The effect of chronic levodopa on haloperidol induced behavioral supersensitivity in the guinea pig

The effect of chronic levodopa-carbidopa administration (200 mg/kg for 21 days) on guinea pigs rendered behaviorally supersensitive by the prior administration of haloperidol (.5 mg/kg for 21 days) was examined. Animals who showed an increased behavioral response to apomorphine after chronic haloperidol administration were treated with levodopa-carbidopa and then apomorphine - induced stereotypy was reexamined. Although the chronic levodopa control groups and the chronic haloperidol control remained supersensitive to the behavioral effect of apomorphine, the haloperidol-levodopa group's behavioral response to apomorphine returned to normal. Both chronic dopaminergic antagonist and agonist administration have been demonstrated to induce heightened apomorphine-induced stereotypy and this has been interpreted as a reflection of altered striatal dopamine receptor site sensitivity. The finding that the serial administration of a chronic dopaminergic antagonist followed by a chronic dopaminergic agonist results in a return to normal of a striatal dopamine receptor-dependent behavior suggests that these chronic treatments affect dopamine receptor sites by different mechanisms of action. Since neuroleptic induced dopaminergic supersensitivity in animals is an accepted model of tardive dyskinesia, levodopa may also reverse dopaminergic supersensitivity in patients and might be a potential therapeutic agent in tardive dyskinesia.     

Influence of substance P on the behavioral changes induced by haloperidol in rats

Locomotor activity and grooming behavior of rats were recorded for a period of 30 min following intraventricular injections of substance P(SP) in doses of 0.60 and 2.50 microgram/rat. The lower dose of the peptide significantly increased locomotion for 10 min and time spent grooming for 25 min. The effects of the same two doses of SP on the hypokinesia induced by various pharmacological treatments modifying catecholaminergic systems were then examined. SP did not affect the behavioral depression produced by alpha-methyl-para-tyrosine (250 mg/kg), FLA-63 (25 mg/kg) and phenoxybenzamine (20 mg/kg). However, SP, in dose of 0.60 microgram/rat, systematically reversed the decrease in locomotor activity induced by a relatively small dose of haloperidol, 0.1 mg/kg. The dame dose of the peptide significantly counteracted the rigidity but not the hypokinesia and catalepsy resulting from the previous administration of a higher dose of haloperidol, 3 mg/kg. The results support the hypothesis that SP may exert direct or indirect function in motor behavior, possible via a modulatory action on brain dopaminergic systems.     

Concurrent treatment with benztropine and haloperidol attenuates development of behavioral hypersensitivity but not dopamine receptor proliferation

Groups of male rats (n = 16 each) were treated with normal saline, haloperidol (0.75 mg/kg), benztropine (1.8 mg/kg) or haloperidol and benztropine once a day for 24 days. Following a 96 hour drug free interval, subsets of these animals were assessed for apomorphine-induced (0.75 mg/kg) stereotypic behavior, sacrificed and analyzed for striatal dopamine biochemistry or sacrificed and analyzed for spiroperidol binding sites. Benztropine cotreatment attenuated the development of behavioral hypersensitivity to haloperidol but did not alter either the dopamine receptor proliferation or the striatal dopamine biochemical changes induced by haloperidol. These results suggest that behavioral hypersensitivity is not an automatic manifestation of dopamine receptor proliferation but must depend, in part, on other factors.     

Tolerance to behavioral effects of haloperidol

Haloperidol was given daily (3 mg/kg, i.p.) for 5 months. Catalepsy and ptosis in response to a single dose of the neuroleptic were measured weekly. Total scores of both responses gradually decreased, indicating the development of tolerance, but with different time courses. Ptosis and catalepsy responses became half of their initial values by approximately 5 and 10 weeks, respectively. In contrast, the $\text{onset}$ of these behavioral responses gradually became more rapid after each dose of haloperidol over the first 3 to 4 months.     

Behavioral evidence for supersensitivity after chronic administration of haloperidol,clozapine, and thioridazine

Rats administered chronic neuroleptics for 6–7 weeks-- haloperidol (2.5 mg/rat or 1 mg/kg), clozapine (25 mg/kg), or thioridazine (20 mg/kg)--after termination of chronic drug treatment exhibited greater apomorphine-induced stereotyped behavior than their saline controls. Rats treated with thioridazine or clozapine, but not haloperidol, also showed increases in locomotor activity during withdrawal. These findings indicate that behavioral supersensitivity may develop after chronic clozapine treatment as well as after chronic haloperidol.     

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.     

