Neuron and neuroblast numbers and cytogenesis in the dentate gyrus of aged APPswe/PS1dE9 transgenic mice: Effect of long-term treatment with paroxetine.

Altered neurogenesis may influence hippocampal functions such as learning and memory in Alzheimer's disease. Selective serotonin reuptake inhibitors enhance neurogenesis and have been reported to reduce cerebral amyloidosis in both humans and transgenic mice. We have used stereology to assess the longitudinal changes in the number of doublecortin-expressing neuroblasts and number of granular neurons in the dentate gyrus of APPswe/PS1dE9 transgenic mice. Furthermore, we investigated the effect of long-term paroxetine treatment on the number of neuroblasts and granular neurons, hippocampal amyloidosis, and spontaneous alternation behaviour, a measure of spatial working memory, in transgenic mice. We observed no difference in granular neurons between transgenic and wild type mice up till 18months of age, and no differences with age in wild type mice. The number of neuroblasts and the performance in the spontaneous alternation task was reduced in aged transgenic mice. Paroxetine treatment from 9 to 18months of age reduced hippocampal amyloidosis without affecting the number of neuroblasts or granular neurons. These findings suggest that the amyloidosis affects the differentiation of neuroblasts and spatial working memory, independent of changes in total granular neurons. Furthermore, while long-term paroxetine treatment may be able to reduce hippocampal amyloidosis, it appears to have no effect on total number of granular neurons or spatial working memory.

Effects of Opioid Agonists on the Suppressed Spontaneous Alternation Behaviour in Rats

This study was designed to evaluated the effects of opioid receptor agonists on the spontaneous alternation behaviour in an animal model of obsessive-compulsive disorder in rats. According to the theory that dopamine is related to the biological etiology of obsessive-compulsive disorder, the effect of the nalbuphine(opioid kappa agonist) and the tramadol(opioid mu agonist), which act as manipulating agents on the inhibition or stimulation of dopamine release, in the spontaneous alternation behaviour were evaluated. 24 hours prior to the experiment, rats were food-deprived. These rats were put into the T-maze, in which white and black goal boxes were baited with small amounts of chocolate milk. Each rat was given 2 set of 7 trials during which it was placed in the start box and allowed to choose the one of the goal boxes for each time. After identifying the stable baseline of spontaneous alternation behaviour, nonselective 5-HT agonist 5-MeODMT(1.25mg/kg/IP) disrupted spontaneous alternation. Rats were stratified into fluoxetine(10mg/kg/IP), nalbuphine(10mg/kg/IP), tramadol(46.4mg/kg/IP), and saline(0.5cc/IP) injection group with experimental drug treatment for 21 days. The effects on the 5-M?DMT(1.25mg/kg/IP) induced disruption of spontaneous alternation behaviour were checked at the next day of discontinuation of drug treatment. The results were as follows : 1) At the day after 21 days of the drug treatment, the nalbuphine treated group and the fluoxetine treated group showed significant difference from the tramadol treated group and the saline treated group in the 5-MeODMT(1.25mg/kg/IP) induced suppression of spontaneous alternation behaviour. 2) Within each drug treatment group, the fluoxetine treated group showed significant difference between before and after the treatment of fluoxetine in the 5-MeODMT(1.25mg/kg/IP) induced suppression of spontaneous alternation behaviour. And also, the nalbuphine treated group showed significant difference between before and after the treatment of nalbuphine in the 5-MeODMT(1.25mg/kg/IP) induced suppression of spontaneous alternation behaviour. There was no difference between the baseline and after the treatment of nalbuphine in the 5-MeODMT(1.25mg/kg/IP) induced suppression of spontaneous alternation behaviour. We indentified that the opioid kappa agonist that act as dopamine release inhibitor affect the spontaneous alternation behaviour which is an animal model of obsessive-compulsive disorder in rat.

Effects of the Clozapine on the Suppressed Spontaneous Alternation Behaviour in Rats / 신경정신의학

OBJECTIVES: The study was designed to evaluate the role of the 5-HT2 and dopanmine D2 antagonist on spontaneous alternation behaviour which is an animal model of obsessive compulsive disorder in rat. On the basis of serotonin-dopamine interaction hypothesis, the effect of clozapine was evaluated by applying the suppressed spontaneous alternation behaviour model. METHODS: The apparatus for spontaneous alternation behaviour was a black plexiglas T-maze with distinctive black and white goal boxes. Black guillotine doors separated the start box and the goal boxes from the main body of the T-maze. Small cups of chocolate milk were placed in the corners of both goal boxes. At 24 hours prior to experiment, rats(spraque-Dawley) were food-deprived. The food-deprived rate were put into T-maze, in which both goal during which it was placed in the start box and allowed to choose one of the goal boxes for each time. The mean number of choices until the occurrence of spontaneous altemation behaviour were checked. After baseline of the number of choices of spontaneous altemation behaviour was stabilized, the spontaneous altemation was disrupted by nonselective 5-HT agonist, 5-MeODMT(1.25mg/kg/IP). The experimental animals were stratified nito 5 groups : clomipramine(5mg/kg/IP), clozapine(10mg/kg/IP), clozapine(20mg/kg/IP), haloperidol(0.1mg/kg/IP), and saline(0.2cc/IP) control groups. They all went through 21 days fo treatment(intraperitoneal). The protective effects against the 5-McODMT-induced disruption of spontaneous alternation behaviour were evaluated on the next day of drug treatment in each group. RESULTS: 1) SAB was supressed by 5-McODMT injection. 2) After 21 days of the drug treatment, the clozapine and the clomipramine groups showed significant difference from the haloperidol and the saline control groups in the reversal of 5-McODMT-induced from the haloperidol and the saline control groups in the reversal of 5-MeODMT-induced suppression of spontaneous altermation behaviour. 3) The clozapine(20mg/kg/IP) group was superior to the clomipramine group in the protective effect of 5-MeODMT-induced suppression of spontaneous alternation behaviour. CONCLUSION: In clinical situation, the we think that atypical antipsychotic drugs those acting as serotonin and dopamine receptor antagonist with no extrapyramidal side effect can be beneficial to improve the symptoms of obsessive-compulsive disorder.