Effects of Naltrexone on the Tyrosine Hydroxylase Expression in the Hypothalamic Areas in Rats with Chronic Ingestion of 5% Ethanol / 대한정신약물학회지

OBJECTIVE: This study was designed to evaluate the effects of nonselective opioid antagonist naltrexone on the expression of tyrosine hydroxylase (TH) in variable areas of hypothalamus in rats with chronic ingestion of 5% ethanol using immunohistochemical measures. METHODS: To induce polydipsia with 5% ethanol, Spraque-Dawley rats were placed in automatic cage where a pellet dispenser automatically dispensed 90 mg pellets at fixed time 60 seconds (FT 60s) feeding schedule over 150-minute test session. After 4 weeks of daily exposure to the FT 60s feeding schedule, experimental rats were administered naltrexone (0.25 mg/kg, i.p), vehicle (1 cc/kg, i.p) for 3 weeks. After completing the 3 weeks of naltrexone and vehicle injections, the polydipsic rats were sacrificed. The brains were removed and postfixed in the same overnight fixation, then frozen sections of 40microM thickness were made in the coronal plane. Sections were stained for detection of tyrosine hydroxylase (H) according to the immunohistochemical method. RESULTS: 1) Both experimental animals with schedule-induced polydipsia (IP) and the bolus with 5% ethanol control showed significant increase in the amounts of 5% ethanol ingestion as compared with their baseline. The naltrexone treated group showed significant decrease in the amount of 5% ethanol ingestion at 2nd and 3rd week as compared with their baseline. Meanwhile, the vehicle control showed no changes in the amount of 5% ethanol ingestion for 3 weeks as compared with their baseline. 2) There was diffused and definite decreases in the TH immunoreactive cells in the bolus control with chronic ingestion of 5% ethanol. The SIP with water group showed marked increase in TH immunoreactive cells in the paraventricular nucleus and the periventricular hypothalamic nucleus. The SIP with 5% ethanol group showed definite decrease of TH immunoreactive cells in the paraventricular nucleus and the periventricular hypothalamic nucleus. The naltrexone treated group showed significant increase of TH immunoreactive cells in the paraventricular nucleus but no changes in the periventricular hypothalamic nucleus. CONCLUSION: These results suggest that the fixed time feeding procedure for schedule induced polydipsia as an animal model of alcoholism was not suitable. The author identified that naltrexone has suppressed the ingestion of ethanol. The chronic ingestion of 5% ethanol suppress the TH immunoreactive cells in the paraventricular nucleus and the periventricular hypothalamic nucleus. Naltrexone increases the TH immunoreactive cells which was suppressed by chronic ingestion of 5% ethanol in the paraventricular nucleus.

Effects of Risperidone on the Schedule-Induced Polydipsia in Rats / 신경정신의학

OBJECTIVES: This study was designed to evaluate the effects of risperidone on the schedule-induced polydipsia (SIP) which is one of animal model of obsessive-compulsive disorder in rats. We administered risperidone as a serotonin and dopamine blocking agent, fluoxetine as a selective serotonin reuptake inhibitor, and haloperidol as a dopamine antagonist to rats which showed schedule-induced polydipsic behaviour. METHODS: Sprage-Dawley rats weighing 200 - 250gm were individually housed and main-tained and allowed free access to water. The rats were placed on a restricted diet. To induce polydipsia, rats were placed in the cage where a pellet dispenser automatically dispensed 90mg pellets on a fixed-time 60 seconds (FT 60s) feeding schedule over 150 minute test session per day. Water was available at all times in the cage. After 4 weeks of daily exposure to the FT 60s feeding schedule, experimental rats met a predetermined criterion for polydipsic behavior (greater than 3 times of water per session on average). 5 groups of rats were administered risperidone (0.1mg/kg, i.p), risperidone (0.5mg/kg, i.p), fluoxetine (5mg/kg, i.p.), haloperidol (0.1mg/kg, i.p.), and vehicle (1cc/kg, i.p. ) for 3 weeks. The rats were tested once a week to access schedule induced polydipsic behavior. Water bottles were weighed before and after the 150-minute test session. The chronic effects of administration of experimental drugs on schedule induced polydipsic behavior were analyzed with ANOVA and Scheffe test as a posthoc comparison. In order to measure water consumption in non-polydipsic food-deprived rats, a separate group of rats (N=8) was individually housed and given a single bolus (14.5gm) of food per day which maintained them at their average body weight. RESULTS: The results were as follows; 1) After 4 weeks of scheduled feeding procedure, the experimental group showed significant differences than the bolus control in the amount of water consumption as compared with their average water intakes for 4 weeks. At the same periods, there were no differences between the experimental group and the bolus control in the body weight. 2) The fluoxetine group showed significant decrease in the amount of water intake at 1st, 2nd, and 3rd weeks of drug treatment as compared with their average amount of polydipsic water intakes. The risperidone 0.1mg group and the risperidone 0.5mg group showed significant decrease in the amount of water intake at the 3rd weeks of drug treatment as compared with their baseline of polydipsic water intakes. However, the haloperidol group and the vehicle control group showed no changes of amounts of water intake for 3 weeks of treatment as compared with their baseline of polydipsic water intakes. 3) The fluoxetine group (22.5+/-10.4ml) showed significantly lower amounts of water intake than haloperidol group (41.3+/-7.1ml) at 2nd weeks of drug treatment. And also the fluoxetine group (18.8+/-3.5ml) showed significantly lower amounts of water intake than the haloperidol group (35.0+/-11.7ml) and the vehicle control (34.4+/-6.8ml) at 3rd weeks of drug treatment. The risperidone 0.1mg group and the risperidone 0.5mg group showed significantly lower amounts of water intake than the haloperidol group (35.0+/-11.7ml) at 2nd weeks and the vehicle control (37.5+/-12.5 , 34.4+/-6.8ml) at 2nd and 3rd weeks of drug treatment. CONCLUSIONS: Above findings suggest that the fixed time feeding procedure for schedule induced polydipsia could be applied as an effective animal model of obsessive compulsive disorder for the evaluation of pharmacological challenge study. We confirmed that chronic treatment with risperidone revealed antipolydipsic effect as effective as fluoxetine on the schedule-induced polydipsic behaviour but the onset of effect was later than fluoxetine.

