Effects of haloperidol metabolites on neurotransmitter uptake and release: possible role in neurotoxicity and tardive dyskinesia

This research explored the effects of haloperidol (HP) metabolites on biogenic amine uptake and release, and compared them to those of MPTP and its toxic metabolite, MPP⁺. In synaptosome preparations from mouse striatum and cortex, the HP metabolites haloperidol pyridinium (HPP⁺), reduced haloperidol pyridinium (RHPP⁺), and haloperidol tetrahydropyridine (HPTP) inhibited the presynaptic uptake of dopamine and serotonin, with greater affinity for the serotonin transporter. HPP⁺ was the most potent inhibitor of dopamine uptake, and HPTP of serotonin uptake, both with IC₅₀ values in the low micromolar range. RHPP⁺ was less active than the other metabolites, but was more active than the parent compound, HP. Inhibition of uptake was reversed when free drug was removed by centrifugation and then resuspension of the synaptosomes in fresh buffer, suggesting that inhibition of uptake was due to interaction with the transporters and was not due to irreversible cytotoxicity. HPP⁺ showed noncompetitive inhibition of both serotonin and dopamine uptake, suggesting that it has a relatively slow dissociation rate for its interaction with the transporter proteins. In experiments on amine release, HPP⁺ and HPTP were four-fold less potent than MPP⁺ for releasing preloaded dopamine from striatal synaptosomes, and only MPP⁺-dependent release was antagonized by the uptake blocker, mazindol. In contrast, RHPP⁺ displayed little ability to release either amine neurotransmitter. HPTP was about two-fold more potent than MPP⁺ for releasing serotonin from cortical synaptosomes, whereas HPP⁺ was less active than MPP⁺. The specific serotonin transport blocker fluoxetine was only able to antagonize release induced by MPP⁺. These results suggest that HP metabolites bind to the transporters for dopamine and serotonin, but are not transporter substrates. In contrast to their potent effects on amine release, HPP⁺ and HPTP were unable to release preloaded GABA from cortical synaptosomes. The implications of these results concerning a possible role of HP metabolites in the development of tardive dyskinesia are discussed.     

Cognitive and social cognitive functioning in spinocerebellar ataxia

Introduction The spinocerebellar ataxias (SCAs), are rare neurodegenerative disorders caused by distinct genetic mutations. Clinically, the SCAs are characterised by progressive ataxia and a variety of other features, including cognitive dysfunction. The latter is consistent with a growing body of evidence supporting a cognitive as well as motor role for the cerebellum. Recent suggestions of cerebellar involvement in social cognition have not been extensively explored in these conditions. The availability of definitive molecular diagnosis allows genetically defined subgroups of SCA patients, with distinct patterns of cerebellar and extracerebellar involvement, to be tested comparatively using a common battery of tests of general, social and emotional cognition. Methods: Nine patients with SCA6, and 6 with SCA3 were assessed using a comprehensive battery of neuropsychological instruments, encompassing domains of memory, language, visuo-spatial skills, calculation, attention and executive function, emotional processing and theory of mind (ToM). Results There were no deficits in visuo-spatial processing or calculation in either group, while individuals with naming and attentional difficulties were seen in both. Deficits in memory and executive function were present in both conditions, albeit more pronounced in SCA3. By contrast, both groups demonstrated consistently poor performance on ToM tests, and normal attribution of social and emotional responses. Conclusion The data support the hypothesis that the cerebellum is important for cognitive as well as motor activity. The pattern of overlap of domain impairments provides tentative preliminary evidence that there is a cerebellar contribution to aspects of memory and executive function and ToM, and that other domains depend more on neural system outside the cerebellum. The findings relating to ToM are relevant to the possibility of cerebellar involvement in autism.     

