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The antipsychotic and procognitive properties of xanomeline were subsequently confirmed in a small study of acutely psychotic patients with chronic schizophrenia. Almost 25 years ago, the muscarinic acetylcholine receptor (mAChR) agonist xanomeline was reported to reduce psychotic symptoms and improve cognition in patients with Alzheimer's disease. An unmet need remains for novel, mechanistically unique, and better tolerated therapeutic agents for treating schizophrenia, especially those that treat not only positive symptoms but also the negative and cognitive symptoms of the disease. Schizophrenia remains a challenging disease to treat effectively with current antipsychotic medications due to their limited efficacy across the entire spectrum of core symptoms as well as their often burdensome side-effect profiles and poor tolerability. M1 mRNA is strongly expressed in the cortex, hippocampus, and striatum of ϩ ͞ ϩ mice and absent in Ϫ ͞ Ϫ mice.
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( D ) In situ hybridization of sagittal brain sections from M1 ϩ ͞ ϩ ( Left ) and M1 Ϫ ͞ Ϫ ( Right ) mice. The filter was stripped and rehybridized with a glyceraldehyde- 3-phosphate dehydrogenase (G3DPH) control probe ( Right ). Total forebrain RNA was prepared from M1 ϩ ͞ ϩ, ϩ ͞ Ϫ, and Ϫ ͞ Ϫ mice and analyzed by Northern hybridization with a M1 cDNA probe ( Left ). ( C ) Absence of M1 message in the M1 Ϫ ͞ Ϫ mice. The endogenous allele is 11 kb, and the targeted allele is 6 kb. Hin dIII digests of tail DNA from progeny of a heterozygous cross were screened with the 5 Ј probe. ( B ) Germ-line transmission of the targeted allele. ( A ) Homologous recombination between the targeting construct and the M1 genomic locus replaces a 3-kb Kpn I – Bam HI genomic fragment containing the entire M1 coding sequence with the neomycin resistance gene. Targeted disruption of the mouse M1 gene.