sch-23390 and Schizophrenia

Positron emission tomography studies examining differences in D1-dopamine receptor binding between control subjects and patients with schizophrenia have been inconsistent, reporting higher, lower, and no difference in the frontal cortex. Exposure to antipsychotic medication has been suggested to be a likely source of this heterogeneity, and thus there is a need for studies of patients at early stages of the disorder who have not been exposed to such drugs.. Here, we compared 17 healthy control subjects and 18 first-episode neuroleptic naive patients with schizophrenia or schizophreniform psychosis using positron emission tomography and the D1-dopamine receptor radioligand [11C]SCH23390.. We observed a statistically significant difference in the dorsolateral prefrontal cortex. Contrary to our expectations, patients had less D1-dopamine receptor availability with a moderate effect size. In a Bayesian analysis, we show that the data are over 50 times more likely to have occurred under the decrease as opposed to the increase hypothesis. This effect was not global, as our analysis showed that the null hypothesis was preferred over either hypothesis in the striatum.. This investigation represents the largest single sample of neuroleptic-naive patients examined for D1-dopamine receptor availability using PET and suggests a reduction of prefrontal D1-dopamine receptor density in the pathophysiology of schizophrenia. However, further work will be required to reach a consensus.

Topics: Adult; Benzazepines; Brain; Brain Mapping; Female; Follow-Up Studies; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Positron-Emission Tomography; Psychotic Disorders; Radiopharmaceuticals; Receptors, Dopamine D1; Schizophrenia; Young Adult

Herein, a novel series of multireceptor ligands was developed as polypharmacological antipsychotic agents using the designed multiple ligand approach between dopamine receptors and serotonin receptors. Among them, compound 47 possessed unique pharmacological features, exhibiting high affinities for D

Topics: Animals; Antipsychotic Agents; Body Weight; Chemistry Techniques, Synthetic; Drug Design; Ether-A-Go-Go Potassium Channels; Heterocyclic Compounds; Memory; Mice; Piperazine; Rats; Schizophrenia; Structure-Activity Relationship; Tissue Distribution

Exaggerated thoughts, diminished mood and impaired cognition are the hallmarks of the schizophrenia-like condition. These symptoms are attributed to the dysregulation of dopamine and glutamate signaling in the brain. Since cocaine- and amphetamine-regulated transcript peptide (CART) modulates actions of dopamine as well as glutamate, we tested the role of this peptide in MK-801-induced schizophrenic dementia-like condition. MK-801-treated rats were allowed to interact with conspecific juvenile and tested for short-term (30-min) and long-term (24-h) social memory acquisition and recall. While MK-801 impaired the social interaction with a juvenile, the behavior was restored in CART [intracerebroventricular (icv) or intra-ventral tegmental area (VTA)] pre-treated animals. This action of CART was blocked by SCH23390 (dopamine D1 receptor antagonist) administered directly into the prefrontal cortex (PFC). Application of neuronal tracer Di-I in the PFC retrogradely labeled dopamine cells of the VTA, which in turn seem to receive CARTergic innervation. A significant increase in CARTimmunoreactivity was evidenced in the VTA, PFC and accumbens of the animals allowed to interact with a juvenile. However, MK-801 treatment attenuated the peptide expression and induced social memory deficits. The schizophrenic dementia-like symptoms following antagonism of glutamatergic receptors may be attributed to the reduced dopamine activity in the mesocortical system. We suggest that CART may, positively modulate the dopamine system to alleviate cognitive deficits associated with schizophrenia.

Topics: Animals; Benzazepines; Brain; Dementia; Disease Models, Animal; Dizocilpine Maleate; Male; Memory; Motor Activity; Nerve Tissue Proteins; Neurons; Psychotropic Drugs; Random Allocation; Rats, Wistar; Receptors, Dopamine D1; Schizophrenia; Schizophrenic Psychology; Social Behavior

AKT1 (also known as protein kinase B, α), a serine/threonine kinase of AKT family, has been implicated in both schizophrenia and methamphetamine (Meth) use disorders. AKT1 or its protein also has epistatic effects on the regulation of dopamine-dependent behaviors or drug effects, especially in the striatum. The aim of this study is to investigate the sex-specific role of Akt1 in the regulation of Meth-induced behavioral sensitization and the alterations of striatal neurons using Akt1(-/-) mice and wild-type littermates as a model. A series of 4 Experiments were conducted. Meth-induced hyperlocomotion and Meth-related alterations of brain activity were measured. The neural properties of striatal medium spiny neurons (MSNs) were also characterized. Further, 17β-estradiol was applied to examine its protective effect in Meth-sensitized male mice. Our findings indicate that (1) Akt1(-/-) males were less sensitive to Meth-induced hyperlocomotion during Meth challenge compared with wild-type controls and Akt1(-/-) females, (2) further sex differences were revealed by coinjection of Meth with raclopride but not SCH23390 in Meth-sensitized Akt1(-/-) males, (3) Meth-induced alterations of striatal activity were confirmed in Akt1(-/-) males using microPET scan with (18)F-flurodeoxyglucose, (4) Akt1 deficiency had a significant impact on the electrophysiological and neuromorphological properties of striatal MSNs in male mice, and (5) subchronic injections of 17β-estradiol prevented the reduction of Meth-induced hyperactivity in Meth-sensitized Akt1(-/-) male mice. This study highlights a sex- and region-specific effect of Akt1 in the regulation of dopamine-dependent behaviors and implies the importance of AKT1 in the modulation of sex differences in Meth sensitivity and schizophrenia.