Differential effects of haloperidol, clozapine and olanzapine on learning and memory functions in mice

Many schizophrenic patients exhibit impairments in neurocognitive functions. Typical antipsychotic drugs such as haloperidol, have limited or even detrimental influence on cognitive functions. In contrast, atypical antipsychotic drugs, such as clozapine and olanzapine, may improve memory function in schizophrenics. However, only a few studies have been conducted to directly compare the effects of olanzapine, clozapine and haloperidol on memory functions in animal models. Thus, their effects on this issue were investigated in the present studies by using one-way step-through passive avoidance task and Morris water maze as models of learning and memory. The results showed that olanzapine did not affect acquisition, consolidation or retrieval process in step-through test. Moreover, it improved spatial learning function in mice in Morris water maze task. Clozapine and haloperidol appeared to impair acquisition process and consolidation process, respectively, in step-through test. Both drugs impaired spatial learning function in mice in Morris water maze task. The results suggested a positive implication for the clinical medication of olanzapine in schizophrenic treatment.     

Health-related quality of life and its relationship to cognitive and emotional functioning in multiple sclerosis patients

The existing knowledge about the health-related quality of life (HRQoL) and its relationship to cognitive and/or emotional functioning in multiple sclerosis (MS) is scarce. We assessed differences between subgroups of MS outpatients (n = 209) on one HRQoL instrument: a version of the Functional Assessment of Multiple Sclerosis quality of life instrument; on two cognitive functioning tests: the Mini-Mental State Examination and the clock drawing test; and on two emotional functioning tests: the Hamilton Rating Scale for Depression and the Hamilton Rating Scale for Anxiety. Three disease-related characteristics were assessed: physical disability, duration of the illness, and clinical course. The results showed that each of these has an effect on at least one dimension of HRQoL and on one mental functioning test. Thus, the more severe, the more progressive, and the longer the illness duration, the lower the HRQoL. Likewise, cognitive mean scores decreased and emotional mean scores increased with greater illness severity and progressive the MS. Furthermore, we also found significant correlations between cognitive and emotional functioning tests and HRQoL dimensions. Thus, the worse cognitive functioning and the higher depressive and anxiety symptoms score the lower the HRQoL.     

氟哌啶醇对MK-801致小鼠高活动性与前脉冲抑制损害的作用

目的观察氟哌啶醇对谷氨酸功能低下小鼠模型表现出的高活动性及前脉冲抑制(prepulse inhibition,PPI)损害的作用。方法昆明种小鼠152只分组(n=8或n=10)进行下述对照观察:观察不同剂量氟哌啶醇(0.03、0.1、0.3 mg/kg)腹腔注射对昆明种小鼠探究行为和自主活动的影响;以0.25 mg/kg MK-801诱导小鼠自主活动增加,观察上述剂量氟哌啶醇对MK-801致小鼠高活动性的影响;以0.5 mg/kg MK-801诱导小鼠PPI损害,观察氟哌啶醇(0.1、0.3、1 mg/kg)对基线水平PPI以及MK-801损害后PPI的作用。结果与对照组比较,氟哌啶醇剂量为0.1 mg/kg和0.3 mg/kg时,小鼠的探究行为及自主活动总路程减少(P<0.05);但剂量为0.03 mg/kg时,对小鼠的探究行为及自主活动均无影响(P>0.05)。氟哌啶醇剂量为0.1~0.3 mg/kg时,呈剂量依赖性抑制由MK-801引起的自主活动增加(F=27.23,P<0.01),0.1mg/kg的氟哌啶醇的抑制程度为22%(P<0.01),0.3 mg/kg的氟哌啶醇的抑制程度为65%(P<0.00...     

Adaptive immunity affects learning behavior in mice

Regulation of neuronal plasticity by the immune system is an evolving field of modern neuroscience. Here we employ immune deficient mice to examine the role of the immune system in learning behavior of mice in a variety of cognitive tasks. While no motivation or motor function deficits are evident in severe combined immune deficient (scid) mice, there was significant impairment in acquisition of cognitive tasks as compared to wild-type (WT) control mice. Moreover, acute depletion of adaptive immunity in adult WT mice significantly impaired learning behavior. Passive transfer of autologous T cells into WT mice following ablation of adaptive immunity restored previously impaired cognitive function. These results suggest that throughout lifetime, immune system supports cognitive function and may therefore have far-reaching therapeutic implications for cognitive disorders.     

