Rita Dost

Comparison of SHR, WKY and Wistar rats in different behavioural animal models: effect of dopamine D1 and alpha2 agonists

Spontaneously hypertensive rats (SHR) and its counterpart, the Wistar-Kyoto rats (WKY), are probably the most often used animal model of ADHD. However, SHR as model of ADHD have also been criticised partly because of not differing to outbred rat strains. In the present study, adolescent SHR, WKY and Wistar rats from Charles River were tested in open-field, elevated plus maze and novel object recognition and on gastrointestinal transport to more intensively evaluate the strain characteristics. Non-habituated SHR and Wistar rats were more active than WKY rats but contrary to Wistar rats SHR stay hyperactive in a familiar environment. SHR were more sensitive to the alpha2-adrenoceptor agonist guanfacine and the dopamine D1 agonist A-68930 than WKY and Wistar rats, whereas amphetamine, the D1/D5 agonist ABT431 and the D2 agonist quinpirole, similarly affected open-field activity in all strains. In the elevated plus maze, SHR and Wistar rats showed less anxiety-related behaviour than WKY rats. Guanfacine and amphetamine induced an anxiolytic-like activity in SHR but not in WKY and Wistar rats. SHR showed the highest long-term memory in the novel object recognition. Gastrointestinal transport was similar and comparably affected by guanfacine in all rat strains. The present study shows clear differences in the behaviour of SHR and Wistar rats but also of WKY and Wistar rats. The use of SHR as animal model of ADHD is supported.

Effect of PDE10A inhibitors on MK-801-induced immobility in the forced swim test.

RationalNegative symptoms of schizophrenia are insufficiently treated by current antipsychotics. However, research is limited by the lack of validated models. Clinical data indicate that phencyclidine (PCP) abuse may induce symptoms resembling negative symptoms in humans. Based on that, Noda et al. proposed a model of PCP-induced increase of immobility in the forced swim test in mice as a model of depression-like negative symptoms of schizophrenia.ObjectivesThe aim of the study was to evaluate the effect of phosphodiesterase 10A (PDE10A) inhibition in this model which was modified by using MK-801 instead of PCP.MethodsIncrease of immobility in the forced swim test was induced by repeated MK-801 treatment followed by a 2-day washout in mice. The effect of haloperidol, clozapine, risperidone and PDE10A inhibitors was evaluated in this model, on open-field activity and acute MK-801-induced hyperactivity.ResultsRepeated MK-801 treatment significantly increased immobility in the forced swim test without affecting open-field activity. It induced hypersensitivity to the dopamine D1 agonist A-68930, suggesting a hypofunction of the D1 pathway. The increase of immobility is reversed by clozapine and PDE10A inhibitors, but not by haloperidol. Clozapine and the PDE10A inhibitors did not enhance activity at effective doses.ConclusionThe possibility to substitute PCP by MK-801 in this model indicates that the effect is mediated by their common mechanism of NMDA antagonism. PDE10A inhibitors similar to clozapine significantly antagonize the increase of immobility, suggesting a therapeutic potential for the treatment of negative symptoms. However, further validation of the model is necessary.

Sulfonamide inhibitors of α2β1 integrin reveal the essential role of collagen receptors in in vivo models of inflammation

Small molecule inhibitors of α2β1 integrin, a major cellular collagen receptor, have been reported to inhibit platelet function, kidney injury, and angiogenesis. Since α2β1 integrin is abundantly expressed on various inflammation‐associated cells, we tested whether recently developed α2β1 blocking sulfonamides have anti‐inflammatory properties. Integrin α2β1 inhibitors were shown to reduce the signs of inflammation in arachidonic acid‐induced ear edema, PAF stimulated air pouch, ovalbumin‐induced skin hypersensitivity, adjuvant arthritis, and collagen‐induced arthritis. Thus, these sulfonamides are potential drugs for acute and allergic inflammation, hypersensitivity, and arthritis. One sulfonamide with potent anti‐inflammatory activity has previously been reported to be selective for activated integrins, but not to inhibit platelet function. Thus, the experiments also revealed fundamental differences in the action of nonactivated and activated α2β1 integrins in inflammation when compared to thrombosis.