Jos Prickaerts

Modeling Parkinson's disease in rats: an evaluation of 6-OHDA lesions of the nigrostriatal pathway.

Human idiopathic Parkinsons disease (PD) is a progressive neurodegenerative disorder that is primarily characterized by degeneration of the dopaminergic neurons of the nigrostriatal pathway. Different 6-OHDA rat models of PD have been developed in which this toxin has been injected into different parts of the nigrostriatal pathway: (a) the medial forebrain bundle which leads to extensive dopamine (DA) depletion; (b) the substantia nigra pars compacta, which leads to more specific and moderate DA depletions; and (c) subregions of the caudate-putamen complex (CPu), which also leads to specific DA depletions. In this article we review the dopaminergic depletion and behavioral consequences of 6-OHDA lesions in the rat. It was examined whether the relation between DA depletion and behavioral deficits mimic idiopathic PD. In addition, it was evaluated which model most closely approximates the human situation, especially in relation to the stage of this progressive disease. It was concluded that with respect to the site of the lesion, rats with partial lesions of the ventrolateral CPu are the most appropriate models to study early and late stages of PD. The choice of the behavioral parameters determines the use of unilateral or bilateral lesions, although it is obvious that the bilateral model mimics the human situation more closely.

Transgenic mice overexpressing glycogen synthase kinase 3beta: a putative model of hyperactivity and mania.

Lithium is used as treatment for bipolar disorder with particular efficacy in the treatment of mania. Lithium inhibits glycogen synthase kinase 3β (GSK-3β) directly or indirectly via stimulation of the kinase Akt-1. We therefore investigated the possibility that transgenic mice overexpressing GSK-3β could be of relevance to model bipolar disorder. Transgenic mice showed hypophagia, an increased general locomotor activity, and decreased habituation as assessed in an open field, an increased acoustic startle response, and again decreased habituation. The forced swim test revealed a reduced immobility in transgenic mice, but this is probably related to the hyperactivity of the animals. There were no differences in baseline and stress-induced increases of plasma adrenocorticotrophic hormone and corticosterone levels. Molecular analysis suggests compensatory mechanisms in the striatum of these transgenic mice for the overload of active GSK-3β by dimming the endogenous GSK-3β signaling pathway via upregulation of Akt-1 expression. Brain-derived neurotrophic factor protein levels were increased in the hippocampus of the transgenic mice. This suggests some kind of compensatory mechanism to the observed reduction in brain weight, which has been related previously to a reduced size of the somatodendritic compartment. Together, in mice overexpressing GSK-3β, specific intracellular signaling pathways are affected, which is accompanied by altered plasticity processes and increased activity and reactivity, whereas habituation processes seem to be decreased. The behavioral observations led to the suggestion that the model at hand recapitulates hyperactivity as observed in the manic phase of bipolar disorder.

Serum levels of brain-derived neurotrophic factor in major depressive disorder: state–trait issues, clinical features and pharmacological treatment

Recent evidence supports ‘the neurotrophin hypothesis of depression’ in its prediction that brain-derived neurotrophic factor (BDNF) is involved in depression. However, some key questions remain unanswered, including whether abnormalities in BDNF persist beyond the clinical state of depression, whether BDNF levels are related to the clinical features of depression and whether distinct antidepressants affect BDNF levels equally. We addressed these questions and investigated serum BDNF levels in 962 depressed patients, 700 fully remitted persons (⩾6 months) and 382 healthy controls. We found serum BDNF levels to be low in antidepressant-free depressed patients relative to controls (P=0.007) and to depressed patients who were treated with an antidepressant (P=0.001). BDNF levels of fully remitted persons (whether unmedicated or treated with an antidepressant) were comparable to those of controls. Analyzing the sample of antidepressant-free depressed patients showed that BDNF levels were unrelated to the core clinical features of depression such as its severity or first versus a recurrent episode. The antidepressant associated upregulation of serum BDNF in depressed patients was confined to selective serotonin reuptake inhibitors (SSRIs) (P=0.003) and St Johns wort (P=0.03). Our results suggest that low serum levels of BDNF are a state abnormality that is evident during depression and normalizes during remission. Increases in serum levels of BDNF during antidepressant treatment appear to be confined to some antidepressants and do not parallel clinical characteristics, such as the severity of depressive symptoms.

Effects of two selective phosphodiesterase type 5 inhibitors, sildenafil and vardenafil, on object recognition memory and hippocampal cyclic GMP levels in the rat.