大鼠癫痫持续状态后认知功能变化模式及海马脑红蛋白表达水平的实验研究

目的观察大鼠癫痫持续状态(SE)后学习记忆功能改变情况及海马组织脑红蛋白(NGB)表达水平,探讨癫痫发作对认知功能影响的可能机制。方法健康成年雄性SD大鼠40只,随机分为对照组(n=5)、癫痫模型实验组(n=35),模型组再依据观察时间分为:0 h、1 h、3 h、12 h、24 h、10 d、30 d。应用氯化锂-匹罗卡品(Li-Pilo)建立SE模型,观察致痫期间大鼠行为学变化;采用Nissl染色检测神经元损伤情况;SABC免疫组化法检测NGB表达水平。同时随机选取同期相同品系SD大鼠40只,在造模前及造模后第5d、10 d、15 d、25 d、35 d进行RMT-100迷宫实验,以评价大鼠SE前后学习记忆功能变化情况。结果大鼠SE后,海马CA1、CA3区和DG区均出现不同程度神经元细胞损伤坏死,且NGB表达上调,而海马CA1和CA3区神经元存活数与NGB表达水平呈正相关(r=0.206,P=0.015;r=0.306,P=0.011)。迷宫实验显示工作记忆错误(WME)和参照记忆错误(RME)次数随SE后时间延长均呈递增趋势。相关性分析证实RME次数与CA1和CA3区神经元存活数呈负相关(r=-0.579,P=0.000;r=-0.454,P=0.002),WME次数与CA1和CA3区神经元存活数也呈负相关(r=-0.470,P=0.001;r=-0.507,P=0.000)。结论 SE后NGB表达上调,且与海马组织神经元存活数呈正相关,提示其可能是SE所致缺血缺氧损害的一种代偿神经保护机制。SE后可导致明显认知功能损害,其可能与SE所致海马组织神经元的病理改变相关。     

Alzheimer's disease and depression: preclinical comorbidity effects on cognitive functioning

Both Alzheimer's disease (AD) and depression (D) are prevalent disorders in old age and may co-occur in the same individual. The present study examined whether a diagnosis of D in AD has negative effects on cognitive functioning in the preclinical stage of the diseases, as well as at the time when the diagnoses were rendered. Population-based samples of 13 individuals with incident AD and D, 109 incident AD cases without D, and 179 normal older adults were followed over a three-year period. The groups were compared preclinically and at the time of diagnosis on global cognitive functioning using the MMSE total and the specific item scores, as well as the occurrence of depressive symptoms. As expected, there were clear AD-related deficits preclinically, which were exacerbated at follow-up. In addition, there were D-related deficits on three MMSE items (i.e., following commands, reading, and writing). The poorer performance on the three MMSE items was linked to an elevation of depressive symptoms. However, D was not associated with greater decline in cognitive functioning over the three-year follow-up period. Thus, although depressive symptoms may result in slight cognitive deficits in preclinical AD, at the time of the dementia diagnosis these effects may be absorbed by the neurodegenerative process.     

Effects of haloperidol on antioxidant defense system enzymes in schizophrenia

Dysregulation of free radical metabolism as reflected by abnormal erythrocyte activities of three critical enzymes of the antioxidant defense system (AODS), i.e. superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT), has been reported in schizophrenic patients. The present study examined the effects of haloperidol, a standard antipsychotic agent, on the AODS enzymes, using a within-subject, repeated-measures, on–off haloperidol treatment design. The mean drug free period was 40 days. At baseline, there were no significant differences for all three enzymes between patients and age and sex-matched normal volunteers. During the drug-free condition, SOD activity, but not GSH-Px and CAT activities, was significantly higher relative to normal control subjects. However, within-subjects both SOD and GSH-Px activities, but not CAT activity, were higher in the drug-free condition compared to the treatment condition. No significant correlation was observed between SOD activity and plasma haloperidol (or daily haloperidol dose) levels. Smoking status, as assessed by the cotinine level, was unrelated to enzyme activities. In addition, none of the major AODS enzymes showed significant differences between relapsed and clinically stable patients. These findings suggest that haloperidol may not have direct regulatory effect on AODS enzyme activities and that SOD and GSH-Px activities may change in response to other factors such as change in symptom severity.     

