OBJECTIVE: Accumulating evidence suggests that oxidative stress plays a role in the pathophysiology of schizophrenia and that the potent antioxidants may be potential therapeutic drugs for schizophrenia. This study was undertaken to examine the effects of the potent antioxidant sulforaphane (SFN), found in cruciferous vegetables, on behavioral abnormalities (e.g., hyperlocomotion and prepulse inhibition [PPI] deficits) in mice after a single administration of the N-methyl-D-aspartate (NMDA)-receptor antagonist phencyclidine (PCP). METHODS: Effects of SFN (3, 10, and 30 mg/kg, intraperitoneally [i.p.]) on hyperlocomotion and PPI deficits in the adult male ddY mice after administration of PCP (3.0 mg/kg, subcutaneously [s.c.]) were examined. RESULTS: Administration of SFN (30 mg/kg, intraperitoneally [i.p.]), but not low doses (3 and 10 mg/kg, i.p.), significantly attenuated hyperlocomotion in mice after PCP administration (3.0 mg/kg, subcutaneously [s.c.]). Furthermore, administration of SFN (3, 10, and 30 mg/kg, i.p.) attenuated the PPI deficits in mice after PCP administration (3.0 mg/kg, s.c.) in a dose-dependent manner. CONCLUSION: These results suggest that SFN has antipsychotic activity in an animal model of schizophrenia. Therefore, it is likely that SFN may be a potential therapeutic drug for schizophrenia.
Adult ; Animals ; Antioxidants ; Humans ; Male ; Mice ; Models, Animal ; N-Methylaspartate ; Oxidative Stress ; Phencyclidine ; Schizophrenia ; Thiocyanates ; Vegetables

OBJECTIVE: Iptakalim is a putative ATP-sensitive potassium (KATP) channel opener. It is also a novel nicotinic acetylcholine receptor (nAChR) blocker and can antagonize nicotine-induced increase in dopamine release in the nucleus accumbens. Our recent work also shows that iptakalim exhibits a clozapine-like atypical antipsychotic profile, indicating that iptakalim may possess a dual action against nicotine addiction and schizophrenia. METHODS: The present study examined the potential therapeutic effects of iptakalim on nicotine use in schizophrenia. We created an animal model of comorbidity of nicotine addiction and schizophrenia by injecting male Sprague-Dawley rats with nicotine (0.40 mg/kg, subcutaneously[sc]) or saline, in combination with phencyclidine (PCP, 3.0 mg/kg, sc) or saline daily for 14 consecutive days. RESULTS: During the PCP/nicotine sensitization phase, PCP and nicotine independently increased motor activity over time. PCP also disrupted prepulse inhibition (PPI) of acoustic startle response. Acute nicotine treatment attenuated the PCP-induced hyperlocomotion and PCP-induced disruption of PPI, whereas repeated nicotine treatment potentiated these effects. Importantly, pretreatment with iptakalim (10-20 mg/kg, intraperitoneally) reduced nicotine-induced hyperlocomotion in a dose-dependent fashion. This reduction effect was highly selective: it was more effective in rats previously sensitized to the combination of PCP and nicotine, but less effective in rats sensitized to saline, nicotine alone or PCP alone. CONCLUSION: To the extent that the combined nicotine and PCP sensitization mimics comorbid nicotine addiction in schizophrenia, the preferential inhibitory effect of iptakalim on nicotine-induced hyperlocomotion suggests that iptakalim may be a potential useful drug for the treatment nicotine abuse in schizophrenia.
Acoustics ; Animals ; Comorbidity ; Dopamine ; Humans ; Male ; Models, Animal ; Motor Activity ; Nicotine ; Nucleus Accumbens ; Phencyclidine ; Potassium ; Propylamines ; Psychotic Disorders ; Rats ; Rats, Sprague-Dawley ; Receptors, Nicotinic ; Schizophrenia

