Acetylcholine serves an important modulatory role in the central nervous system. Pharmacological evidence has suggested that cholinergic activity can modulate central dopaminergic transmission; however, the nature of this interaction and the receptors involved remain undefined. In this study we have generated mice lacking the M1 muscarinic acetylcholine receptor and examined the effects of M1 deletion on dopaminergic transmission and locomotor behavior. We report that M1 deficiency leads to elevated dopaminergic transmission in the striatum and significantly increased locomotor activity. M1-deficient mice also have an increased response to the stimulatory effects of amphetamine. Our results provide direct evidence for regulation of dopaminergic transmission by the M1 receptor and are consistent with the idea that M1 dysfunction could be a contributing factor in psychiatric disorders in which altered dopaminergic transmission has been implicated. Muscarinic acetylcholine receptors are members of the family of G protein-coupled receptors and are widely expressed in the central nervous system and periphery (1, 2). Molecular cloning studies identified genes for five distinct muscarinic receptors, M1-M5, which are expressed in overlapping patterns in the brain. Of these, M1 is predominant in the cortex and hippocampus (3) and, together with M4, is the major muscarinic receptor in the striatum (4), where it is expressed on the majority of cell types (5, 6). M1 receptors couple with a G q type of G protein, and activation of this pathway leads to stimulation of phospholipase C-␤, mobilization of intracellular calcium, and increased neuronal excitability (2). Activation of pharmacologically defined M1 receptors has been shown to enhance the excitability of cortical (7) and striatal (8) neurons. Muscarinic receptors mediate many of the cholinergic effects described in the central nervous system and have been implicated in a variety of central processes, including locomotion, sleep, thermoregulation, generation of seizures, antinociception, and learning and memory (1, 2, 9).A large body of evidence suggests the existence of a complex balance between the cholinergic and dopaminergic systems in the basal ganglia and that disruption of this balance could contribute to movement disorders such as parkinsonism (10, 11). Dopamine can exert both positive and negative regulatory influences on striatal cholinergic transmission, with D1 and D2 receptors exerting facilitative and inhibitory actions, respectively (11). Cholinergic regulation of striatal dopaminergic transmission is less well defined and can occur at multiple levels of the nigrostriatal system. Although a number of pharmacological studies have addressed the effects of muscarinic function on striatal dopaminergic transmission, such studies are limited by the lack of highly subtype-specific muscarinic antagonists (2) and the expression of multiple muscarinic receptors affecting nigrostriatal function. Thus, evidence for both facilitative (12-15) and inhibitory (16-19) mu...

A nucleic acid probe specific for heavy chains bearing the cross-reactive idiotype (Id) associated with the anti-p-azophenylarsonate response of strain A mice has been prepared. Analysis of arsonate-binding Id+ hybridoma cell lines has revealed that all of them contain the same germ-line VH gene rearranged to the JH2 segment. An Id+ hybridoma which is unable to bind arsonate utilized the same VH gene, but it has apparently rearranged to the JH4 segment. Id- cell lines contain other rearranged VH genes. Analysis of DNa of strain A mice revealed that there is apparently only one germ line gene that can give rise to Id+ heavy chains. Since the Id is expressed as a large collection (greater than 50) of related but nonidentical heavy chain sequences, we conclude that their diversity is the result of a somatic mutation process. Analysis of a single hybridoma cell line (45-59) reveals that somatic mutation can operate on an Id-encoding gene and result in an antigen-binding molecule that has lost all of its Id determinants. Further analysis of the genome of strain A mice has revealed the presence of germ-line genes differing from the Id-encoding gene by at least 8 base pairs. These genes, however, apparently do not contribute to the anti-arsonate Id response.

SummaryA hamster monoclonal antibody (mAb) recognizing an epitope in the Vy1 Jy4-Cy4 chain of the y/8 T cell receptor has been generated. Using this mAb, we have quantitated the occurrence of Vyl-bearing y/8 T cells in the developing thymus and in the lymphoid organs and several epithelia ofadult mice. The Vyl-expressing cells constitute a minor y/8 T cell subpopulation during fetal and early postnatal life, but they constitute a major population of 'Y/8 T cells in the thymus and in the peripheral lymphoid organs in adult mice. In addition, we found that Vy1-bearing cells comprise a large proportion (15-60%) of the y/8 T cells present in the intestinal epithelium (i-IEL) in all strains of mice tested. Vy1 + i-IEL are present in athymic (nude) mice and in antigen-free mice, demonstrating that they can develop extrathymically and that their presence in the intestinal epithelium is independent of the antigenic load of the gut . Our results show that Vyl-bearing lymphocytes account for the largest population of y/8 T cells in the mouse. This population includes a thymus-dependent component that homes to the secondary lymphoid organs and a thymus-independent component that constitutes a major fraction of the y/8 i-IELs.