Impact of life-long macronutrient choice on neuroendocrine and cognitive functioning in aged mice: differential effects in stressor-reactive and stressor-resilient mouse strains

Nutrient selection emerges as a result of both genetic and environmental factors and may be further modified by stressors. The impact of this complex interrelationship on pathological outcomes is poorly understood. In the present investigation the stressor-reactive BALB/cByJ and the relatively stressor resilient C57BL/6ByJ mice were maintained on a macronutrient selection protocol or given free access to chow for 20 months. The C57BL/6ByJ mice exhibited a marked preference for fat over carbohydrates, whereas BALB/cByJ mice preferred carbohydrates over fat. Cognitive testing in a Morris water maze indicated that while BALB/cByJ mice were clearly more impaired in this task relative to their C57BL/6ByJ counterparts, there was no substantial effect of the diet at either 13 or 19 months of age. Furthermore, despite their stressor resiliency, at 19 months of age, C57BL/6ByJ mice who invariably consumed fat, exhibited greater plasma corticosterone responses to a 20-min period of restraint than chow fed animals. Indeed, the corticosterone rise was as pronounced as in the more reactive BALB/cByJ strain. Furthermore, the C57BL/6ByJ diet-fed mice showed features of insulin insensitivity and increased adiposity. These data suggest that the adverse effects of fat consumption need to be considered in the context of genetically determined vulnerability/resilience factors.     

The reciprocal relationship between participation in leisure activities and cognitive functioning: the moderating effect of self-rated literacy level

Objective: Participation in leisure activities is beneficial for cognitive functioning of older adults, but it is less known whether it is also beneficial for those with low basic cognitive level. This study examined the reciprocal relationship between participating in leisure activities and cognitive functioning among low and higher literacy level older adults.

Method: Respondents aged 60 years and older who participated in both first waves (2005–2006 and 2009–2010) of the Israeli component of the Survey of Health, Ageing and Retirement in Europe (SHARE-Israel) were divided into low (n = 139) and higher literacy level respondents (n = 714). They reported participation in leisure activities and completed measures of cognitive functioning at both waves.

Results: Cross-lagged models showed that participation in leisure activities predicted higher cognitive functioning four years later only among older adults with low literacy level. On the other hand, cognitive functioning predicted more participation in leisure activities four years later only among higher literacy level older adults.

Conclusions: Participating in leisure activities may be especially beneficial to cognitive functioning among older adults with low literacy level, as their initial low cognitive level allows more room for cognitive improvement than among higher literacy level older adults. Public efforts aimed at increasing participation in leisure activities may therefore target particularly older adults with low basic cognitive level.     

Compression of cognitive morbidity by higher education in individuals aged 75+ living in Germany

Background

Previous studies have shown that higher education may reduce dementia risk and promote a better cognitive functioning in older age.

Objective

The study investigated to what extent higher education leads to compression of cognitive morbidity, and thus a shorter lifetime affected by cognitive impairment and dementia, in individuals aged 75 years and older living in Germany.

Methods

Our sample included n = 742 individuals of the population‐based Leipzig Longitudinal Study of the Aged (LEILA75+; 1998‐2013), who were free of dementia at baseline. The impact of higher education on compression of cognitive morbidity was studied by analyzing the association between education and (1) cognitive functioning over the study period and age at dementia onset, (2) age at death, and (3) the cumulative lifetime cognitive morbidity.

Results

Individuals with more years of education had a higher cumulative cognitive functioning over the lifetime period 75 to 100 years (weighted for survival probability), but not a later age of dementia onset nor a later age at death.

Conclusion

Our results suggest, in individuals aged 75 years and older, higher education only compresses cognitive morbidity prior to dementia onset. Findings may be specific to countries where education is not a necessary requirement for access to good quality health care services.     

