OBJECTIVETo set the measuring method of tyrosine hydroxylase activity in the brain of conscious rats.

METHODBy using microdialysis and High Performance Liquid Chromatography-Electrochemical Detector system, the 3, 4-dihydrioxphenylalanine (DOPA) formation in the striatum of 6-hydroxdopamine-pretreated rats during infusion of an L-aromatic amino-acid decarboxylase inhibitor (NSD1015) was monitored.

RESULTThe absence of DOPA in dialysates of 6-hydroxdopamine-pretreated rats, the measurable DOPA and the steady decreasing of 3,4-dihydroxyphenylacetic acid(DOPAC) during infusion of NSD1015 and the disappearance of DOPA after administration of alpha-methyl-rho-tyrosine indicated that the dialyzed DOPA was derived from dopaminergic nerve terminals. After intraperitoneal administration of dopamine receptor agonist apomorphine the DOPA output was deseased. After intraperitoneal administration of dopamine recepter antagonist haloperidol, the DOPA output was increased. The study showed that twenty-four hours ofter implantation of the probe with infusion of 0.01 mmol.L-1 NSD1015, the DOPA level in the striatum of 6-hydroxdopamine-pretreated rats was 0.39 +/- 0.12 pmol/min (X +/- S, n = 5).

CONCLUSIONThe DOPA concentration in striatal dialysates could be considered as an index of tyrosion hydroxlase activity during infusion of 0.01 mM NSD1015. The method in vivo to monitor tyrosine hydroxlase activity in the brain is reliable.

Animals ; Apomorphine ; pharmacology ; Brain ; enzymology ; Dihydroxyphenylalanine ; metabolism ; Dopamine Agonists ; pharmacology ; Dopamine Antagonists ; pharmacology ; Female ; Haloperidol ; pharmacology ; Male ; Microdialysis ; Rats ; Rats, Sprague-Dawley ; Tyrosine 3-Monooxygenase ; metabolism

OBJECTIVEChildren with Tourette's syndrome (TS) have a poor treatment compliance due to side effects and inconvenient administration of oral drugs. This study explored the efficacy and safety of clonidine transdermal patch for treating TS in children.

METHODSA total of 119 children with TS were randomly treated with the clonidine transdermal patch (n=65) or with oral haloperidol (n=54). The therapeutic efficacy was assessed based on the results of the Yale Global Tic Severity Scale (YGTSS) 4 weeks after treatment.

RESULTSThe clonidine transdermal patch group showed a higher reduction in the overall tic symptom scores (61.5+/-7.5%) than that in the haloperidol group (41.0+/-6.3%; p<0.05). Clonidine transdermal patch treatment was effective in 53 patients (81.5%) and 36 patients (67.5%) showed effective to oral haloperidol (p>0.05). Mild side effects (decrease of blood pressure and dizziness) were observed in 1 patient in the clonidine transdermal patch group. Mild hypermyotonia, drowsiness or lassitude as side effects occurred in 6 patients in the haloperidol group.

CONCLUSIONSClonidine transdermal patch is effective for the treatment of TS in children and its side effects are mild and rare.

Administration, Cutaneous ; Adolescent ; Child ; Child, Preschool ; Clonidine ; administration & dosage ; adverse effects ; pharmacology ; Female ; Haloperidol ; therapeutic use ; Humans ; Male ; Tourette Syndrome ; drug therapy

OBJECTIVETo observe the effect of salidroside on tic behavior and in vivo dopamine DA) and serotonin (5-HT) levels in Tourette syndrome (TS) model rats.

METHODSForty rats were randomly divided into the blank control group, the TS model group, the haloperidol-treated group (0.5 mg/kg x d(-1)), and the salidroside-treated group (50 mg/kg x d(-1)), 10 in each group. TS rat model was induced by imino-dipropio-nitrile (IDPN). Peritoneal injection of haloperidol and salidroside was started from the 4th day of modeling in the haloperidol-treated group and the salidroside-treated group respectively. Normal saline was peritoneally injected to rats in the blank control group and the TS model group respectively. Stereotyped behavior was scored, and changes of DA and 5-HT levels in blood and striatum were measured before modeling, after modeling, and after intervention.

RESULTSCompared with the blank control group, the score of the tic behavior was elevated (P < 0.01) , levels of DA and 5-HT in plasma and striatum were reduced in the model group (P < 0.01, P < 0.05). Compared with the same group after modeling, the tic behavior score decreased and plasma DA levels increased in the two treated groups after intervention (P < 0.01). 5-HT content increased in the salidroside-treated group (P < 0.01). Compared with the model group after intervention, the tic behavior score was significantly reduced (P < 0.01), and DA levels in plasma and striatum were elevated (P < 0.01, P < 0.05) in the salidroside-treated group and the haloperidol-treated group. Compared with the haloperidol-treated group, the tic behavior score increased (P < 0.01), DA levels in plasma and striatum were lowered (P < 0.01, P < 0.05), the 5-HT level increased in plasma and striatum (P < 0.01, P < 0.05) in the salidroside-treated group.

