Cornelius R. Pawlak

Decreased expression and activity of G-protein-coupled receptor kinases in peripheral blood mononuclear cells of patients with rheumatoid arthritis

β2‐Adrenergic and chemokine receptor antagonists delay the onset and reduce the severity of joint injury in rheumatoid arthritis. β2‐Adrenergic and chemokine receptors belong to the G‐protein‐coupled receptor family whose responsiveness is turned off by the G‐protein‐coupled receptor kinase family (GRK‐1 to 6). GRKs phosphorylate receptors in an agonist‐dependent manner resulting in receptor/G‐protein uncoupling via subsequent binding of arrestin proteins. We assessed the activity of GRKs in lymphocytes of rheumatoid arthritis (RA) patients by rhodopsin phosphorylation. We found a significant decrease in GRK activity in RA subjects that is mirrored by a decrease in GRK‐2 protein expression. Moreover, GRK‐6 protein expression is reduced in RA patients whereas GRK‐5 protein levels were unchanged. In search of an underlying mechanism, we demonstrated that proinflammatory cytokines induce a decrease in GRK‐2 protein levels in leukocytes from healthy donors. Since proinflammatory cytokines are abundantly expressed in RA, it may provide an explanation for the decrease in GRK‐2 expression and activity in patients. No changes in β2‐adrenergic receptor number and Kd were detected. However, RA patients showed a significantly increased cAMP production and inhibition of TNF‐α production by β2‐adrenergic stimulation, suggesting that reduced GRK activity is associated with increased sensitivity to β2‐adrenergic activation.—Lombardi, M. S., Kavelaars, A., Schedlowski, M., Bijlsma, J. W. J., Okihara, K. L., Van de Pol, M., Ochsmann, S., Pawlak, C., Schmidt, R. E., Heijnen, C. J. Decreased expression and activity of G‐protein‐coupled receptor kinases in peripheral blood mono‐nuclear cells of patients with rheumatoid arthritis. FASEB J. 13, 715–725 (1999)

NEUROENDOCRINE AND CARDIOVASCULAR RESPONSE TO SEXUAL AROUSAL AND ORGASM IN MEN

Data regarding the neuroendocrine response pattern to sexual arousal and orgasm in man are inconsistent. In this study, ten healthy male volunteers were continuously monitored for their cardiovascular and neuroendocrine response to sexual arousal and orgasm. Blood was continuously drawn before, during and after masturbation-induced orgasm and analyzed for plasma concentrations of adrenaline, noradrenaline, cortisol, luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin, growth hormone (GH), beta-endorphin and testosterone. Orgasm induced transient increases in heart rate, blood pressure and noradrenaline plasma levels. Prolactin plasma levels increased during orgasm and remained elevated 30 min after orgasm. In contrast, none of the other endocrine variables were significantly affected by sexual arousal and orgasm.

Animal models of human psychopathology based on individual differences in novelty-seeking and anxiety

The role of individual factors in behavioural neuroscience is an important, but still neglected area of research. The present review aims to give, first, an outline of the most elaborated theory on animal behaviour, and second, an overview of systematic approaches of historic and present animal models of human psychopathology based on individual differences. This overview will be focused on animal models of unselected subjects (i.e. natural variance of a specific behaviour within a given population) and selected breeding for a specific behaviour. Accordingly, an outline of the personality model from Gray and McNaughton of individual behaviour in animals is given first. Then, a comprehensive overview of past and current animal models in novelty-seeking (i.e. psychomotor activation and exploration behaviour) based on systematic individual differences and its relationship to addiction is presented. Third, this will be followed by a comprehensive overview of individual differences in previous and present animal models for anxiety. Finally, critical aspects of such approaches in animal research are discussed, and suggestions are given where to go from here.

