It is diagnosed following a presentation of a constellation of symptoms [30], and thus, like additional disorders diagnosed on this basis, is probably a syndrome that consists of a number of diseases, with comparable clinical presentations [31]. Schizophrenia, Substance abuse Introduction Pralidoxime Iodide This review will focus on central muscarinic receptors, discussing the data implicating them in the pathophysiology of psychiatric disorders, such as schizophrenia, bipolar disorder, major depressive disorder (MDD), and substance abuse, as well as neurological diseases such as Alzheimer’s and Parkinson’s disease. This information will be coupled with recent advances in the development of compounds that selectively target individual muscarinic receptors and the outcomes of preclinical testing, in order to assess whether or not targeting the implicated receptors can produce the desired physiological effect. Acetylcholine The presence of acetylcholine predates the development of the nervous system, with the chemical present in primitive plants and bacteria Pralidoxime Iodide (see [1]). Thus, it is not surprising that this molecule, normally considered a neurotransmitter, is involved in the regulation of a myriad of functions fundamental to continued existence, such as cell proliferation, differentiation, migration, and maintaining homoeostasis (see [1] regarding nonneuronal roles for acetylcholine). Species that diverged more than 350 million years ago have central cholinergic systems, with acetylcholine underlying aspects of behavior and learning in insects [2] and mammals [3]. In primates, the central cholinergic system has three main components: (1) projections from the basal forebrain, innervating the hippocampus, most cortical regions and some subcortical nuclei, (2) projections from the brainstem, which innervate the thalamus and midbrain as well as other regions of the brainstem, and (3) interneurons, predominantly striatal but also present in the nucleus accumbens (see [4] for a review on central cholinergic function). With this widespread innervation of phylogenetically old and new brain structures, acetylcholine has been implicated as playing vital roles in modulating diverse central functions such as sleep, cognition, motor control, and sensory processing. These actions are mediated by two families of receptors, the nicotinic and muscarinic receptors [5]. While this review focuses on muscarinic receptors, the high degree of integration between the two arms of the cholinergic system makes it unlikely that they function independently of each other [6]. Muscarinic Receptors The muscarinic receptor family consists of five metabotropic receptors, M1C5; upon activation they trigger second messenger cascades within the neurons that express them [Table 1]. Individual receptors are preferentially coupled to distinct G proteins, with M1, 3, and 5 coupling to Gq/11 subunits, leading to the activation of phospholipase C. M2 and 4 receptors, on the other hand, couple to Gi/o subunits, resulting in the inhibition of adenylyl cyclase [7]. However, in addition to their canonical signaling pathways, cell expression systems have revealed that muscarinic receptors are capable of activating multiple signal transduction pathways, often depending on the cell type studied. For example, the M1, 3, and 5 receptors can stimulate pathways involving phospholipase A2, phospholipase D, and tyrosine kinase as well as calcium channels. In addition to inhibiting adenylyl cyclase, M2 and M4 receptors can also use phospholipase A2 as a second messenger [8].While these findings have the potential to make it difficult to determine the physiological consequences of changes in the functionality of different muscarinic receptors, they need to be interpreted with caution since such studies often involve the overexpression of nonnative receptors in a particular cell line and thus the activation of diverse signal transduction systems, which may not occur physiologically. Table 1 The properties of the five muscarinic receptors, including the nature of their allosteric ligands thead valign=”bottom” th align=”left” valign=”bottom” rowspan=”1″ colspan=”1″ Receptor /th th align=”left” valign=”bottom” rowspan=”1″ colspan=”1″ M1 /th th align=”left” valign=”bottom” rowspan=”1″ colspan=”1″ M2 /th th align=”left” valign=”bottom” rowspan=”1″ colspan=”1″ M3 /th th align=”left” valign=”bottom” rowspan=”1″ colspan=”1″ M4 /th th align=”left” valign=”bottom” rowspan=”1″ colspan=”1″ M5 /th /thead G\protein subunitq/11i/oq/11i/oq/11Canonical signalingPLCInhibits adenylyl cyclasePLCInhibits adenylyl cyclasePLCCNS distributionCortex, basal gangliaNucleus basalis, hippocampus, basal gangliaCortex, basal gangliaBasal ganglia, cortexHippocampus, substantia nigra, VTALigands (type)AC\260584 (ag; [59]) BQCA (PAM; [60]) TBPB (ag; [61])THRX\160209 (dualsteric antagonist; [79])LY2033298 (PAM; [62]) VU0152099 (PAM;[64]) VU0152100 (PAM; [64])VU0238429 (PAM; [97]) Amiodarone (PAM; [98]) Open in a separate window PLC, phospholipase C; VTA, ventral tegmental area; ag, agonist; PAM, positive allosteric modulator; AC\260584, (4\[3\(4\butylpiperidin\1\yl)\propyl]\7\fluoro\4H\benzo[1,4]oxazin\3\one; BQCA, benzylquinolone carboxylic acid; TBPB, [1\(1\2\methylbenzyl)\1,4\bipiperidin\4\yl)\1H\benzo[d]imidazol\2(3H)\one]; LY2033298, (3\amino\5\chloro\6\methoxy\4\methyl\thieno[2,3\b]pyridine\ 2\carboxylic acid cyclopropylamide); VU0152099, [3\amino\ em N /em \(benzo[d][1,3]dioxol\5\ylmethyl)\4,6\dimethylthieno[2,3\ em b Rabbit polyclonal to CLOCK /em ]pyridine carboxamide]; VU0152100, [3\amino\ em N /em \(4\methoxybenzyl)\4,6\dimethylthieno[2,3\ em b /em ]pyridine carboxamide]; Dualsteric, targets both orthosteric and allosteric sites; [x] indicates reference for the compound. Muscarinic M1 receptors are found throughout the brain, with the highest concentrations in cortical regions, including the hippocampus [9]. Cortical M1 receptors are primarily located postsynaptically; there they are predominantly associated with excitatory synapses but are also found at cholinergic synapses [10]. Although they are present in all cortical layers, M1 receptors are most dominant in cortical layers III and V/VI [10], where they are Pralidoxime Iodide found on pyramidal neurons [11]. M2 receptors are highly expressed in the nucleus basalis and occipital cortex, being.