Effects of haloperidol on motor and cognitive functioning in aged mice

The effects of haloperidol on motor and functioning and cognitive functioning were studied in young (3-5 months old) and aged (20-22 months old) male mice by examining haloperidol-induced catalepsy and haloperidol-induced decrements in performance on a radial arm maze. The aged mice were much more sensitive to these adverse effects of haloperidol than were the young mice. Studies of the distribution of radioactivity from [3H]haloperidol to the brain indicated that the differences in sensitivity to this drug were not due to pharmacokinetic differences. The results demonstrate that mice are suitable for studies of aging-induced changes in the behavioral effects of neuroleptic agents.     

Glucocorticoids attenuate haloperidol-induced catalepsy through adrenal catecholamines

Summary To examine the influence of adrenal secretions on neuroleptic induced catalepsy, we studied the effect of adrenocorticoids, noradrenaline (NA) or adrenaline (AD) on haloperidol (HAL) induced catalepsy in adrenalectomised (ADX) and sham-adrenalectomised (sham-ADX) rats. HAL (1 mg/kg, i.p.) induced a greater degree of catalepsy in ADX rats as compared to sham-ADX rats. Corticosterone (CORT, 1–2 mg/kg, s.c.) or dexamethasone (1–2 mg/kg, s.c.) attenuated the HAL catalepsy in sham-ADX but not in ADX rats. Further, when the HAL (1 mg/kg) catalepsy score was maximal (at 120 min), the rats were subjected to cold stress (3 °C for 10 min) or treated with NA, AD (2 g/kg, i.v.) or CORT (2 mg/kg, s.c.). After cold stress procedure or CORT treatment, the catalepsy was significantly reduced in sham-ADX but not in ADX rats, whereas NA or AD infusion caused an immediate but short lasting significant decrease in HAL catalepsy in both sham-ADX and ADX rats. The anticataleptic effect of NA or glucocorticoids was blocked by an ₁adrenoceptor blocker, prazosin.These findings suggest that peripheral noradrenergic and adrenergic mechanisms play an important role in the neuroleptic induced catalepsy. Such mechanisms may mediate the anticataleptic action of glucocorticoids.     

Animal models of Parkinson's disease: An empirical comparison with the phenomenology of the disease in man

Summary Animal models are an important aid in experimental medical science because they enable one to study the pathogenetic mechanisms and the therapeutic principles of treating the functional disturbances (symptoms) of human diseases. Once the causative mechanism is understood, animal models are also helpful in the development of therapeutic approaches exploiting this understanding. On the basis of experimental and clinical findings. Parkinson's disease (PD) became the first neurological disease to be treated palliatively by neurotransmitter replacement therapy.The pathological hallmark of PD is a specific degeneration of nigral and other pigmented brainstem nuclei, with a characteristic inclusion, the Lewy body, in remaining nerve cells. There is now a lot of evidence that degeneration of the dopaminergic nigral neurones and the resulting striatal dopamine-deficiency syndrome are responsible for its classic motor symptoms akinesia and bradykinesia. PD is one of many human diseases which do not appear to have spontaneously arisen in animals. The characteristic features of the disease can however be more or less faithfully imitated in animals through the administration of various neurotoxic agents and drugs disturbing the dopaminergic neurotransmission.The cause of chronic nigral cell death in PD and the underlying mechanisms remain elusive. The partial elucidation of the processes underlie the selective action of neurotoxic substances such as 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), has however revealed possible molecular mechanisms that give rise to neuronal death. Accordingly, hypotheses concerning the mechanisms of these neurotoxines have been related to the pathogenesis of nigral cell death in PD.The present contribution starts out by describing some of the clinical, pathological and neurochemical phenomena of PD. The currently most important animal models (e.g. the reserpine model, neuroleptic-induced catalepsy, tremor models, experimentally-induced degeneration of nigro-striatal dopaminergic neurons with 6-OHDA, methamphetamine, MPTP, MPP⁺, tetrahydroisoquinolines, -carbolines, and iron) critically reviewed next, and are compared with the characteristic features of the disease in man.     

Rotarod Impairment: Catalepsy-Like Screening Test for Antipsychotic Side Effects

Extrapyramidal motoric symptoms are casual side effects under antipsychotic medication. New generation antipsychotics are expected to have a reduced risk due to different receptor affinities. Here, haloperidol and the new generation antipsychotics, risperidone, amisulpride, and aripiprazole, were examined with both catalepsy test and rotarod performance test to screen for their usability in mice. Mice treated with haloperidol, risperidone, and aripiprazole showed dose and time-dependent impairment. Amisulpride-treated mice showed no signs of catalepsy. Catalepsy test and rotarod performance test were useful methods to detect side effects of both generation antipsychotics. Catalepsy test provided more specificity whereas the rotarod test provided higher degree of sensitivity to motor impairment including catalepsy.     