Flares in Patients with Systemic Lupus erythematosus Are Associated with Daily Psychological Stress

Background: The aetiology of systemic lupus erythematosus (SLE) remains unclear. Clinical observations and a small number of studies performed so far suggest an association between psychological stress and self-reported symptoms of SLE patients. This longitudinal study was designed to investigate whether daily psychological stress is associated with flares in SLE patients, measured by clinical and laboratory parameters. Methods: Female SLE patients (n = 41) were followed over a period of six months. Daily stress was monitored by a hand-held PC diary programmed with 44 items based on standardized measures and clinical experience. Once every four weeks patients visited the outpatient clinic for medical evaluation. Disease activity was evaluated using the European Consensus Lupus Activity Measurement (ECLAM), laboratory parameters, and intake of steroids. Results: Classification and regression tree (CART) patient-wise analyses revealed that SLE patients with vs. without flares using complement and ECLAM as activity measures show greater negative self-ratings in mood, and social duties (p < 0.01). In addition, mixed model analysis of variance showed that daily hassles with social relationships were significantly associated with flares in SLE measured by an increase in steroid medication >5mg/d (p < 0.01). Conclusions: These results suggest that psychological stress is associated with flares in SLE. Particularly daily stress with social relationships and social duties may be factors to be related to the course of disease activity in SLE.

Effects of d-cycloserine on MPTP-induced behavioral and neurological changes: Potential for treatment of Parkinson's disease dementia

Glutamatergic dysfunction has been implicated in the neurodegeneration seen in Parkinsons disease (PD). Sub-chronic intraperitoneal injection with D-cycloserine (DCS), a partial agonist at the glycine binding site of the N-methyl-D-aspartate (NMDA) receptor, at dosages of 30, 100, or 200 mg/kg/day, was used to evaluate the role of NMDA receptors in neuronal and behavioral changes in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat model. Starting one day after intra-nigral infusion of MPTP, transient disturbance of motor function in the rotarod test was observed. This impairment spontaneously recovered to control levels 6 days after MPTP lesioning and DCS treatment facilitated recovery. MPTP lesioning also caused deficits in working memory and anxiety-like behavior in the T-maze and elevated plus-maze tests, respectively. Further, object recognition was disrupted in MPTP-lesioned rats, and interleukin-2 levels in the striatum, amygdala, and non-prefrontal cortex were increased, both changes being restored by DCS treatment. Furthermore, MPTP lesion-induced dopaminergic degeneration, microglial activation, and cell loss in the hippocampal CA1 area were all improved by DCS treatment. These results suggest that NMDA receptors are involved in PD-related neuronal and behavioral dysfunctions and that DCS may have clinical potential in the treatment of dementia associated with PD.

Object preference and nicotine consumption in rats with high vs. low rearing activity in a novel open field.

Our previous work has shown that normal male wistar rats can differ systematically with respect to rearing activity in a novel open field: animals with high rearing activity (HRA rats) differed from those with low rearing activity (LRA rats) in dopaminergic and cholinergic brain activity, as well as in their behavioral responsiveness to a cholinergic antagonist, but not in measures of anxiety in the elevated plus-maze. Here, we tested (a) whether HRA vs. LRA reflects responsiveness to novelty, (b) whether such rats voluntarily consume different amounts of the cholinergic agonist nicotine and (c) whether these measures are related to those of anxiety in the plus-maze. Using a novel object test, we found that HRA showed a trend for more object exploration than LRA rats when confronted with two identical novel objects in a familiar open field. When subsequently confronted with a familiar vs. a new object, HRA rats showed substantially more exploration of the new but not of the familiar object than LRA rats. In a subsequent test, HRA vs. LRA rats did not differ in voluntary or forced consumption of oral nicotine, or water. In contrast to rearing activity in a novel open field, measures of anxiety in the plus-maze were neither related to behavior in the novel object test nor to voluntary oral consumption of nicotine, or water. Among others, these data are discussed with respect to dopaminergic and cholinergic forebrain mechanisms, which have previously been found to differ between HRA and LRA rats. Since forebrain dopamine and acetylcholine functions are critical for novelty processing, we suggest that they are also important for the differential behavioral patterns of HRA and LRA rats in the open field, and in the novel object test.

