Enhancement of D1 dopamine receptor-mediated locomotor stimulation in M ₄ muscarinic acetylcholine receptor knockout mice

Abstract

Members of the muscarinic acetylcholine receptor family (M 1 -M 5 ) are widely expressed in the central nervous system and in the body periphery (1-7). Central muscarinic receptors are known to play key roles in memory and learning as well as in the regulation of many sensory, motor, and autonomic processes (1-3). In the body periphery, muscarinic receptors mediate the well known activities of acetylcholine released from parasympathetic nerves (1-3).Based on the overlapping expression patterns of the different muscarinic receptor subtypes (4-7) and the lack of ligands that display a high degree of receptor subtype selectivity (8, 9), the precise functional roles of the individual muscarinic receptor species remain to be determined. To address this issue, we therefore decided to use gene-targeting technology to generate mouse lines deficient in individual muscarinic receptor subtypes. In this study, we present an initial pharmacologic analysis of a mouse line that lacks functional M 4 muscarinic receptors.At the molecular level, the M 4 receptor subtype, like the structurally closely related M 2 receptor, couples to G proteins of the G i ͞G o family (8, 9). M 4 receptors are expressed abundantly in the striatum (caudate-putamen) and are also present, though at lower levels, in several other brain regions including cerebral cortex and hippocampus (4-7, 10, 11). In the striatum, a region known to be critically involved in extrapyramidal motor control, the M 4 as well as other muscarinic receptor subtypes are coexpressed with D1 and D2 dopamine receptors on striatal projection neurons (12-16). Considerable evidence suggests that complex interactions between these two neurotransmitter receptor systems are critical for the proper regulation of motor control (2,17,18). Consistent with this notion, the severe motor deficits observed in patients suffering from Parkinson's disease and other extrapyramidal motor disorders are thought to reflect an imbalance between muscarinic cholinergic and dopaminergic tone in the striatum (2, 17). To shed light on the potential interactions of M 4 muscarinic receptors with the different dopamine receptor subtypes, we have investigated systematically the locomotor effects induced by administration of D1-and D2-selective ligands in wild-type and M 4 receptor knockout (KO) mice.Interestingly, recent pharmacologic studies suggested that the M 4 receptor subtype may be responsible for mediating muscarinic receptor-dependent antinociception (19,20). Thus, another main focus of the present study was to study muscarinic agonistinduced analgesic effects in the M 4 receptor KO mice. In addition, we also examined the potential involvement of the M 4 receptor subtype in muscarinic receptor-mediated tremor, salivation, and hypothermia, three of the most striking effects caused by administration of centrally acting muscarinic agonists (21).We demonstrate that M 4 receptor-deficient mice show an increase in basal locomotor activity and are hypersensitive to the stimulatory locomotor effects of...

The deletion of M4 muscarinic receptors increases motor activity in females in the dark phase

“…(1999) were hyperactive in an open field during the first 40 min. By contrast, M 4 KO male mice on pure 129SvEv background present increased locomotor activity only in the first 10 min (Koshimizu et al., 2012), and M 4 KO males fully backcrossed to the C57BL/6NTac genetic background do not differ in open‐field locomotor activity from wild‐type controls, in spite of altered dopaminergic responses (Fink‐Jensen et al., 2011).…”

“…The mice lacking the M 4 muscarinic receptor were generated in Wess’ laboratory (Gomeza et al., 1999) and then bred in our animal facility (Prague, Czech Republic). Their genetic background was C57Bl6/6NTac.…”

“…The initial knockout study (Gomeza et al., 1999) strongly indicated that M 4 knockout significantly increases the overall animal motor activity. The increased locomotion of M 4 KO mice has been attributed to the enhanced dopaminergic signaling at D 1 dopamine receptors.…”

Towards a muscarinic hypothesis of schizophrenia

“…63,64 However, the M 5 -subtype may be relevant to schizophrenia as it is located in the brainstem and midbrain, where it has an effect on dopamine release. 65 Based on their functional activity, muscarinic receptors can be subdivided into two groups (M 1 , M 3 [66][67][68][69] A better understanding of the physiological role of the different subtypes of the muscarinic receptors has been gained from the study of knockout animals that lack one or more of these receptors; [70][71][72][73][74][75] for a review see Bymaster et al 76 ). Depending on the muscarinic receptor subtype involved, cholinergic activation can have different effects on the peripheral and central nervous function.…”

The Muscarinic M1/M4 Receptor Agonist Xanomeline Exhibits Antipsychotic-Like Activity in Cebus apella Monkeys

“…Five muscarinic receptor subtypes (M 1 -M 5 ) have been cloned and these receptor subtypes are widely distributed in the central nervous system including the prefrontal cortex and limbic areas, such as the nucleus accumbens, hypothesized to be associated with schizophre-nia (Levey et al, 1991). In addition, functional as well as anatomical studies suggest considerable interaction between the cholinergic and the dopaminergic systems (Di Chiara et al, 1994;Gomeza et al, 1999;Hartvig et al, 2002;Weiner et al, 1990).…”