Effects of Olanzapine on the Schedule-Induced polydipsic Rats

OBJECT: This study was designed to evaluate the effects of olanzapine on the schedule-induced polydipsia(SIP) which is one of animal model of obsessive-compulsive disorder in rats. We administered olanzapine as a serotonin and dopamine blocking agent, fluoxetine as a selective serotonin reuptake inhibitor, and haloperidol for the dopamine antagonist to rats which showed schedule-induced polydipsic behavior. METHODS: Spraque-Dawley rats weighing 200-250gm were individually housed and maintained and allowed free access to water. The rats were placed on a restricted diet. To induce polydipsia, rats were placed in the cage where a pellet dispenser automatically dispensed 90mg pellets on a fixed-time 60 seconds(FT-60s) feeding schedule over 150 minute test session per day. Water was available at all times in the cage. After 4 weeks of daily exposure to the FT 60s feeding schedule, experimental rats met a predetermined criterion for polydipsic behavior(greater than 3 times of water per session on average). 5 groups of rats were administered olanzapine(3mg/kg, i.p), olanzapine(10mg/kg, i.p), fluoxetine(5mg/kg, i.p.), haloperidol(0.1mg/kg, i.o), and vehicle(1cc/kg, i.p) for 3 weeks. The rats were tested once a week to access schedule induced polydipsic behavior. Water bottles were weighted before and after the 150-minute test session. The chronic effects of administration of experimental drugs on schedule induced polydipsic behavior were analyzed with ANOVA and Scheffe test as a post-hoc comparison. In order to measure water consumption in non-polydipsic food-deprived rats, a separate group of rats(N=8) were individually housed and given a single bolus(14.5gm) of food per day which maintained them at their average body weight. RESULTS AND CONCLUSION: There results were as follows : 1) After 4 weeks of scheduled feeding procedure, the experimental group showed significant differences than the bolus control in the amount of water consumption as compared with their average water intakes for 4 weeks. At the same periods, there were no differences between the experimental group and the bolus control in the body weight. 2) The fluoxetine group showed significant decrease in the amount of water intake over the 3 weeks of drug treatment as compared with their average amount of polydipsic water intakes. The olanzapine 3mg group showed significant decrease in the amount of water intake at 3rd weeks of drug treatment as compared with their average amount of polydipsic water intakes. The olanzapine 10mg group showed significant decrease in the amount of water intake at 2nd and 3rd weeks of drug treatment as compared with their average amount of polydipsic water intakes. However, the haloperidol group and the vehicle control group showed no changes of amounts of water intake for 3 weeks of treatment as compared with their average amount of polydipsic water intakes. 3) The fluoxetine group showed significantly lower amounts of water intake than the haloperidol group at 2nd weeks of drug treatment. And also the fluoxetine group showed significantly lower amounts of water intake than the haloperidol group and the vehicle control at 3rd weeks of drug treatment. The olanzapine 3mg group and the olanzapine 10mg group showed significantly lower amounts of water intake than the haloperidol group and the vehicle control at 3rd weeks of drug treatment. Above findings suggest that the fixed time feeding procedure for schedule-induced polydipsia as an animal model of obsessive compulsive disorder was effective to the evaluation of pharmacological challenge study. The authors assume that the serotonin hypothesis and the serotonin-dopamine interaction hypothesis are preferred to the dopamine hypothesis in the biological etiology of obsessive-compulsive disorder.