OBJECTIVE: In humans, a single exposure to phencyclidine (PCP) can induce a schizophrenia-like psychosis which can persist for up to two weeks. In rats, an acute dose of PCP increases dopaminergic activity and causes changes in dopamine related behaviours some of which are sexually dimorphic. To better understand the effects of PCP on dopamine receptor adaptations in the short term we examined dopamine D1-like receptors (D1R) and D2-like receptors (D2R) in the mesolimbic and nigrostriatal dopamine pathways, 4 hours after exposure to PCP in female rats. METHODS: Animals received a single dose of 40 mg/kg PCP and were sacrificed 4 hours later. In vitro autoradiography was carried out using [3H] SCH 23390 and [3H] raclopride that target D1R and D2R respectively, in cryostat brain sections. RESULTS: Two way analysis of variance (ANOVA), revealed an overall effect of PCP treatment (F [1,63]=9.065; p=0.004) on D1R binding with an 18% decrease (p<0.01) in binding in the medial caudate putamen. PCP treatment also had an overall effect on D2R binding (F [1,47]=5.450; p=0.024) and a trend for an increase in D2R binding across all the brain regions examined. CONCLUSION: These results suggest opposing D1R and D2R adaptations in striatal subregions of female rats following acute exposure to PCP that may occur through indirect mechanisms.
Animals ; Autoradiography ; Benzazepines ; Brain ; Dopamine ; Female ; Humans ; Phencyclidine ; Psychotic Disorders ; Putamen ; Raclopride ; Rats ; Receptors, Dopamine

OBJECTIVE: To evaluate the features of autopsy cases involved in electronic weapon (TASER) in the State of Maryland, and to discuss the appraisable points. METHODS: Thirteen autopsy cases involving TASER were collected from 2004 to 2011 in the Office of the Chief Medical Examiner, State of Maryland. All the cases include detailed scene investigations, complete autopsy, toxicological analysis and histopathological examination. Statistical analysis were conducted including general information of victim, type of TASER, type of contact, toxicological results, manner and cause of death. RESULTS: Majority of victims were male with an acute onset of agitated and delusional behavior. Drugs were often involved. Deaths were attributed to multiple factors. CONCLUSION Most of cases involved in TASER resulted from multiple fatal factors. Further researches are needed for the principal mechanism. Thorough scene investigation and complete autopsy examination play crucial role in evaluation of such cases.
Adult ; Autopsy/methods* ; Cause of Death ; Cocaine/analysis* ; Conducted Energy Weapon Injuries/etiology* ; Female ; Forensic Pathology ; Humans ; Male ; Maryland/epidemiology* ; Mental Disorders/complications* ; Middle Aged ; Phencyclidine/analysis* ; Retrospective Studies ; Substance-Related Disorders/complications* ; Trauma Severity Indices

Schizophrenia is one of the common mental diseases. Because the mechanism of the schizophrenia is significantly complicated, the cause is still unknown. N-methyl-D-aspartate receptor antagonist can simulate the positive and negative symptoms, as well as the cognitive disorder of schizophrenia. Thus it has been widely used to establish the animal models of schizophrenia. The relationship of the three blocking agents of ion channels (phencyclidine, MK-801, ketamine) and the establishment of schizophrenia animal models is reviewed in this article.
Animals ; Behavior, Animal/drug effects* ; Brain/physiopathology* ; Consciousness Disorders/physiopathology* ; Disease Models, Animal ; Dizocilpine Maleate/pharmacology* ; Excitatory Amino Acid Antagonists/pharmacology* ; Humans ; Ketamine/pharmacology* ; Mice ; Phencyclidine/pharmacology* ; Rats ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors* ; Schizophrenia/physiopathology*