The present study investigated the effects of two cyclic GMP-specific phosphodiesterase enzyme type 5 inhibitors, sildenafil and vardenafil, on the memory performance in the object recognition task. Both compounds were given per orally (1, 3 and 10 mg/kg sildenafil; 0.1, 0.3, 1 and 3 mg/kg vardenafil) immediately after the exposure to two identical objects. The memory for the objects was tested 24 h later. Vehicle-treated rats spent equal times exploring a new and the familiar object demonstrating that they did not remember the familiar one. However, sildenafil improved the object discrimination performance of the rats with a high discrimination performance at a dose of 3 mg/kg. Rats treated with vardenafil also showed an improved object discrimination performance. Compared with sildenafil, vardenafil appeared to be even more potent in this respect since it already produced a high discrimination performance at a dose of 0.3 mg/kg. The effects of both compounds on cyclic GMP and cyclic AMP accumulation were studied in rat hippocampal slices incubated in vitro. Cyclic GMP levels were increased after incubation with the highest concentration of 100 microM vardenafil (together with 0.1 mM sodium nitroprusside), although no changes in cyclic GMP levels were detected after incubation with different concentrations of sildenafil. Both compounds had no effect on cyclic AMP levels. Additional cyclic GMP immunocytochemistry showed that incubation with vardenafil (in the presence of sodium nitroprusside) resulted in a concentration-dependent staining of cyclic GMP. Staining was predominantly found in neuronal fibres in the hippocampal CA2/CA3 region. It was already detected at a concentration of 0.1 microM vardenafil. Also positive fibres were detected after incubation with sildenafil but at a higher concentration of 10 microM. Taken together, these results suggest that inhibition of phosphodiesterase enzyme type 5 improves object recognition memory. This effect might be explained by increased levels of central cyclic GMP.

Selective phosphodiesterase inhibitors: a promising target for cognition enhancement

RationaleOne of the major complaints most people face during aging is an impairment in cognitive functioning. This has a negative impact on the quality of daily life and is even more prominent in patients suffering from neurodegenerative and psychiatric disorders including Alzheimer’s disease, schizophrenia, and depression. So far, the majority of cognition enhancers are generally targeting one particular neurotransmitter system. However, recently phosphodiesterases (PDEs) have gained increased attention as a potential new target for cognition enhancement. Inhibition of PDEs increases the intracellular availability of the second messengers cGMP and/or cAMP.ObjectiveThe aim of this review was to provide an overview of the effects of phosphodiesterase inhibitors (PDE-Is) on cognition, the possible underlying mechanisms, and the relationship to current theories about memory formation.Materials and methodsStudies of the effects of inhibitors of different PDE families (2, 4, 5, 9, and 10) on cognition were reviewed. In addition, studies related to PDE-Is and blood flow, emotional arousal, and long-term potentiation (LTP) were described.ResultsPDE-Is have a positive effect on several aspects of cognition, including information processing, attention, memory, and executive functioning. At present, these data are likely to be explained in terms of an LTP-related mechanism of action.ConclusionPDE-Is are a promising target for cognition enhancement; the most suitable candidates appear to be PDE2-Is or PDE9-Is. The future for PDE-Is as cognition enhancers lies in the development of isoform-specific PDE-Is that have limited aversive side effects.

Determinants of serum brain-derived neurotrophic factor

BACKGROUND Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family of growth factors and affects the survival and plasticity of neurons in the adult central nervous system. The high correlation between cortical and serum BDNF levels has led to many human studies on BDNF levels in various populations, however knowledge about determinants that influence BDNF is lacking. AIMS To gain insight into the factors that influence BDNF levels in humans. METHODS In 1168 people aged 18 through 65, free of antidepressants and current psychiatric disease, from the Netherlands study of depression and anxiety four categories of determinants (sampling, sociodemographics, lifestyle indicators and diseases) were measured as well as BDNF level. We used univariate analyses as well as multivariate linear regression analyses in particular to determine which of the possible determinants significantly influenced serum BDNF levels. RESULTS The mean BDNF level was 8.98ng/ml (SD 3.1ng/ml) with a range from 1.56ng/ml through 18.50ng/ml. Our final multivariate regression analysis revealed that a non-fasting state of blood draw (β=-.067; p=.019), later measurement (β=-.065; p=.022), longer sample storage (β=-.082; p=.004) and being a binge drinker (β=-.063; p=.035) all resulted in attenuated BDNF levels. This was in contrast to smoking (β=.098; p=.001) and living in an urban area (β=.109; p<.001), which resulted in increased BDNF levels. Moreover we found that older subjects also had higher BDNF levels, but this only applied to women (β=.226; p<.001). CONCLUSIONS Future studies on serum levels of BDNF in humans should correct for the time of blood withdrawal, storage, urbanicity, age, sex, smoking status and food and alcohol intake.

Possible role of nitric oxide-cyclic GMP pathway in object recognition memory: effects of 7-nitroindazole and zaprinast.

