Abstract:All together, the pharmacological reactivity of STOP null mice to antipsychotics evokes the pharmacological response of humans to such drugs. Totally, our study suggests that STOP null mice may provide a useful preclinical model to evaluate pharmacological properties of antipsychotic drugs.
“…In STOP null mice, mesolimbic dopaminergic hyperactivity is accompanied by reduced glutamatergic transmission (Brenner et al, 2007), an interrelationship now thought to be a neurochemical hallmark of schizophrenia (Carlsson et al, 2000;Jablensky, 2004). Delotterie et al, (2010) reported that long-term treatment with risperidone, a representative atypical antipsychotic drug, did not improve working memory of STOP null mice assessed with the Y maze. This finding is consistent with the lack or weak effects of antipsychotic drugs on cognitive deficits associated with schizophrenia (Young et al, 2009) suggesting that the STOP null mouse may be a useful model for the identification of therapeutics capable of improving the cognition of schizophrenics.…”
STOP (stable tubule only polypeptide) null mice display neurochemical and behavioral abnormalities that resemble several well-recognized features of schizophrenia. Recent evidence suggests that the hematopoietic growth factor erythropoietin improves the cognitive performance of schizophrenics. The mechanism, however, by which erythropoietin is able to improve the cognition of schizophrenics is unclear. To address this question, we first determined whether acute administration of the erythropoietin analog known as darbepoetin alpha (D. alpha) improved performance deficits of STOP null mice in the novel objective recognition task (NORT). NORT performance of STOP null mice, but not wild-type littermates, was enhanced 3 h after a single injection of D. alpha (25 microg/kg, i.p.). Improved NORT performance was accompanied by elevated NADPH diaphorase staining in the ventral hippocampus as well as medial and cortical aspects of the amygdala, indicative of increased nitric oxide synthase (NOS) activity in these structures. NOS generates the intracellular messenger nitric oxide (NO) implicated in learning and memory. In keeping with this hypothesis, D. alpha significantly increased NO metabolite levels (nitrate and nitrite, NOx) in the hippocampus of both wild-type and STOP null mice. The NOS inhibitor, N (G)-nitro-L- arginine methyl ester (L-NAME; 25 mg/kg, i.p.), completely reversed the increase in hippocampal NOx levels produced by D. alpha. Moreover, L-NAME also inhibited the ability of D. alpha to improve the NORT performance of STOP null mice. Taken together, these observations suggest D. alpha enhances the NORT performance of STOP null mice by increasing production of NO.
“…In STOP null mice, mesolimbic dopaminergic hyperactivity is accompanied by reduced glutamatergic transmission (Brenner et al, 2007), an interrelationship now thought to be a neurochemical hallmark of schizophrenia (Carlsson et al, 2000;Jablensky, 2004). Delotterie et al, (2010) reported that long-term treatment with risperidone, a representative atypical antipsychotic drug, did not improve working memory of STOP null mice assessed with the Y maze. This finding is consistent with the lack or weak effects of antipsychotic drugs on cognitive deficits associated with schizophrenia (Young et al, 2009) suggesting that the STOP null mouse may be a useful model for the identification of therapeutics capable of improving the cognition of schizophrenics.…”
STOP (stable tubule only polypeptide) null mice display neurochemical and behavioral abnormalities that resemble several well-recognized features of schizophrenia. Recent evidence suggests that the hematopoietic growth factor erythropoietin improves the cognitive performance of schizophrenics. The mechanism, however, by which erythropoietin is able to improve the cognition of schizophrenics is unclear. To address this question, we first determined whether acute administration of the erythropoietin analog known as darbepoetin alpha (D. alpha) improved performance deficits of STOP null mice in the novel objective recognition task (NORT). NORT performance of STOP null mice, but not wild-type littermates, was enhanced 3 h after a single injection of D. alpha (25 microg/kg, i.p.). Improved NORT performance was accompanied by elevated NADPH diaphorase staining in the ventral hippocampus as well as medial and cortical aspects of the amygdala, indicative of increased nitric oxide synthase (NOS) activity in these structures. NOS generates the intracellular messenger nitric oxide (NO) implicated in learning and memory. In keeping with this hypothesis, D. alpha significantly increased NO metabolite levels (nitrate and nitrite, NOx) in the hippocampus of both wild-type and STOP null mice. The NOS inhibitor, N (G)-nitro-L- arginine methyl ester (L-NAME; 25 mg/kg, i.p.), completely reversed the increase in hippocampal NOx levels produced by D. alpha. Moreover, L-NAME also inhibited the ability of D. alpha to improve the NORT performance of STOP null mice. Taken together, these observations suggest D. alpha enhances the NORT performance of STOP null mice by increasing production of NO.