OBJECTIVE: Schizophrenia, a devastating mental disorder, displays a wide range of cognitive impairments including attentional impairment. Prepulse inhibition (PPI), in which a startle response to a loud acoustic noise is reduced by a preceding auditory stimulus of a lower intensity, is impaired in schizophrenic patients and rats injected with apomorphine (APO) or phencyclidine (PCP) mimicking attentional deficits in schizophrenics. Here we examined therapeutic efficacy of a newly developed atypical antipsychotic compound (YKP1447;YKP) on PPI impairment induced by various doses of APO and PCP. METHODS: This study was composed of 3 experiments. YKP (0.5-15 mg/kg) or vehicle (VEH) was administered 15 min before the injection of APO (0.5 mg/kg, Exp1) or PCP (2.0 mg/kg, Exp2:1.5 mg/kg, Exp3). They were then tested for PPI in which a mix of startle stimulus and prepulse was presented. RESULTS: APO or PCP treatment effectively impaired PPI in tested animals (VEH/APO or VEH/PCP). Impaired PPI in APO group was reversed in animals that were pretreated with YKP (5-10 mg/kg) (Exp1). However YKP treatment was not effective in PCP group (Exp2-3). CONCLUSION: High concentration of YKP pretreatment had antipsychotic effect on APO-induced impairment in attentional function suggesting that the compound could potentially be used to treat cognitive impairment due to increased dopaminergic receptorbinding.
Acoustics ; Animals ; Antipsychotic Agents ; Apomorphine ; Humans ; Mental Disorders ; Noise ; Phencyclidine ; Rats ; Schizophrenia

Animal models can provide a useful tool for the study of some aspects of psychiatric disorders and their treatment. The four criteria for the evaluation of animal models of psychiatric disorders are as following : 1) similarity of inducing conditions 2) similarity of behavioral state 3) common underlying neurobiological mechanisms 4) reversal by clinically effective treatment techniques. Several animal models have been proposed for schizophrenia : phenylethylamine model, L-dopa model, hallucinogen model. cocaine model, amphetamine model, phencyclidine model, noradrenergic reward system lesion model, reticular stimulation model, social isolation model, conditioned avoidance reaction, catalepsy test, paw test, self-stimulation paradigms, latent inhibition paradigms, blocking paradigms, prepulse inhibition of the startle reflex, rodent interaction, social behavior in monkeys, hippocampal damage, high ambient pressure, and models using selective breeding. Among them, animals with bilateral lesion of the hippocampus may provide an adequate animal model for several symptoms of schizophrenia, and ketamine model can reproduce negative symptoms and cognitive deficits as well as positive symptoms of schizophrenia. In conclusion, no model of schizophrenia is entirely representative of the disease, and findings gleaned from model systems must be cautiously interpreted. Furthermore, the process of developing and validating animal models must work in concert with the process to identify reliable measures of human phenomenology.
Amphetamine ; Animals ; Breeding ; Catalepsy ; Cocaine ; Haplorhini ; Hippocampus ; Humans ; Interpersonal Relations ; Ketamine ; Levodopa ; Models, Animal ; Models, Theoretical* ; Phencyclidine ; Reflex ; Reward ; Rodentia ; Schizophrenia* ; Social Isolation

Ketamine hydrochloride is a phencyclidine derivatives and dissociative anesthetics. Ketamine induce the pulmonary vasoconetrietion in vivo. This study was designed to deter- mine the direct effect of the ketamine on the rabbit pulmonary artery in vitro. Isolated pulmonary artery was precontracted with norepinephrine (NE) 10-7M in the 20 ml organ bath. Concentration of ketamine was gradually increased 10-5M, 10 4M and 10-3M at 10 minutes intervals. I divided forty three experimental speeimens into 5 groups : pulmonary artery with and without endothelium, pretreated with indomethacin, nitrow-L-arginine methyl ester(L-NAME) and methylene blue. The results were as follows : 1. Norepinephrine precontracted pulmonary arterial tone wss significantly decreased by ketamine(10-3M), and the relaxing percent were 81.0 19.3, 60.6 55.4 (Mean S.D.) in unrubbed and rubbed endothelium, respectively (p<0.05). 2. The changes of vascular tone in denuding and intact groups were not significantly different. 3. Vasorelaxation induced by ketamine was not related with nitric oxide(NO) synthase, cyclooxygenase and soluble guanylate cyclase. Ketamine induce relaxation of the rabbit pulmonary artery, especially at 10-3 M concentra- tion. The relaxing effect was not related with endothelium presence, nitric oxide synthase, cyclooxygenase and soluble guanylate cyclase pathways. This data suggest that the relaxing effect of ketamine was not associated with endothelium, Nitric oxide, prostacyclin and cyclic guanosinemonophosphate.
Anesthetics, Dissociative ; Arteries ; Baths ; Endothelium ; Epoprostenol ; Guanylate Cyclase ; Indomethacin ; Ketamine* ; Methylene Blue ; NG-Nitroarginine Methyl Ester ; Nitric Oxide ; Nitric Oxide Synthase ; Norepinephrine ; Phencyclidine ; Prostaglandin-Endoperoxide Synthases ; Pulmonary Artery ; Relaxation ; Vasodilation

