Trans-generation enrichment of clozapine-responsiveness trait in mice using a subchronic hypo-glutamatergic model of schizophrenia:A preliminary study.

BACKGROUND: Schizophrenia patients who do not respond to clozapine treatment represent the most debilitating type of schizophrenia with unmet needs for novel interventions. To date there is no validated animal model for clozapine-refractory schizophrenia. METHODS: We used poor performance in the social preference (SP) test of C57/BL mice exposed to subchronic phencyclidine (PCP) as a correlate of negative signs of schizophrenia. Subsequently the mice were treated with clozapine and according to their SP they were defined as responding (i.e. clozapine/PCP ratio>1.5 SD) or non-responsive to clozapine. In each generation the responding mice were mated to produce the next generation. Unfortunately, the clozapine- non-responsive mice failed to proliferate and were thus excluded from the analyses. This forward genetic paradigm was used to produce the next generation of clozapine-responding mice. We assessed brain glutamic acid decarboxylase-67 (GAD67) protein levels, as a GABA-ergic marker, in the F2 and F3 generations. RESULTS: Already in the F1 generation of male mice, but not females, it was possible to discriminate between clozapine-responders and non-responders. The rate of responders within each consecutive generation, increased. The increase was more pronounced in females. Up-regulation of GAD67 levels was detected between F2 and F3 only in male clozapine-responder mice, but not in females. CONCLUSIONS: This preliminary proof-of-concept study succeeded in producing a trans-generation enrichment of clozapine-responsiveness trait in a hypo-glutamatergic animal model of negative signs of schizophrenia. This model may serve as a platform to better characterize the clozapine responsiveness trait and offer a model for clozapine-responsive schizophrenia.

Attenuated Weight Gain with the Novel Analog of Olanzapine Linked to Sarcosinyl Moiety (PGW5) Compared to Olanzapine.

Olanzapine-induced weight gain is associated with atherosclerosis, hypertension, dyslipidemia, and diabetes. We synthesized a novel antipsychotic drug (PGW5) possessing an olanzapine moiety linked to sarcosine, a glycine transporter 1 inhibitor. In this study, we compared the metabolic effects of PGW5 and olanzapine in a female rat model of weight gain. Female rats were treated daily with oral olanzapine (4 mg/kg), PGW5 (25 mg/kg), or vehicle for 16 days. Behavioral tests were conducted on days 12-14. Biochemical analyses were performed at the end of the treatment. A significant increase in body weight was observed in the olanzapine-treated group, while the PGW5 group did not differ from the controls. The open field test showed hypo-locomotion in the olanzapine-treated animals as compared to PGW5 and control groups. A significant increase in hypothalamic protein expression of the neuropeptide Y5 receptor and a decrease in pro-opiomelanocortin messenger ribonucleic acid (mRNA) levels were detected following PGW5 treatment, but not after olanzapine administration. PGW5 appears to possess minor metabolic effects compared with the parent compound olanzapine. The differential modulation of brain peptides associated with appetite regulation is possibly involved in the attenuation of metabolic effects by PGW5.

A novel analog of olanzapine linked to sarcosinyl moiety (PGW5) demonstrates high efficacy and good safety profile in mouse models of schizophrenia.

UNLABELLED: Schizophrenia is a chronic mental disorder related to hypo-functioning of glutamatergic neurotransmission. N-methyl-D-aspartate-receptor (NMDA-R) positive modulators were reported to reduce schizophrenia symptoms. However, their efficacy is low and inconsistent. We developed a novel antipsychotic possessing an olanzapine moiety linked to the positive modulator of glutamate NMDA-R sarcosine (PGW5) and characterized the pharmacodynamic properties of the novel molecule in-vivo using MK-801 and in-vitro using receptor binding analysis. We investigated the pharmacological activity of PGW5 (olanzapine linked to sarcosinyl moiety) in male mice (BALB/c or C57BL). In an open field test, up to 50mg/kg PGW5 did not affect motility while higher doses were sedative. PGW5 (25-50mg/kg po) antagonized MK-801 (0.15 mg/kg ip) and amphetamine-induced (5mg/kg ip) hyperactivity. PGW5 (25mg/kg po/d) treatment for 15 or 22 days exhibited antidepressant and anxiolytic activity in mice. Moreover, PGW5, but not olanzapine, attenuated phencyclidine (PCP)-induced deficits of social preference in mice and promoted the expression of brain derived neurotrophic factor (BDNF) in the hippocampus and the frontal cortex and glutamic acid decarboxylase (GAD67) in the hippocampus. Mice treated with PGW5 (25 and 50mg/kg/d) for 28 days did not show toxic effects in terms of weight gain and blood-chemistry analysis. CONCLUSIONS: PGW5 is a novel and safe antipsychotic, efficacious against schizophrenia-like positive and negative symptoms at nonsedative doses. The drug shows anxiolytic and antidepressant activity, and improves impaired social performance in phencyclidine (PCP) treated mice. The mechanism underlying its activity seems to involve potentiation of NMDA receptor as well as stimulation of brain BDNF and GAD67 expression.