(S)-Carbamic acid 2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-1-phenyl-ethyl ester hydrochloride (YKP1447) is a novel "atypical" antipsychotic drug which selectively binds to serotonin (5-HT2A, Ki=0.61 nM, 5-HT2C, Ki=20.7 nM) and dopamine (D2, Ki=45.9 nM, D3, Ki=42.1 nM) receptors with over 10~100-fold selectivity over the various receptors which exist in the brain. In the behavioral studies using mice, YKP1447 antagonized the apomorphine-induced cage climbing (ED50=0.93 mg/kg) and DOI-induced head twitch (ED50=0.18 mg/kg) behavior. In the dextroamphetamine-induced hyperactivity and conditioned avoidance response (CAR) paradigm in rats, YKP1447 inhibited the hyperactivity induced by amphetamine (ED50=0.54 mg/kg) and the avoidance response (ED50=0.48 mg/kg); however, unlike other antipsychotic drugs, catalepsy was observed only at much higher dose (ED50=68.6 mg/kg). Based on the CAR and catalepsy results, the therapeutic index (TI) value for YKP1447 is over 100 (i.p.). These results indicate that YKP1447 has an atypical profile and less undesirable side effects than currently available drugs.
Amphetamine ; Animals ; Antipsychotic Agents ; Brain ; Catalepsy ; Dopamine ; Head ; Mice ; Rats ; Schizophrenia ; Serotonin

As comparing to typical antipsychotics, atypical antipsychotics have several characters such as no causing catalepsy in animal models or extrapyramidal side effects in schizophrenia patients, no or transient prolactin elevation (except risperidone, amisulpride), effects on negative symptoms, mood and affective symptoms, and efficacy in refractory schizophrenia. In views of the results of several studies so far achieved, the action at the dopamine D2/3 receptors, is by itself, sufficient to provide the contemporary kind of atypical antipsychotic activity. This review will attempt to address the modulation of dopamine D2 receptors as a basis of atypical antipsychotic action by looking over dopamine receptor occupancy, differential effects at the striatal versus extrastriatal dopamine D2 receptor, D2 receptor affinity and Koff consideration, effects for psychotic symptoms.
Affective Symptoms ; Antipsychotic Agents ; Catalepsy ; Dopamine* ; Humans ; Models, Animal ; Prolactin ; Receptors, Dopamine ; Receptors, Dopamine D2* ; Risperidone ; Schizophrenia

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

Parkinson's disease (PD) a neurodegenerative disorder for which no preventive or long-term effective treatment strategies are available. Epidemiologic studies have failed to identify specific environmental, dietary or lifestyle risk factors for PD. However, oxidative stress in the SN is the most broadly accepted hypothesis for the etiopathology of PD. The Symptoms do not appear until there is a decline of striatal dopamine levels by 80% making it difficult to have early therapeutic interventions. Thus, the present experiment was designed to track down the sequential changes starting from the initiation of motor dysfunction and associated biochemical abnormality in rotenone based PD model. The study also evaluated the neuroprotective efficacy of vitamin E. Rats were treated with rotenone 2 mg/kg b.wt (s.c.) for 35 days. The level of dopamine decreased by 70~80% which was in turn reflected by marked deterioration in motor function such as (Total locomotor activity and catalepsy). Along with these the level of GSH and SOD declined significantly which was associated with elevated lipid peroxidation levels as much as by 60%.Vitamin E co-administration at a dose of 100 I.U/kg b.wt (i.m.) ameliorated rotenone induced changes in motor functions i.e Total locomotor activity and Catalepsy at the end of 5th week. Further, vitamin E supplementation significantly decreased lipid peroxidation and improved associated biochemical parameters i.e SOD and GSH level. Most interestingly the changes appeared as early as 3rd week suggesting that supplementation of vitamin E right at the beginning should be neuroprotective in PD.
Animals ; Catalepsy ; Dopamine ; Life Style ; Lipid Peroxidation ; Motor Activity ; Neurodegenerative Diseases ; Oxidative Stress ; Parkinson Disease ; Rats ; Risk Factors ; Rotenone ; Substantia Nigra ; Track and Field ; Vitamin E ; Vitamins

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