Galantamine ameliorates the impairment of recognition memory in mice repeatedly treated with methamphetamine: involvement of allosteric potentiation of nicotinic acetylcholine receptors and dopaminergic-ERK1/2 systems.

Galantamine, a drug used to treat Alzheimer's disease, inhibits acetylcholinesterase (AChE) and allosterically modulates nicotinic acetylcholine receptors (nAChRs) resulting in stimulation of catecholamine neurotransmission. In this study, we investigated whether galantamine exerts cognitive-improving effects through the allosteric modulation of nAChRs in an animal model of methamphetamine (Meth) psychosis. The mice treated with Meth (1 mg/kg.d) for 7 d showed memory impairment in a novel object recognition test. Galantamine (3 mg/kg) ameliorated the memory impairment, and it increased the extracellular dopamine release in the prefrontal cortex (PFC) of Meth-treated mice. Donepezil, an AChE inhibitor (1 mg/kg) increased the extracellular ACh release in the PFC, whereas it had no effect on the memory impairment in Meth-treated mice. The nAChR antagonist, mecamylamine, and dopamine D1 receptor antagonist, SCH 23390, blocked the ameliorating effect of galantamine on Meth-induced memory impairment, whereas the muscarinic AChR antagonist, scopolamine, had no effect. The effects of galantamine on extracellular dopamine release were also antagonized by mecamylamine. Galantamine attenuated the defect of the novelty-induced activation of extracellular signal-regulated kinase 1/2 (ERK1/2). The ameliorating effect of galantamine on recognition memory in Meth-treated mice was negated by microinjection of an ERK inhibitor, PD98059, into the PFC. These results suggest that the ameliorating effect of galantamine on Meth-induced memory impairment is associated with indirect activation of dopamine D1 receptor-ERK1/2 following augmentation with dopaminergic neurotransmission in the PFC through the allosteric activation of nAChRs. Galantamine could be a useful therapeutic agent for treating cognitive deficits in schizophrenia/Meth psychosis, as well as Alzheimer's disease.

[Development of animal models for schizophrenia based on clinical evidence: expectation for psychiatrists].

Schizophrenic patients show positive symptoms, negative symptoms and cognitive dysfunction. In humans, phencyclidine (PCP), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, reproduces the schizophrenia-like psychosis including positive symptoms, negative symptoms and cognitive dysfunction. Ketamine, another non-competitive NMDA receptor antagonist, also reproduces a schizophrenia-like psychosis in healthy volunteers, and exaggerates the psychosis in schizophrenic patients. It has been hypothesized that insufficient glutamate neurotransmission is involved in the pathophysiology of schizophrenia. Therefore, attempts have been made to develop animal models of schizophrenia by using NMDA receptor antagonists such as PCP, ketamine and dizocilpine. In addition to pharmacological approaches, genetic approaches have been adopted to develop animal models of schizophrenia. The disrupted in schizophrenia 1 (DISC1) gene has been identified as a schizophrenia susceptibility gene based on linkage and single nucleotide polymorphism (SNP) association studies and clinical data, demonstrating that risk SNPs impact on the hippocampal structure and function in clinical and functional roles of DISC1 are analyzed in many kinds of transgenic mice developed. In this review, we focused on PCP and DISC1 transgenic animal models of schizophrenia and summarized recent evidence from several investigators. The basic researchers would need to collaborate with clinical psychiatrists to develop appropriate animal models for schizophrenia based on clinical evidence.

Genetic analysis of the gene coding for DARPP-32 (PPP1R1B) in Japanese patients with schizophrenia or bipolar disorder.

Several lines of evidence, including genome-wide linkage scans and postmortem brain studies of patients with schizophrenia or bipolar disorder, have suggested that DARPP-32 (dopamine- and cAMP-regulated phosphoprotein, 32 kDa), a key regulatory molecule in the dopaminergic signaling pathway, is involved in these disorders. After evaluating the linkage disequilibrium pattern of the gene encoding DARPP-32 (PPP1R1B; located on 17q12), we conducted association analyses of this gene with schizophrenia and bipolar disorder. Single-marker and haplotypic analyses of four single nucleotide polymorphisms (SNPs; rs879606, rs12601930, rs907094, and rs3764352) in a sample set (subjects with schizophrenia=384, subjects with bipolar disorder=318, control subjects=384) showed that PPP1R1B polymorphisms were not significantly associated with schizophrenia, whereas, even after Bonferroni corrections, significant associations with bipolar disorder were observed for rs12601930 (corrected genotypic p=0.00059) and rs907094 (corrected allelic p=0.040). We, however, could not confirm these results in a second independent sample set (subjects with bipolar disorder=366, control subjects=370). We now believe that the significant association observed with the first sample set was a result of copy number aberrations in the region surrounding these SNPs. Our findings suggest that PPP1R1B SNPs are unlikely to be related to the development of schizophrenia and bipolar disorder in the Japanese population.

Immunohistochemical study of vesicle monoamine transporter 2 in the hippocampal formation of PCP-treated mice.

The exact pathophysiology of schizophrenia is unknown despite intensive scientific studies using molecular biology, psychopharmacology, neuropathology, etc. It is thought that neurodevelopmental failures such as neuronal network incompetence and the inappropriate formation of neurons affect the neurotransmitters. Several animal models have been created to investigate the etiology of this disease. In this study, we investigated the expression of vesicle monoamine transporter 2 (VMAT2), which has a significant role in neurotransmission, in the hippocampal formation in 1-phenylcyclohexylpiperazine (PCP)-treated mice using immunohistochemical staining technique to clarify neuronal abnormalities. PCP-treated mice are thought to be one of novel animal models for schizophrenia. The expression of VMAT2 in the hippocampal formation was significantly reduced overall in the PCP-treated mice compared to that in control (saline-treated) mice, also these reductions were observed throughout the brain. These facts implied that the pathophysiology of this disease involves abnormal monoaminergic transmission through VMAT2, despite PCP was the N-methyl-d-aspartate (NMDA) receptor antagonist that might induce glutamatergic abnormality. Since insufficient or excess release of neurotransmitter might alter neurochemical function and neurotransmission, VMAT2 might be an important target for biological research in psychiatric disease including schizophrenia.