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Benzazepines; Disease Models, Animal; Estradiol; Estrogens; Female; Hyperkinesis; Male; Methamphetamine; Mice; Mice, Inbred C57BL; Mice, Knockout; Neostriatum; Neurons; Proto-Oncogene Proteins c-akt; Psychoses, Substance-Induced; Raclopride; Schizophrenia; Sex Factors

A relevant role for dopamine-glutamate interaction has been reported in the pathophysiology and treatment of psychoses. Dopamine and glutamate may interact at multiple levels, including the glutamatergic postsynaptic density (PSD), an electron-dense thickening that has gained recent attention as a switchboard of dopamine-glutamate interactions and for its role in synaptic plasticity. Recently, glutamate-based strategies, such as memantine add-on to antipsychotics, have been proposed for refractory symptoms of schizophrenia, e.g. cognitive impairment. Both antipsychotics and memantine regulate PSD transcripts but sparse information is available on memantine's effects under dopamine perturbation. We tested gene expression changes of the Homer1 and PSD-95 PSD proteins in models of sustained dopamine perturbation, i.e. subchronic treatment by: a) GBR-12909, a dopamine receptor indirect agonist; b) haloperidol, a D2R antagonist; c) SCH-23390, a dopamine D1 receptor (D1R) antagonist; and d) SCH-23390+haloperidol. On the last day of treatment, rats were acutely treated with vehicle or memantine. The Homer1a immediate-early gene was significantly induced by haloperidol and by haloperidol+SCH-23390. The gene was not induced by SCH-23390 per se or by GBR-12909. Expression of the constitutive genes Homer1b/c and PSD-95 was less affected by these dopaminergic paradigms. Acute memantine administration significantly increased Homer1a expression by the dopaminergic compounds used herein. Both haloperidol and haloperidol+SCH-23390 shifted Homer1a/Homer1b/c ratio of expression toward Homer1a. This pattern was sharpened by acute memantine. Dopaminergic compounds and acute memantine also differentially affected topographic distribution of gene expression and coordinated expression of Homer1a among cortical-subcortical regions. These results indicate that dopaminergic perturbations may affect glutamatergic signaling in different directions. Memantine may help partially revert dopamine-mediated glutamatergic dysfunctions.

Topics: Animals; Benzazepines; Brain; Carrier Proteins; Disks Large Homolog 4 Protein; Dopamine; Dopamine Agents; Dopamine Antagonists; Dopamine Uptake Inhibitors; Gene Expression; Haloperidol; Homer Scaffolding Proteins; Intracellular Signaling Peptides and Proteins; Male; Memantine; Membrane Proteins; Piperazines; Random Allocation; Rats, Sprague-Dawley; RNA, Messenger; Schizophrenia

A deficit in dopamine-1 (D1) receptor function in the prefrontal cortex is suggested to play a role in the cognitive dysfunction observed in patients with schizophrenia. However, the results from positron emission tomography imaging studies of D1 receptor levels in individuals with schizophrenia are mixed.. The aim of this investigation was to determine whether the in vivo characteristics of the different D1 receptor tracers used in previous reports, [(11)C]SCH23390 and [(11)C]NNC112, may have contributed to these discrepancies reported in the literature.. Eight patients with schizophrenia and 12 healthy control subjects were scanned with both [(11)C]SCH23390 and [(11)C]NNC112.. [(11)C]SCH23390 and [(11)C]NNC112 binding potentials in both patients and control subjects were compared and no tracer by diagnosis interactions were observed.. The results of this study suggest that differences in the binding of [(11)C]SCH23390 and [(11)C]NNC112 observed in previous studies are not due to differences in the in vivo behavior of these tracers.

Topics: Adolescent; Adult; Benzazepines; Benzofurans; Carbon Radioisotopes; Case-Control Studies; Female; Humans; Male; Positron-Emission Tomography; Radioactive Tracers; Radiopharmaceuticals; Receptors, Dopamine D1; Schizophrenia; Young Adult

