sb-271046 and Schizophrenia

Schizophrenia is a serious mental disorder that affects 1% of the world's population. Although various therapeutic tools have been developed since the appearance of the first generation of antipsychotics, the effect of these agents does not manage to attenuate a significant part of psychotic symptoms. Ketamine is an anesthetic agent able to produce psychotic-like symptoms through the antagonism of the glutamatergic N-methyl-d-aspartic acid (NMDA) receptors (NMDARs). This drug has been widely used to study new pharmacological tools with potential antipsychotic properties. On the contrary, it is known that the 5-HT6 receptor agonist and antagonist drugs induce procognitive, anxiolytic and antidepressant effects in different preclinical models. Therefore, the aim of this study was to evaluate the behavioral actions of the 5-HT6 receptors' agonist E-6837 and the antagonist SB-271046, in ICR-CD1 mice previously treated with a subchronic ketamine scheme (10 mg/kg i.p. daily for 5 days). Results showed that repeated administration of ketamine induced recognition memory deficit, anxiogenic effects, obsessive-compulsive behaviors and stereotyped movements. The acute administration of both 5-HT6 agents reversed the memory deficit and induced a decrease in anxiety, whereas SB-271046 administration produced a decrease in climbing behavior. The injection of either of these 5-HT6 drugs had no effect in the light-dark test. Surprisingly, when these drugs were injected together with ketamine, anxiogenic actions were produced. Current findings suggest that both agonist and antagonist 5-HT6 drugs play an important role in modulating psychotic-like symptoms induced by the subchronic blockade of NMDAR.

Topics: Animals; Antipsychotic Agents; Humans; Indoles; Ketamine; Memory Disorders; Mice; Mice, Inbred ICR; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Sulfonamides; Thiophenes

Major depression is one of the most common affective disorders caused by schizophrenia. The administration of N-methyl-D-aspartate receptor antagonists, such as ketamine, can reproduce the negative and affective symptoms of this disorder in animals. Preclinical studies have shown that 5-HT6 receptor (5-HT6R) agonists and antagonists have a considerable antipsychotic response. The aim of the present study was to evaluate the effect of an acute treatment with an agonist, E-6837, and an antagonist, SB-271046, of 5-HT6R on the immobility induced in mice by a subchronic ketamine regimen (5 days; 10 mg/kg/day, intraperitoneal). Repeated ketamine administration alone increased the immobility time in the forced-swimming test and the tail-suspension test. E-6837 at 10 and 20 mg/kg caused a significant reduction of immobility in the tail-suspension test and forced-swimming test, respectively. Interestingly, SB-271046 (10 mg/kg) also elicited an antidepressant-like effect in both tests. The current findings suggest an important role for these 5-HT6R ligands as mood modulators. However, it is necessary to explore the physiological mechanisms involved in this process in greater detail.

Topics: Animals; Antidepressive Agents; Antipsychotic Agents; Depression; Depressive Disorder, Major; Disease Models, Animal; Hindlimb Suspension; Indoles; Ketamine; Male; Mice; Motor Activity; Receptors, N-Methyl-D-Aspartate; Receptors, Serotonin; Schizophrenia; Sulfonamides; Swimming; Thiophenes

Prepulse inhibition (PPI) is the reduction in the startle response caused by a low intensity non-startling stimulus (the prepulse) which is presented shortly before the startle stimulus and is an operational measure of sensorimotor gating. PPI is impaired in psychiatric disorders such as schizophrenia. Ketamine, a non-competitive N-methyl-D-aspartate antagonist has been shown to induce schizophrenia-like behavioural changes in humans and PPI deficits in rats, which can be reversed by antipsychotics. Thus, ketamine-induced PPI deficits in rats may provide a translational model of schizophrenia. The aim of this study was to investigate the effects of antipsychotic drugs and drugs known to alter the glutamate system upon ketamine-induced PPI deficits in rats. Rats were habituated to the PPI procedure [randomized trials of either pulse alone (110 dB/50 ms) or prepulse + pulse (80 dB/10 ms)]. Animals were assigned to pre-treatments based on the level of PPI on the last habituation test and balanced across startle chambers. Ketamine (1-10 mg/kg s.c; 15 min ptt) increased startle amplitude and induced PPI deficits at 6 and 10 mg/kg. PPI deficits induced by ketamine at 6 mg/kg were not attenuated by clozapine (2.5-10 mg/kg s.c.; 60 min ptt), risperidone (0.1-1 mg/kg i.p.; 60 min ptt), haloperidol (0.1-1 mg/kg i.p.; 60 min ptt), lamotrigine (3-30 mg/kg p.o.; 60 min ptt), or SB-271046-A (5-20 mg/kg p.o.; 2 hour ptt) nor potentiated by 2-methyl-6-(phenylethynyl)-pyridine (3-10 mg/kg i.p.; 30 min ptt). These results suggest that under these test conditions ketamine-induced PPI deficits in rats is relatively insensitive and does not represent a translational model for drug discovery in schizophrenia.

Topics: Animals; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Glutamic Acid; Haloperidol; Ketamine; Lamotrigine; Male; Pyridines; Rats; Rats, Sprague-Dawley; Reflex, Startle; Risperidone; Schizophrenia; Sulfonamides; Thiophenes; Triazines

The 5-HT(6) receptor is targeted by several new antipsychotics such as clozapine, olanzapine, and sertindole. We studied the effect of SB-271046 [5-chloro-N-(4-methoxy-3-piperazin-1-yl-phenyl)-3-methyl-2-benzothiophenesulfonamide], a specific 5-HT(6) receptor antagonist, in three models for the positive symptoms of schizophrenia---D-amphetamine-induced hyperactivity, and D-amphetamine- or phencyclidine (PCP)-disrupted prepulse inhibition (PPI). We also tested this compound in a model for the negative symptoms of schizophrenia, PCP-disrupted social interaction (SIT) in rats. Induction of side effects by this compound was evaluated by testing its potency to reduce spontaneous motility, and to induce catalepsy in rats. The effect of SB-271046 was compared to clozapine in all models tested. This study showed that SB-271046 had no beneficial effect in PCP-disrupted SIT. However, SB-271046 dose-dependently normalised D-amphetamine-disrupted PPI, but did not reverse PCP-disrupted PPI. In addition, SB-271046 did not antagonise D-amphetamine-induced hyperactivity. Thus, this specific 5-HT(6) receptor antagonist was associated with a clear positive outcome in only one model for the positive symptoms of schizophrenia, and had no beneficial effect in the model for negative symptoms. Consequently, it is clear that SB-271046 is not expected to have an antipsychotic efficacy, at least when given as monotherapy.

Topics: Animals; Catalepsy; Central Nervous System Stimulants; Clozapine; Dextroamphetamine; Dose-Response Relationship, Drug; Hyperkinesis; Male; Rats; Rats, Wistar; Receptors, Serotonin; Reflex, Startle; Schizophrenia; Serotonin Antagonists; Social Behavior; Sulfonamides; Thiophenes