CONCLUSIONSIn the salidroside-treated group, the tic behavior was significantly reduced, and DA levels in plasma and striatum were elevated. Its mechanism might be related to regulating activities of dopamine neurons in striatum.

Animals ; Corpus Striatum ; Dopamine ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Glucosides ; pharmacology ; therapeutic use ; Haloperidol ; Phenols ; pharmacology ; therapeutic use ; Rats ; Serotonin ; Stereotyped Behavior ; Tics ; drug therapy ; Tourette Syndrome ; drug therapy

OBJECTIVETo investigate effect of inhibiting melatonin biosynthesis on activities of protein kinase A (PKA), glycogen synthase kinase-3 (GSK-3) and tau phosphorylation at PS214 and M4 epitopes using haloperidol, a specific inhibitor of 5-hydroxyindole-O-methyltransferase.

METHODSBrain ventricular and intraperitoneal injections were used for haloperidol administration, Western blots for tau phosphorylation, 32P-labeling for PKA and GSK-3 activity, and high performance liquid chromatograph for detection of serum melatonin levels.

RESULTSHaloperidol injection through the lateral ventricle and intraperitoneal reinforcement significantly stimulated PKA activity with a concurrent hyperphosphorylation of tau at M4 (Thr231/Ser235) and PS214 (Ser214) sites. Prior treatment of the rats using melatonin supplement for one week and reinforcement during the haloperidol administration arrested PKA activity and attenuated tau hyperphosphorylation. GSK-3 activity showed no obvious change after haloperidol injection, however, melatonin supplements and reinforcements during haloperidol infusion inactivated basal activity of GSK-3.

CONCLUSIONDecreased melatonin may be involved in Alzheimer-like tau hyperphosphorylation, and overactivation of PKA may play a crucial role in this process.

Animals ; Cyclic AMP-Dependent Protein Kinases ; metabolism ; Epitopes ; Glycogen Synthase Kinase 3 ; metabolism ; Haloperidol ; administration & dosage ; pharmacology ; Hippocampus ; enzymology ; metabolism ; Injections, Intraperitoneal ; Injections, Intraventricular ; Male ; Melatonin ; biosynthesis ; blood ; Phosphorylation ; drug effects ; Rats ; Rats, Wistar ; tau Proteins ; metabolism

OBJECTIVETo develop a mouse model to mimic the behavioral and neurochemical changes of Tourette syndrome (TS) by 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) induction and to investigate the effects of fluoxetine and haloperidol on head twitch response (HTR) induced by DOI.

METHODS1) Preparation of mouse model of TS: Forty mice were randomly divided into experimental and control groups (n=20 each). DOI (1 mg/kg) was administered by peritoneal injection in the experimental group. The control group was injected with normal saline. The levels of dopamine (DA) and homovanillic acid (HVA), the metabolite of DA, in both groups were measured by high performance liquid chromatography and electrochemical detection. 2) Effects of fluoxetine and haloperidol on HTR: Eighty mice were randomly administered with either fluoxetine (2 mg/kg), haloperidol (0.8 mg/kg), fluoxetine + haloperidol or normal saline. DOI (1 mg/kg) was peritoneally injected 20 minutes later (acute trial) or 18-20 hrs after a 21 days injection of fluoxetine or haloperidol (chronic trial). The frequency of DOI induced HTR was observed immediately after DOI injection.

RESULTSThe levels of DA and HVA in the experimental group were significantly lower than those in the control group (DA: 45.00 +/-11.24 ng/mg vs 58.16 +/-14.51 ng/mg; HVA:10.54 +/-1.86 ng/mg vs 12.82 +/-2.66 ng/mg). In both acute and chronic trials, the frequency of DOI-induced HTR decreased significantly in mice administered with haloperidol alone or together with fluoxetine (P < 0.05), but it did not change significantly in mice administered with fluoxetine alone compared with the normal saline group.

CONCLUSIONSThe levels of DA and HVA are reduced in mice with DOI-induced HTR. DOI-induced mouse mode of HTR can mimic the neurochemical and behavioral changes of TS paritially. Haloperidol can inhibit DOI-induced HTR in mice, but fluoxetine can not.

Amphetamines ; pharmacology ; Animals ; Disease Models, Animal ; Dopamine ; analysis ; Fluoxetine ; therapeutic use ; Haloperidol ; therapeutic use ; Homovanillic Acid ; analysis ; Male ; Mice ; Receptor, Serotonin, 5-HT1A ; physiology ; Tourette Syndrome ; chemically induced ; drug therapy