The effect of haloperidol on the performance of stereotyped behavior in sows

Environmentally induced stereotypies in gestating sows were inhibited by haloperidol. This inhibitory effect was stronger in sows that directed stereotyped activities toward objects in the environment than in sows performing self-directed stereotypies. The results indicate that dopamine is involved in the performance of stereotypies in pigs, and that haloperidol seem to impair motivational arousal primarily by reducing the rewarding impact of stereotyped self-stimulation.     

The effect of lithium on chronic haloperidol enhanced apomorphine aggression in rats

The effect of chronic haloperidol or haloperidol plus lithium on apomorphine-induced aggressive and stereotyped behaviors was assessed. Rats withdrawn from chronic haloperidol treatment showed increased aggressiveness and had an increased duration of stereotyped behavior. Rats treated chronically with haloperidol in combination with lithium did not display a supersensitive response. These findings are discussed in relation to the results of other investigators.     

Clastogenic effect of the psychotropic drug thioridazine on human chromosomes in vivo

Summary This paper deals with some other population genetic aspects associated with the incidence of a type of primary congenital glaucoma that occurs very frequently in the Gypsy population of Slovakia. In addition to the decreased fertility of affected individuals of Gypsy origin being determined, the relative reproduction fitness and the selection coefficient against this disease were estimated. An increased number of kinship intermarriages in parents of the patients were recorded, namely in the Gypsy group (45.6%). The average inbreeding coefficient for the Gypsy group (F=0.0091) and the non-Gypsy group (F=0.0030) was calculated. Based on the high frequency of primary congenital glaucoma in a relatively small Gypsy subpopulation and on data about their origin, immigration, and settlements in the territory of Slovakia, the authors consider a special case of gene drift—the founder effect—to be the most plausible explanation of the given fact.     

The impact of the bystander effect on the low-dose hypersensitivity phenomenon

The aim of this study was to investigate the possible relationship between the bystander effect and the low-dose hypersensitivity/increased radio-resistance phenomenon in BJ fibroblast cells taking as response criteria different end points of radiation damage such as cell survival, chromosomal damage (as detected by using micronucleus assay) and double strand breaks (DSBs) of the DNA. Although γ-H2AX foci were observed in confluent bystander BJ cells, our data suggest that X-irradiation does not lead to a significant rate of DSBs in bystander cells. Thus, neither bystander effect induced unstable chromosomal aberrations nor bystander effect induced DSBs are sufficiently pronounced to explain the apparent relationship between bystander effect and low-dose hypersensitivity. The experiments described here suggest that the hyper-radiosensitivity phenomenon might be related to bystander factor induced cell inactivation in the low-dose region (lower than 1 Gy).     

Des-tyrosine1-gamma-endorphin and haloperidol: behavioral and biochemical differentiation.

Des-tyrosine -γ-endorphin and haloperidol were found to produce markedly different response profiles in the rat. Behavioral tests used included response to amphetamine and apormorphine challenge, assessment of catalepsy using the vertical grid and horizontal bar, and characterization of exploratory behavior in a multicompartment chamber. In addition, the effect of these agents on caudate synaptosomal dopamine formation was determined. These data are not consistent with the previous report that des-tyrosine -γ-endorphin is a haloperidol-like neuroleptic (6).     

Differential effects after repeated treatment with haloperidol, clozapine, thioridazine and tefludazine on SNC and VTA dopamine neurones in rats

The effects of repeated treatment (21 days) with different antipsychotic compounds (haloperidol, clozapine, thioridazine and tefludazine) on dopamine (DA) neurones in substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) were studied in rats using single unit recording techniques. A dose-dependent decrease in the number of spontaneously active DA neurones in SNC and in VTA was observed with haloperidol. Clozapine showed no significant effect on the activity in SNC while a dose-dependent decrease in the number of active DA neurones in VTA was observed. Thioridazine showed no or weak effect in SNC while repeated treatment induced a marked inhibitory effect on the DA neurones in VTA. Tefludazine, a potential antipsychotic compound, induced a dose-dependent decrease in both SNC and VTA DA activity. However, the effect on the DA neurones in VTA was more pronounced at all doses. Since the classical neuroleptic haloperidol is equally effective in both regions, while the atypical neuroleptics clozapine and thioridazine have selective or predominant effect in the VTA area it has previously been thought that the inhibition of spontaneously active DA neurones in VTA should indicate an antipsychotic effect of a compound while the inhibition of DA neurones in SNC should account for the development of neurological side effects. The data suggests that the potential antipsychotic compound tefludazine should not induce neurological side effects at lower doses but still has an antipsychotic activity while repeated treatment with higher doses of tefludazine might cause extrapyramidal side effects.