MPTP Lesion Causes Neuroinflammation and Deficits in Object Recognition in Wistar Rats

Animal models of Parkinsons disease with dementia would greatly facilitate research into the underlying causes of this disorder. Here, we showed that bilateral infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into the substantia nigra pars compacta (SNc) of Wistar rats caused degeneration of nigrostriatal dopaminergic neurons, cell loss in the hippocampal CA1 area, as well as microglial activation and increase of interleukin-2 levels in several brain regions. In addition, increase of anxiety-like behavior and impairment of object recognition were observed in the MPTP-lesioned rats. These findings suggest that neuroinflammation may contribute to MPTP-induced neurodegeneration and behavioral deficits, which is suggested as an animal model of Parkinsons disease dementia.

MPTP-induced dopaminergic degeneration and deficits in object recognition in rats are accompanied by neuroinflammation in the hippocampus

Emotional changes, impairment of object recognition, and neuroinflammation are seen in Parkinsons disease with dementia (PDD). Here, we show that bilateral infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into the rat substantia nigra pars compacta (SNc) of Wistar rats caused degeneration of nigrostriatal dopaminergic neurons, microglial activation in the SNc and hippocampus, and cell loss in the hippocampal CA1 area. With regard to behavior, an increase in anxiety-like behavior and impairment of object recognition were observed during the fourth week after MPTP lesioning. The behavioral changes were not caused by motor impairment, since the rats had already recovered from MPTP-induced catalepsy before the tests were performed. These findings show that MPTP-induced neuroinflammation and its consequences, for example, microglial activation and cell loss in the hippocampus, may be involved in dopaminergic degeneration-related behavioral deficits and suggest that, in addition to the dopaminergic system, the limbic system may also participate in the pathophysiology of PDD. MPTP-lesioned rats are therefore proposed as a useful tool for assessing the ability of pharmacological agents to prevent recognition deficits in PDD.

Relationship between striatal levels of interleukin-2 mRNA and plus-maze behaviour in the rat

Our previous experiments have shown that adult male Wistar rats can differ systematically in elevated plus-maze (EPM) behaviour, which was related to the neurotransmitter serotonin in the ventral striatum. The EPM serves as a model of anxiety-like behaviour, and there is evidence that interleukin (IL)-2 in the brain may be related to anxiety-like behaviour, and that IL-2 interacts with the striatal serotonergic system. We asked whether EPM behaviour may also be related to constitutive levels of cytokines in the striatum. Based on open arm time in the EPM, male Wistar rats were divided into sub-groups with either low or high anxiety-like behaviour. Then, IL-1beta, IL-2, IL-6, and tumour necrosis factor (TNF)-alpha cDNA levels were measured post mortem in striatal tissues using semi-quantitative, competitive, reverse transcription polymerase chain reaction. Rats with high anxiety-like behaviour in the EPM showed significantly higher levels of IL-2 mRNA compared to those with low anxiety-like behaviour, but did not differ significantly in expression of IL-1beta, IL-6, and TNF-alpha mRNA. These results provide new evidence indicating that specific cytokine patterns in the striatum may be associated with EPM behaviour in adult male Wistar rats.

Blockade of metabotropic glutamate receptors inhibits cognition and neurodegeneration in an MPTP-induced Parkinson's disease rat model

Hyperactivity of the glutamatergic system is involved in excitotoxicity and neurodegeneration in Parkinsons disease (PD). Metabotropic glutamate receptor subtype 5 (mGluR5) modulates glutamatergic transmission and thus has been proposed as a potential target for neuroprotective drugs. The aim of this study was to determine the effects of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), an mGluR5 antagonist, on working memory, object recognition, and neurodegeneration in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat model. Male Wistar rats were stereotaxically injected with MPTP into the substantia nigra pars compacta (SNc). Starting 1 day after lesioning (day 1), the rats were treated daily with MPEP (2mg/kg/day, i.p.) for 14 days and rats underwent a T-maze test on days 8-10 and an object recognition test on days 12-14. MPTP-lesioned rats showed impairments of working memory in the T-maze test and of recognition function in the object recognition test and both effects were prevented by MPEP treatment. Furthermore, MPTP lesion-induced dopaminergic degeneration in the nigrostriatal system, microglial activation in the SNc, and cell loss in the hippocampal CA1 area were all inhibited by MPEP treatment. These data provide support for a role of mGluR5s in the pathophysiology of PD and suggest that MPEP is a promising pharmacological tool for the development of new treatments for dementia associated with PD.