Glycogen synthase kinase 3 (GSK3) was recently suggested to be a potential target of psychotropics used in psychiatric illnesses such as schizophrenia and bipolar disorder. Relevant studies have found that antipsychotic drugs regulate GSK3 activity via an increase in either inhibitory serine phosphorylation or amount of GSK3 after acute or subchronic treatment. Recent evidence shows that GSK3 is regulated by dopaminergic or serotonergic systems implicated in the pathophysiology and treatment mechanisms of schizophrenia and bipolar disorder. Therefore, antipsychotics may regulate GSK3 via antagonizing dopaminergic or serotonergic activity. However, the signaling pathway that is involved in GSK3 regulation by dopaminergic or serotonergic systems has not been well established. Haloperidol is a typical antipsychotic with potent dopamine D(2) receptor antagonism. Clozapine is an atypical antipsychotic with potent serotonin 5HT(2) receptor antagonism. We injected rats with haloperidol or clozapine and examined the phosphorylation and amount of GSK3alpha/beta and its well-known upstream regulators Akt and Dvl in the rat frontal cortex by Western blotting. Both haloperidol and clozapine induced Ser21/9 phosphorylation of GSK3GSK3alpha/beta. Haloperidol increased the Ser473 phosphorylation of Akt transiently, whereas clozapine maintained the increase for 1 h. Haloperidol did not affect the phosphorylation and amount of Dvl, whereas clozapine increased both phosphorylation and the amount of Dvl. Our results suggest that GSK3 activity may be regulated by both typical and atypical antipsychotics and that Akt or Dvl, depending on the D(2)- or 5HT(2)- receptor antagonism properties of typical and atypical antipsychotics, mediate the regulation differently.
Adaptor Proteins, Signal Transducing/metabolism/*physiology ; Animals ; Antipsychotic Agents/*pharmacology ; Clozapine/*pharmacology ; Dopamine Antagonists/pharmacology ; Frontal Lobe/*drug effects/enzymology ; Glycogen Synthase Kinase 3/*metabolism ; Haloperidol/*pharmacology ; Male ; Phosphoproteins/metabolism/*physiology ; Phosphorylation ; Proto-Oncogene Proteins c-akt/metabolism/*physiology ; Rats ; Rats, Sprague-Dawley ; Serotonin Antagonists/pharmacology ; Signal Transduction

OBJECTIVETo investigate the reversal effect of haloperidol (Hal) on doxorubicin (Dox) resistance and its inhibition effect on P-glycoprotein and swelling-activated chloride channel in Dox-resistant erythro-leukemic cell line K562/Dox.

METHODSTumor cell proliferation was measured by LDH assay. mRNA expressions of P-glycoprotein (MDR1), glutathione S-transferase Pi (GSTpi) and MDR-associated protein (MRP) of K562/Dox treated with Hal were assayed by RT-PCR. Chloride-sensitive dye MQAE was loaded into K562/Dox cells and the intracellular fluorescence intensity was measured to evaluate the effect of Hal on chloride channel in swelling-activated K562/Dox cells. Coulter counter ZM and Channelyzer 256 were used to measure cell volume regulation.

RESULTSHal significantly reversed Dox resistance in K562/Dox cells after 12.50, 6.25 and 3.12 micromol/L Hal treatment, the chemosensitivity to Dox increased by 8.61, 4.35 and 2.25 times respectively. After treatment with Hal 12.50 micromol/L, MDR1 and MRP mRNA expression were gradually down-regulated in a time-dependent manner on d1-d3, reducing to 76.3% and 64.6% of the control level on d3 (P < 0.05), while GSTpi mRNA expression decreased by 66.1% (P < 0.05) on d1-d2, and began to recover on d3. The swelling-activated chloride channel and cell regulatory volume decreased (RVD) in K562/Dox cells were also inhibited by Hal. Under hypotonic challenge the cellular fluorescence intensity which represented chloride concentration declined by (34.46 +/- 5.91)%. After adding 6.25 micromol/L and 18.75 micromol/L Hal, the hypotonic challenge only caused decrease in fluorescence intensity by (24.43 +/- 3.25)% and (16.63 +/- 4.98)% (P < 0.01). RVD in hypotonic condition was (84.95 +/- 5.69)%. RVD under hypotonic condition with 6.25 micromol/L and 18.75 micromol/L Hal were (51.12 +/- 6.01)% and (39.51 +/- 4.79)% respectively (P < 0.01).

CONCLUSIONA nontoxic concentration of haloperidol can significantly reverse drug resistance through a multi-pathway effect, including down-regulating mRNA expressions of MDR, GSTpi and MRP, inhibition of swelling-activated chloride channel and RVD in K562/Dox cells.

ATP-Binding Cassette, Sub-Family B, Member 1 ; biosynthesis ; genetics ; Antibiotics, Antineoplastic ; pharmacology ; Chloride Channels ; drug effects ; Doxorubicin ; pharmacology ; Drug Resistance, Multiple ; drug effects ; Drug Resistance, Neoplasm ; drug effects ; Glutathione S-Transferase pi ; Glutathione Transferase ; biosynthesis ; genetics ; Haloperidol ; pharmacology ; Humans ; Isoenzymes ; biosynthesis ; genetics ; K562 Cells ; Multidrug Resistance-Associated Proteins ; biosynthesis ; genetics ; RNA, Messenger ; biosynthesis ; genetics