Effects of Fluoxetine on Tyrosine Hydroxylase Expression in Schedule-Induced Polydipsia Rats / 신경정신의학

OBJECTIVE: It has been suggested that fluoxetine inhibits the dopaminergic neurotransmission by serotonergic mediation. And also, it has been shown to inhibit synthesis of DOPA in dopamine-rich areas of the rat forebrain. These dopamine-antagonistic capacity of fluoxetine is only supported by anecdotal report that the increased amount of motor disability in patients with idiopathic Parkinson's disease after exposure to fluoxetine. However, there is still no evidence of the direct effect of fluoxetine on dopaminergic neuronal cell body in the substantia nigra, VTA, caudate & putamen. This study was designed to evaluate the effects of fluoxetine in rat brain which showed decreased numbers of dopaminergic neuronal cell body induced by schedule-induced polydipsia(SIP). METHODS: We incidentally found that 4 weeks of schedule-induced polydipsic rats revealed the suppression of tyrosine hydroxylase expression in the substantia nigra, VTA, caudate & putamen with the immunohistochemistric measures. After 3 weeks of intraperitoneal injection of 10mg/kg of fluoxetine to the schedule induced polydipsic rats, the tyrosine hydroxylase expression was also measured with immunohistochemistry. We compared the tyrosine hydroxylase expression among the normal control, the polydipsic rats, and the rats with fluoxetine treatment. RESULTS: 1) By contrast with the control, the polydipsic rats revealed the evidence of decreased tyrosine hydroxylase expression in the substantia nigra, VTA, caudate & putamen. 2) After daily injection of fluoxetine for 3 weeks, the polydipsic rats showed increment of tyrosine hydroxylase expression in those areas. CONCLULSION: In previous studies, a great deal of results suggest that fluoxetine negatively influence the dopaminergic systems indirectly via serotonergic activation such as inhibition of dopamine synthesis or transport system. Although our results are obtained from rodents, we suggest that fluoxetine directly and positively enhance the dopamine system in the substantia nigra, VTA, caudate & putamen. The chronic adminstration of fluoxetine may be helpful to dopamine-depleted condition in clinical situations. We anticipate the replication studies of our findings and well-controlled clinical trial.

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 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.

A Cabe of Clozapine-Induced Agranulocytosis / 신경정신의학

We report a 20-year-old female patient who developed clozapine-induced agranulocytosis on the 29th day of clozapine treatment. She recovered from the agranulocytosis on the 8th day of progression after treatment with G-CSE, GM-CSF, antibiotics and associated aseptic procedures. The cause of clozapine-induced agranulocytosis is still un known and it is proposed that the dominant gene of major histocompatibility complex region and the reactive metabolites which suppress the myeloid system may be responsible. We recommend that careful attentions such as the selection of patient, evaluation of the risk factors, and the thorough control of CPMS should be paid. If the agranulocytosis happens, it is helpful to consult to the department of medicine immediately.