Effect of Tribulus terrestris on Haloperidol-induced Catalepsy in Mice

Haloperidol, an antipsychotic drug, leads to the development of a behavioural state called catalepsy, in which the animal is not able to correct an externally imposed posture. In the present study we have attempted to evaluate the anticataleptic effect of Tribulus terrestris on haloperidol-induced catalepsy in albino mice. Mice were allocated to four groups, each group containing six animals. Both, the test drug, Tribulus terrestris and the standard drug trihexyphenidyl were uniformly suspended in 1% gum acacia solution. Catalepsy was induced in mice with haloperidol (1.0 mg/kg, intraperitoneally). The first group received the vehicle (10 ml/kg, orally), the second group received trihexyphenidyl (10 mg/kg, orally) and the remaining two groups received Tribulus terrestris (100, 200 mg/kg, orally). The animals were assessed after single and repeated dose administration for ten days, 30 min prior to haloperidol, using standard bar test. The result of the present study demonstrates Tribulus terrestris has a protective effect against haloperidol-induced catalepsy, which is comparable to the standard drug used for the same purpose. Our study indicates Tribulus terrestris can be used to prevent haloperidol-induced extrapyramidal side effects.     

Effect of Withania somnifera root extract on haloperidol-induced catalepsy in albino mice

The objective of the study was to evaluate the anticataleptic effect of Withania somnifera (WS) extract, on haloperidol-induced catalepsy in albino mice. Catalepsy was induced with haloperidol (1 mg/kg) i.p. in five groups of male albino mice (n = 6). Three groups received Withania somnifera extract (1.7, 4.25, 8.5 mg/kg) respectively, one group received scopolamine (1 mg/kg) and one group received the vehicle (1% gum acacia) orally, 30 min prior to haloperidol administration. Catalepsy was measured by using standard bar test at 30, 60, 90, 120 and 240 min. This constituted the acute study. For the chronic study, the drugs were administered for 6 more days. Catalepsy was again measured on day 7. Animals were then sacrificed by cervical dislocation and superoxide dismutase (SOD) activity was estimated in the brain. In this study, Withania somnifera extract treated groups showed a dose dependent reduction in cataleptic scores, both in the acute and chronic study. The SOD activity in brain was also found to be lowered in the WS (4.25 mg, 8.5 mg/kg) treated groups. In conclusion, Withania somnifera was found to be more efficacious than scopolamine in reversing haloperidol induced catalepsy. A clear correlation between the SOD levels and cataleptic scores was observed. We believe that the antioxidant properties of this drug could have contributed to the anticataleptic effect.     

Anticataleptic activity of cathinone and MDMA (Ecstasy) upon acute and subchronic administration in rat

It was recently demonstrated that acute administration of 3,4-methylenedioxymethamphet-amine (MDMA, "Ecstasy") is capable of counteracting haloperidol-induced catalepsy in rats. The present study was done with another psychostimulant, S-(-)-cathinone. In these experiments, 32 male Sprague-Dawley rats, 225 +/- 25 g, were used. They were divided into three groups. All groups received 0.5 mg/kg haloperidol in normal saline (s.c.) as a first injection. Then 30 min later each group received either isotonic phosphate-buffered saline, 1 mg/kg S-(-)-cathinone, or 2.5 mg/kg (RS)-MDMA (s.c.) as a second injection. The results of descent latency on both the horizontal bar and vertical grid showed that S-(-)-cathinone or (RS)-MDMA upon acute administration induces a strong anticataleptic activity (P < 0.0001) compared to rats treated with haloperidol plus vehicle. The effect of both drugs was later masked upon subchronic administration (days 2-7, 26-29). This is probably due to sensitization of cataleptic behavior. However, when the same groups of rats were tested on day 8 in a different task, i.e., open-field, they showed a significant difference (P < 0.05). The detailed mechanism of the observed strong anticataleptic activity of S-(-)-cathinone (which is considered a potent dopamine releaser) requires further investigation.     

氯代斯阔任旋光异构体作用于多巴胺受体对动物行为的比较(英文)

目的:比较氯代斯阔任(CSL)旋光异构体对DA受体的作用特性。方法:采用小牛纹状体DA受体结合分析和小鼠、大鼠的行为实验。结果:d-CSL对D_1和D_2受体的K_i值分别是135和9150nmol·L~(-1),而l-CSL对D_1和D_2的亲和力(K_i)均为5.7nmol·L~(-1),分别为d-CSL的24倍和1605倍。dl-CSL对D_1和D_2受体的K_i值分别为8.9和9.6nmol·L~(-1),比l-CSL稍弱。大鼠刻板活动和木僵实验、小鼠的跳跃和自发活动实验均证明CSL旋光异构体对DA受体有阻滞作用。结论:CSL旋光异构体为DA受体阻滞剂的作用特性,其作用强度为:l-CSL>dl-CSL>>d-CSL。     

Neurohormonal changes during formation of latent inhibition in rats predisposed to catalepsy

The response of two monoaminergic systems to induction of latent inhibition has been studied in two rat strains. The noradrenergic system of the Wistar rat brain responded uniformly and systemically in the hippocampus, hypothalamus, amygdala, and frontal cortex. It has been shown that footshock induced a decrease in the norepinephrine level and the return of the mediator level to the control level in the “adaptation + footshock” groups for the four brain regions studied. Significant differences in norepinephrine levels were found in the “footshock” group in the hippocampus and hypothalamus of Wistar rats but not GC rats. The lowest serotonin level in the hippocampus was found in the “adaptation + footshock” group of the cataleptic strain. Opposite changes in corticosterone levels in the blood plasma of GC and Wistar rats were significant according to the F test (F[2, 70] = 3.908, p < 0.05). Differences in the testosterone levels between the two strains during induction of the latent inhibition were absent.