The effects of 7-nitroindazole, a putative selective inhibitor of neuronal nitric oxide (NO) synthase and zaprinast, a cGMP-selective phosphodiesterase inhibitor, were evaluated on recognition memory of rats in the object recognition test. This test is based on the differential exploration of a new and a familiar object. Two doses of 7-nitroindazole (10 and 30 mg/kg) and zaprinast (3 and 10 mg/kg) were used. The substances were administered i.p. immediately after the exposure to two identical objects, i.e., at the start of the delay interval. After a delay interval of 1 h, control rats spent more time exploring the new object which demonstrates that they recognized the familiar one. Both doses of 7-nitroindazole impaired the discrimination between the two objects after the 1 h interval. After a 4 h interval, control rats did not discriminate between the objects. The highest dose of zaprinast facilitated object recognition after the 4 h interval. In addition, this dose of zaprinast (10 mg/kg) reversed the recognition memory deficit induced by 7-nitroindazole (10 mg/kg) at the 1 h interval. The highest dose of 7-nitroindazole slightly increased mean arterial blood pressure 1 h after its administration. 4 h after administration of zaprinast (10 mg/kg), mean arterial blood pressure was also slightly increased, but not after 1 h after zaprinast administration. However, these effects on blood pressure do not explain the differential effects on object recognition memory. These results therefore suggest that NO-cGMP signal transduction is involved in object recognition memory independently of its cardiovascular role. Finally, since 7-nitroindazole affected mean arterial blood pressure it can not be regarded as a selective inhibitor of neuronal NO synthase.

Prenatal stress and neonatal rat brain development

Chronic or repeated stress during human fetal brain development has been associated with various learning, behavioral, and/or mood disorders, including depression in later life. The mechanisms accounting for these effects of prenatal stress are not fully understood. The aim of this study was to investigate the effects of prenatal stress on early postnatal brain development, a disturbance of which may contribute to this increased vulnerability to psychopathology. We studied the effects of prenatal stress on fetal growth, stress-induced corticosterone secretion, brain cell proliferation, caspase-3-like activity and brain-derived neurotrophic factor protein content in newborn Fischer 344 rats. In addition to a slight reduction in birth weight, prenatal stress was associated with elevated corticosterone levels (33.8%) after 1 h of maternal deprivation on postnatal day 1, whereas by postnatal day 8 this pattern was reversed (-46.5%). Further, prenatal stress resulted in an approximately 50% decrease in brain cell proliferation just after birth in both genders with a concomitant increase in caspase-3-like activity within the hippocampus at postnatal day 1 (36.1%) and at postnatal day 5 (females only; 20.1%). Finally, brain-derived neurotrophic factor protein content was reduced in both the olfactory bulbs (-24.6%) and hippocampus (-28.2%) of prenatally stressed male offspring at postnatal days 1 and 5, respectively. These detrimental central changes observed may partly explain the increased susceptibility of prenatally stressed subjects to mood disorders including depression in later life.

Improving Memory: A Role for Phosphodiesterases

During the last decennia, our understanding of the neurobiological processes underlying learning and memory has continuously improved, leading to the identification of targets for the development of memory-enhancing drugs. Here we review a class of drugs which has more recently been identified: the phosphodiesterase (PDE) inhibitors. An overview is given of the different PDEs that are known and we focus on three PDEs which have been identified as possible relevant targets for memory improvement: PDE2, PDE4 and PDE5. PDEs differ in the substrate, i.e. cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP), being hydrolyzed. Since these cyclic nucleotides have been suggested to play distinct roles in processes of memory, selective PDE inhibitors preventing the breakdown of cAMP and/or cGMP could improve memory. The present data suggest that PDE4 (cAMP) is involved in acquisition processes, although a possible role in late consolidation processes cannot be excluded. PDE5 (cGMP) is involved in early consolidation processes. Since PDE2 inhibition affects both cAMP and cGMP, PDE2 inhibitors may improve both memory processes. The field of PDEs is highly dynamic and new isoforms of PDEs are still being described. This may lead to the discovery and development of new memory enhancing drugs that selectively inhibit such isoforms. Such drugs may exert their effects only in specific brain areas and hence possess an improved side effect profile.

Performance of different mouse strains in an object recognition task.

In the present study, we tested the memory performance of different mouse strains (129/Sv, BALB/c, C57BL and Swiss) in an object recognition task. In this one-trial learning task, mice showed a good object memory performance when a 1-h delay was interposed between the first and second trial. However, when a 24-h delay was used, the mice did not discriminate between the novel and the familiar object in the second trial, indicating that the mice did not remember the object, which was presented in the first trial. Using a 4-h delay, the discrimination performance was at an intermediate level, suggesting a delay-dependent forgetting in this task. Although strain differences were found in the absolute level of exploration activity, no strain differences were found on the relative discrimination index (d2). The present data show that object memory can be assessed in mice and, in contrast to other memory tasks, appears to be less strain-dependent. The reliability of the discrimination measures is discussed.