Schizophrenia, described as the worst disease affecting mankind, is a severe and disabling mental disorder. Schizophrenia is characterized by complicated symptoms and still lacks a diagnostic neuropathology, so developing schizophrenia animal models which have quantifiable measures tested in a similar fashion in both humans and animals will play a key role in new therapeutic approaches. According to the symptoms of cognitive impairment and emotional disorder, the N-methyl-d-aspartate (NMDA)-receptor antagonist MK-801 was applied to induce schizophrenia-like behavior in mice. Locomotor activity and prepulse inhibition (PPI) were selected as indices and the effect of clozapine was also investigated in this model. The results showed that compared with the normal group, MK-801-treated mice exhibited significantly increased locomotor activity and impaired PPI, and pre-exposure to clozapine could ameliorate the abnormality and make it back to normal level. These findings suggest that the model we established could be a useful tool for antipsychotic drug screening.
Animals ; Antipsychotic Agents ; pharmacology ; Clozapine ; pharmacology ; Disease Models, Animal ; Dizocilpine Maleate ; Inhibition (Psychology) ; Male ; Mice ; Motor Activity ; drug effects ; Receptors, N-Methyl-D-Aspartate ; antagonists & inhibitors ; Schizophrenia ; chemically induced ; physiopathology

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

Psychopharmacology has developed over approximately the past five decades. The remarkable proliferation of information in this area has made it difficult for clinicians to understand the characteristics of various psychotropic agents. Atypical antipsychotics including amisulpride, asenapine, aripiprazole, blonanserin, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone, and zotepine cause fewer extrapyramidal problems and have many clinical applications, but they can cause metabolic disturbances. Mood stabilizers and lamotrigine are widely used for bipolar disorder. Other novel anticonvulsants such as topiramate, oxcarbazepine, gabapentin, tiagabine, pregabalin, vigabatrin, levetiracetam, and riulzole have also been tested with diverging or inconclusive results. Antidepressants are commonly used in the clinical treatment of depression and anxiety disorder. However, the mechanism of action of medications used in the treatment of psychiatric disorders remains unclear. Understanding the mechanisms of action and clarifying the diagnosis may enhance the treatment outcome in psychiatry. In this review, we analyzed clinical pharmacology data for each drug within a class and discussed clinical strategies for administering currently available antipsychotics, mood stabilizer/anticonvulsants, and antidepressants widely used for various psychiatric indications.
Aripiprazole ; Amines ; Anticonvulsants ; Antidepressive Agents ; Antipsychotic Agents ; Anxiety Disorders ; Benzodiazepines ; Bipolar Disorder ; Carbamazepine ; Clozapine ; Cyclohexanecarboxylic Acids ; Depression ; Dibenzothiazepines ; Dibenzothiepins ; Fructose ; gamma-Aminobutyric Acid ; Heterocyclic Compounds with 4 or More Rings ; Lurasidone Hydrochloride ; Isoindoles ; Isoxazoles ; Nipecotic Acids ; Quetiapine Fumarate ; Pharmacology, Clinical ; Pregabalin ; Piperazines ; Piperidines ; Piracetam ; Psychopharmacology ; Pyrimidines ; Quinolones ; Risperidone ; Sulpiride ; Thiazoles ; Treatment Outcome ; Triazines ; Vigabatrin