Effects of cognitive remediation therapy versus other interventions on cognitive functioning in schizophrenia inpatients

Computerised cognitive remediation therapy (CCRT) has been shown to improve cognitive function in individuals with schizophrenia beyond effects of other forms of therapy. However, results vary between studies, and most are aimed at individuals who are living in the community. Very few studies have investigated its efficacy in psychiatric wards in order to assess whether or not this is a suitable site to start the therapy. This study evaluated CCRT efficacy among schizophrenia inpatients who received a broad range of therapeutic interventions in a psychiatric ward. A randomised controlled trial of CCRT versus an active control in 66 young inpatients with a diagnosis of schizophrenia was conducted. The intervention lasted for 6 weeks and its efficacy was assessed with the composite score of the MATRICS Consensus Cognitive Battery. Both groups improved similarly in cognitive function and psychopathological symptoms. However, the CCRT group improved more than the controls in negative symptoms. This result shows that providing a drill and practice cognitive remediation to inpatients does not produce benefits for cognitive functioning substantially greater than other forms of therapy provided in a ward, but it is more efficient in reduction of negative symptoms. Our results suggest that CRT might be considered as a promising intervention for reducing negative symptoms in schizophrenia individuals.     

Effects of haloperidol and risperidone on psychomotor performance relevant to driving ability in schizophrenic patients compared to healthy controls

The effects of antipsychotic treatment on the psychomotor performance and driving ability of schizophrenic patients is subject of investigation. The present study was designed to evaluate the effects of an atypical neuroleptic (risperidone) in comparison to a conventional dopamine antagonist neuroleptic (haloperidol) on several dimensions of psychomotor performance (visual perception, attention, reaction time, and sensorimotor performance) considered to be of relevance in evaluating driving fitness. Psychomotor performance was assessed by means of the ART 90 (act-and-react test), a computerized test battery which is frequently used in diagnosis of psychomotor performance. The 40 participating patients were examined at discharge following psychopathological stabilisation; 20 received haloperidol medication, 20 received the atypical neuroleptic risperidone. Nineteen healthy individuals were studied as a control group. Our findings indicate a remarkably reduced psychomotor performance in both groups of schizophrenic patients compared to healthy controls. We did find a significant but low correlation between age and some items of the RST3 and between age and the tracking performance on the PVT. The younger patients showed a better test performance than older patients. The BPRS-score was significantly correlated with only two items of the RST3. However, patients under treatment with risperidone showed significantly better results compared to patients treated with haloperidol. Only one (5%) subject passed all subtests without major failures and could be regarded as competent to drive. Among patients with risperidone, seven patients (35%) passed all test parameters without major failures. Clinical implications of these findings are discussed.     

Systemic treatment with GPI 1046 improves spatial memory and reverses cholinergic neuron atrophy in the medial septal nucleus of aged mice

Systemic treatment with GPI 1046, a non-immunosuppressive ligand of the immunophilin FKBP12 (FK-506-binding protein 12 kDa), has previously been shown to promote morphological recovery of the nigrostriatal dopaminergic projection after MPTP lesion in mice, and of lesioned sciatic nerve fibres after nerve crush in rats. In the present study, we investigated whether chronic systemic treatment with GPI 1046 could affect the decline of spatial learning and memory, and the atrophy of medial septal cholinergic neurons, associated with late senescence in C57 black mice. Three-month old (young) and 18-19-month old (aged) male C57BL/6N-Nia mice were first trained in a place learning task in the Morris water maze. Based on their performance relative to young controls, aged animals were then allocated to treatment groups (10 mg/kg GPI 1046, or vehicle). Retention of the spatial platform location was assessed after 3 weeks of dosing. We found that aged animals that had been dosed with GPI 1046 now performed at a significantly better level than their vehicle control group. Aged animals that had shown the greatest degree of impairment during training in the place learning task showed the greatest relative degree of improvement under treatment and were statistically indistinguishable from young, or aged unimpaired control animals. Cell volumes of cholinergic cells in the medial septal nucleus were assessed after an additional 10 months of dosing at 30 months of age, using stereological methods. We found that aged animals displayed a significant 34% decrease in volume of these cells relative to young controls. This atrophy was significantly reversed in aged GPI 1046-treated animals (13% shrinkage). We conclude that chronic systemic treatment with GPI 1046 positively affects memory mechanisms in the aged mouse, possibly by acting on the septohippocampal cholinergic system.