of the drug.

Neurochemical correlates of the waltzing-shaker syndrome in the Varitint-waddler mouse.

In the order to examine activity of the dopamine system in the Varitint-waddler (Va) mouse, behavioral effects of haloperidol and dexamphetamine on waltzing Va, non-waltzing Va and non-mutant mice were investigated. The dopamine system of these mice was studied by macro-autoradiography with 14C-dihydroxyphenylalanine. High doses (5.0–10.0 μmol/kg) of haloperidol were similarly effective in both mutant and non-mutant mice: they induced a highly characteristic cataleptic effect in all types of mice. Low doses (0.10–3.16 μmol/kg) were significantly less effective in the waltzing Va mice: they induced a marked shift from a small increase of the sitting frequency in the waltzing mice to a large increase of this measure in the non-mutant mice. Several behavioral measures of the untreated waltzing mice mimicked those of control mice treated with amphetamine. Amphetamine reversed original strain differences and depressed several stereotyped Va activities. The autoradiograms of the waltzing Va mice, which showed a marked labelling of the Harderian gland, differed significantly from those of the nonwaltzing Va mice and controls, which showed no labelling of this gland. It is suggested that a hyperactive dopaminergic mechanism is involved in the waltzingshaker syndrome of the Varitint-waddler.

Behavioral effects of haloperidol after tyrosine hydroxylase inhibition

The effect of haloperidol after pretreatment with H 44/68, a tyrosine hydroxylase inhibitor, on food-reinforced operant behavior (fixed ratio 40:1) was investigated. Intraperitoneal injections of haloperidol in doses that had no effect per se, resulted in a marked depression of the behavior studied when given after a subthreshold dose of H 44/68. The effects are indicative of potentiation and are discussed in terms of a feed-back mechanism connecting the pre- and postsynaptic neurons.

Daily fluctuation (circadian and ultradian) in biogenic amines of the rat brain.

Daily fluctuation (circadian and ultradian) in biogenic amines of the rat brain.