Delineation of key molecules that act epigenetically to transduce diverse stressors into established patterns of disease would facilitate the advent of preventive and disease-modifying therapeutics for a host of neurological disorders. Herein, we demonstrate that selective overexpression of the stress protein heme oxygenase-1 (HO-1) in astrocytes of novel GFAP.HMOX1 transgenic mice results in subcortical oxidative stress and mitochondrial damage/autophagy; diminished neuronal reelin content (males); induction of Nurr1 and Pitx3 with attendant suppression of their targeting miRNAs, 145 and 133b; increased tyrosine hydroxylase and α-synuclein expression with downregulation of the targeting miR-7b of the latter; augmented dopamine and serotonin levels in basal ganglia; reduced D1 receptor binding in nucleus accumbens; axodendritic pathology and altered hippocampal cytoarchitectonics; impaired neurovascular coupling; attenuated prepulse inhibition (males); and hyperkinetic behavior. The GFAP.HMOX1 neurophenotype bears resemblances to human schizophrenia and other neurodevelopmental conditions and implicates glial HO-1 as a prime transducer of inimical (endogenous and environmental) influences on the development of monoaminergic circuitry. Containment of the glial HO-1 response to noxious stimuli at strategic points of the life cycle may afford novel opportunities for the effective management of human neurodevelopmental and neurodegenerative conditions.

Topics: Acoustic Stimulation; Age Factors; alpha-Synuclein; Analysis of Variance; Animals; Animals, Newborn; Astrocytes; Benzamides; Benzazepines; Biogenic Monoamines; Brain; Chromatography, High Pressure Liquid; Disease Models, Animal; Dopamine Agents; Embryo, Mammalian; Enzyme-Linked Immunosorbent Assay; Gait Disorders, Neurologic; Gene Expression Regulation, Developmental; Glial Fibrillary Acidic Protein; Heme Oxygenase-1; Homeodomain Proteins; Humans; Inhibition, Psychological; Laser-Doppler Flowmetry; Mice; Mice, Transgenic; MicroRNAs; Nuclear Receptor Subfamily 4, Group A, Member 2; Protein Binding; Receptors, Dopamine D1; Receptors, Dopamine D2; Reelin Protein; RNA, Messenger; Schizophrenia; Sensory Gating; Superoxide Dismutase; Transcription Factors; Tritium; Tyrosine 3-Monooxygenase

Abnormality of cognitive function in schizophrenia has been suggested to be related to dopamine D1 receptor. However, the results of previous positron emission tomography (PET) studies of dopamine D1 receptor in schizophrenia were not consistent.. In this study, six patients with schizophrenia in severe residual phase with chronic antipsychotic treatment and twelve healthy age-matched controls participated. Two different radioligands, [11C]NNC112 and [11C]SCH23390, for dopamine D1 receptor were used on the same subjects. Binding of the ligands was measured by PET, and statistical analysis was performed using one-way analysis of covariate (ANCOVA) with age as covariate.. Good correlations between binding potential values (BP(ND)) and age were observed in all regions of interest (ROIs) with both ligands. ANCOVA with age as covariate of BP(ND) values of all ROIs revealed that the patient group showed significantly lower BP(ND) value compared with the control group in both ligands.. In patients with chronic schizophrenia in severe residual phase with chronic antipsychotic treatment, the binding potential values of both ligands were significantly lower in the striatum and cortical regions than those of healthy controls.

Topics: Adult; Antipsychotic Agents; Benzazepines; Benzofurans; Brain; Cerebral Cortex; Cognition; Corpus Striatum; Female; Humans; Ligands; Magnetic Resonance Imaging; Male; Middle Aged; Positron-Emission Tomography; Receptors, Dopamine D1; Schizophrenia

Cognitive impairment has been found across all subtypes of schizophrenia. The location and function of dopamine-1 receptors (D1Rs) make them attractive targets for the treatment of cognitive impairment in schizophrenia. Here we investigate the systemic effect of a D1R agonist (A77636) and antagonist (SCH 23390) on hyperlocomotor activity and cognitive deficit induced by an NMDA receptor antagonist (MK-801). Wistar rats (250-300 g) received A77636 (0.1, 0.5 or 1 mg/kg) or SCH 23390 (0.02 or 0.05 mg/kg) with MK-801 (0.1 mg/kg) or saline for 4 d. On day 4 we assessed the prepulse inhibition of the acoustic startle response, locomotor activity in a novel arena and active allothetic place avoidance (spatial memory task) 15 min after the last injection. Systematic administration of the D1R agonist at 0.1 mg/kg ameliorates cognitive dysfunction in our model of schizophrenia, but increases stereotypy and locomotor activity (model of psychotic symptoms) at higher doses (0.5 or 1 mg/kg). Administration of the D1R antagonist had no effect on cognitive function, but decreased hyperlocomotion induced by MK-801. Thus, based on our results, over-activation of D1Rs may exacerbate psychotic symptoms in patients with schizophrenia.

Topics: Acoustic Stimulation; Adamantane; Analysis of Variance; Animals; Behavior, Animal; Benzazepines; Benzopyrans; Cognition; Disease Models, Animal; Dizocilpine Maleate; Dopamine Agonists; Dopamine Antagonists; Male; Memory; Motor Activity; Rats; Rats, Wistar; Receptors, Dopamine D1; Receptors, N-Methyl-D-Aspartate; Reflex, Startle; Schizophrenia; Schizophrenic Psychology; Sensory Gating; Stereotyped Behavior; Time Factors