“…Next steps could include (1) generating (or further characterizing) a preclinical model that mirrors these findings; can an animal that goes through development with an NMDA receptor signaling complex deficit be rescued? (Delotterie et al, 2010;Nagai et al, 2011), (2) further elucidating the contribution of genetic risk factors on PSD95 biology, and/or (3) developing pharmacological interventions that are targeted not at the underlying genetic risk factors (such as DISC1 in subjects with the DISC1 translocation) but instead at common pathophysiological factors such as impaired NMDA receptor signaling.…”
Section: A Mechanism For Nmda Receptor Dysfunction In Schizophreniamentioning
We propose that postmortem tissue is an underutilized substrate that may be used to translate genetic and/or preclinical studies, particularly for neuropsychiatric illnesses with complex etiologies. Postmortem brain tissues from subjects with schizophrenia have been extensively studied, and thus serve as a useful vehicle for illustrating the challenges associated with this biological substrate. Schizophrenia is likely caused by a combination of genetic risk and environmental factors that combine to create a disease phenotype that is typically not apparent until late adolescence. The complexity of this illness creates challenges for hypothesis testing aimed at understanding the pathophysiology of the illness, as postmortem brain tissues collected from individuals with schizophrenia reflect neuroplastic changes from a lifetime of severe mental illness, as well as treatment with antipsychotic medications. While there are significant challenges with studying postmortem brain, such as the postmortem interval, it confers a translational element that is difficult to recapitulate in animal models. On the other hand, data derived from animal models typically provide specific mechanistic and behavioral measures that cannot be generated using human subjects. Convergence of these two approaches has led to important insights for understanding molecular deficits and their causes in this illness. In this review, we discuss the problem of schizophrenia, review the common challenges related to postmortem studies, discuss the application of biochemical approaches to this substrate, and present examples of postmortem schizophrenia studies that illustrate the role of the postmortem approach for generating important new leads for understanding the pathophysiology of severe mental illness.
“…Deletion of the CB 2 r gene induced depressive-like responses in the tail suspension test. Similarly, Homer1-KO mice and STOP-null mice show increased depressive-like behavior in the Porsolt test (Delotterie et al, 2010;Szumlinski et al, 2005). However, other animal models based on schizophrenia susceptibility gene mutations showed an antidepressant-like response (Barbier and Wang, 2009;Perona et al, 2008;Sakae et al, 2008;Tanda et al, 2009;Yamasaki et al, 2008).…”
The possible role of the CB 2 receptor (CB 2 r) in psychiatric disorders has been considered. Several animal models use knockout (KO) mice that display schizophrenia-like behaviors and this study evaluated the role of CB 2 r in the regulation of such behaviors. Mice lacking the CB 2 r (CB 2 KO) were challenged in open field, light-dark box, elevated plus-maze, tail suspension, step down inhibitory avoidance, and pre-pulse inhibition tests (PPI). Furthermore, the effects of treatment with cocaine and risperidone were evaluated using the OF and the PPI test. Gene expression of dopamine D 2 (D 2 r), adrenergic-a 2C (a 2C r), serotonergic 5-HT 2A and 5-HT 2C receptors (5-HT 2A r and 5-HT 2C r) were studied by RT-PCR in brain regions related to schizophrenia. Deletion of CB 2 r decreased motor activity in the OF test, but enhanced response to acute cocaine and produced mood-related alterations, PPI deficit, and cognitive impairment. Chronic treatment with risperidone tended to impair PPI in WT mice, whereas it 'normalized' the PPI deficit in CB 2 KO mice. CB 2 KO mice presented increased D 2 r and a 2C r gene expressions in the prefrontal cortex (PFC) and locus coeruleus (LC), decreased 5-HT 2C r gene expression in the dorsal raphe (DR), and 5-HT 2A r gene expression in the PFC. Chronic risperidone treatment in WT mice left a 2C r gene expression unchanged, decreased D 2 r gene expression (15 mg/kg), and decreased 5-HT 2C r and 5-HT 2A r in PFC and DR. In CB 2 KO, the gene expression of D 2 r in the PFC, of a 2C r in the LC, and of 5-HT 2C r and 5-HT 2A r in PFC was reduced; 5-HT 2C r and 5-HT 2A r gene expressions in DR were increased after treatment with risperidone. These results suggest that deletion of CB 2 r has a relation with schizophrenia-like behaviors. Pharmacological manipulation of CB 2 r may merit further study as a potential therapeutic target for the treatment of schizophrenia-related disorders.
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