Ketamine, a phencyclidine derivative, has been used as an anesthetic agent since 1965 and it has received much attention as an anesthetic for minor surgical procedures, in some diagnostic procedures in children or as an induction agent for poor risk patients. A troublesome problem has been psychic disturbance on emergence. There are many reports on ketamine anesthesia but some cases describing the failure of recommended doses of ketamine to produce adequate analgesia have been reported with cerebral cortical disease or massive craniocerebral trauma. In this case, we experienced a failure to produce adequate analgesia with intramuscular ketamine (11 mg/kg). It was not confirmed in this case whether the patient had suffered any cerebral cortcial disease or not.
Analgesia* ; Anesthesia ; Child ; Craniocerebral Trauma ; Humans ; Ketamine* ; Minor Surgical Procedures ; Phencyclidine

In the late 1950, Greifenstein and associates have studied the properties of phenylcyelohexylamine derivatives and reported that these chemicals produced amnesia, analgesia, catatonia and catalepsy. Phencyclidine was the first of these drugs used in clinical anesthesia, but convulsive movement as well as excitatory behavior discouraged the use of the agent in human beings. Continued research for a more suitable derivative of phencyclidine with similar analgesic action, but shorter duratoin and lesser psychotomimetic action led McCarthy and Chen to investigate the pharmacologic properties of a large series of compounds. One of these, 2-ochlorophenylcyclohexylamine, was shown to have some advantages. Ketamine hydrochloride, chemically related to both phencyclidine and cyclohexylamine, proved to be more satisfactory for clinical anesthesia. Clinical investigations were begun in 1965 by Dominos group who first termed it dissociative anesthesia. As noted by Pender, the clinical signs of anesthesia with ketamine are completely different from those seen with conventional intravenous agents and gaseous compounds. Ketamine acts rapidly on intravenous or intramuscular administration to produce a state chracterized by catalepsy, analgesia and amnesia. It is devoid of sedation, hypnotic or convulsive properties. Normal pharyngeal-laryngeal reflexes are maintained and skeletal tone remains normal or increased. Since the introduction of ketamine by Domino's group, numerous reports have appeared to explain various aspects of the cardiovascular response(increased cardiac output, hypertention, little or no change in peripheral resistance) and respiratory response. However there are few reports on the effect of ketamine on intestinal motility. Thus we have made a study to observe the effect of ketamine on the intestinal motility of chickens. Strips of isolated muscle, 1 cm long, from adult fowl weighing l.2-1.5 kg and isolated smooth muscle of a patient with stomach cancer, were suspended in a muscle chamber containing Tyrode's solution into which was bubbled oxygen gas. The solution was. kept constant at 38 degrees C and contraction of the preparations was recorded on a polygraph. After being washed several times with fresh solution, the muscle strips attained constant motility and tonus. Ketamine and other drugs were added in various concentrations to the chamber. The results are as follows: 1) Ketamine did not exert any effect on human intestinal motility. It relaxed fowl intestinal muscle strips and potentiated the effect of epinephrine, norepinephrine, and isoproterenol. 2) The relaxing effects of ketamine on fowl intestinal muscle strips were not abolished by adrenergic blocking agents. 3) Ketamine demonstrated anticholinergic effect on the intestinal motility of the human and fowl. From the above results, it may be concluded that ketamine exerts a anticholinergic effect and depressant effect on intestinal motility of fowl without relation to adrenergic receptors.
Adrenergic Antagonists ; Adult ; Amnesia ; Analgesia ; Anesthesia ; Cardiac Output ; Catalepsy ; Catatonia ; Chickens* ; Cyclohexylamines ; Epinephrine ; Gastrointestinal Motility* ; Humans ; Isoproterenol ; Ketamine* ; Muscle, Smooth ; Norepinephrine ; Oxygen ; Phencyclidine ; Receptors, Adrenergic ; Reflex ; Stomach Neoplasms