Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P < 0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P = 9.8 × 10-12, R2 = 1.9%) and continuous (P = 6.4 × 10-9, R2 = 2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P = 3.9 × 10-4, R2 = 0.9%), but not for the continuous outcome (P = 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.

• MeSH
• acetylcholin metabolismus   MeSH
• antimanika terapeutické užití   farmakologie   MeSH
• Bayesova věta MeSH
• bipolární porucha * farmakoterapie   genetika   MeSH
• celogenomová asociační studie metody   MeSH
• dospělí MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• kohortové studie MeSH
• kyselina glutamová metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lithium * terapeutické užití   farmakologie   MeSH
• multifaktoriální dědičnost * genetika   MeSH
• sloučeniny lithia terapeutické užití   farmakologie   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Acetylcholine is an important modulator of striatal activity, and it is vital to controlling striatal-dependent behaviors, including motor and cognitive functions. Despite this significance, the mechanisms determining how acetylcholine impacts striatal signaling are still not fully understood. In particular, little is known about the role of nAChRs expressed by striatal interneurons. In the present study, we used FISH to determine which neuronal types express the most prevalent beta2 nicotinic subunit in the mouse striatum. Our data support a common view that nAChR expression is mostly restricted to striatal interneurons. Surprisingly though, cholinergic interneurons were identified as a population with the highest expression of beta2 nicotinic subunit. To investigate the functional significance of beta2-containing nAChRs in striatal interneurons, we deleted them by injecting the AAV-Cre vector into the striatum of beta2-flox/flox male mice. The deletion led to alterations in several behavioral domains, namely, to an increased anxiety-like behavior, decrease in sociability ratio, deficit in discrimination learning, and increased amphetamine-induced hyperlocomotion and c-Fos expression in mice with beta2 deletion. Further colocalization analysis showed that the increased c-Fos expression was present in both medium spiny neurons and presumed striatal interneurons. The present study concludes that, despite being relatively rare, beta2-containing nAChRs are primarily expressed in striatal neurons by cholinergic interneurons and play a significant role in behavior.SIGNIFICANCE STATEMENT A large variety of nAChRs are expressed in the striatum, a brain region that is crucial in the control of behavior. The complexity of receptors with different functions is hindering our understanding of mechanisms through which striatal acetylcholine modulates behavior. We focused on the role of a small population of beta2-containing nAChRs. We identified neuronal types expressing these receptors and determined their impact in the control of explorative behavior, anxiety-like behavior, learning, and sensitivity to stimulants. Additional experiments showed that these alterations were associated with an overall increased activity of striatal neurons. Thus, the small population of nicotinic receptors represents an interesting target for a modulation of response to stimulant drugs and other striatal-based behavior.

• MeSH
• acetylcholin metabolismus   MeSH
• cholinergní látky farmakologie   MeSH
• corpus striatum metabolismus   MeSH
• interneurony metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nikotinové receptory * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The membrane cholesterol was found to bind and modulate the function of several G-protein coupled receptors including muscarinic acetylcholine receptors. We investigated the binding of 20 steroidal compounds including neurosteroids and steroid hormones to muscarinic receptors. Corticosterone, progesterone and some neurosteroids bound to muscarinic receptors with the affinity of 100 nM or greater. We established a structure-activity relationship for steroid-based allosteric modulators of muscarinic receptors. Further, we show that corticosterone and progesterone allosterically modulate the functional response of muscarinic receptors to acetylcholine at physiologically relevant concentrations. It can play a role in stress control or in pregnancy, conditions where levels of these hormones dramatically oscillate. Allosteric modulation of muscarinic receptors via the cholesterol-binding site represents a new pharmacological approach at diseases associated with altered cholinergic signalling.

• MeSH
• acetylcholin metabolismus   MeSH
• alosterická regulace MeSH
• hormony kůry nadledvin metabolismus   MeSH
• kortikosteron metabolismus   MeSH
• křečci praví MeSH
• kultivované buňky MeSH
• lidé MeSH
• neurosteroidy metabolismus   MeSH
• pohlavní steroidní hormony metabolismus   MeSH
• progesteron metabolismus   MeSH
• receptory muskarinové metabolismus   MeSH
• zvířata MeSH
• Check Tag
• křečci praví MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Nejrozšířenějším neuropřenašečem mozku je acetylcholin, který aktivuje nikotinové a muskarinové receptory. A právě muskarinové re¬ceptory jsou nejčastěji se vyskytující cholinergní receptory CNS. Muskarinové receptory existují v pěti podtypech. Jsou exprimovány napříč celou centrální soustavou, ale bohatě zastoupeny jsou i na periferii. Tyto s G-proteiny spřažené receptory zajišťují přenos signálu skrze systém druhých poslů, pomocí kterých dochází uvnitř buňky ke změnám v koncentracích iontů, konformacích enzymů, či ke změ¬nám až na úrovni buněčné exprese. Všech pět podtypů pokrývá celou škálu různorodých funkcí spojených se zajištěním správného fyziologického chodu celého těla. Po aktivaci receptoru vyvolané vazbou acetylcholinu dochází k přenosu signálu do buňky prostřed¬nictvím G-proteinů umístěných na plazmatické membráně, kdy sudé podtypy muskarinových receptorů jsou spřaženy s Gi/o proteiny, liché s Gq proteiny. V centrální nervové soustavě se vyskytují v různém zastoupení všechny podtypy muskarinových receptorů. Muskarinové receptory mají celou řadu regulačních funkcí, účastní se i celé řady behaviorálních a kognitivních dějů, které jsou v tomto přehledném článku diskutovány.

The most prevalent neurotransmitter of the brain is acetylcholine, which activates nicotinic and muscarinic receptors. And muscarinic receptors are the most common CNS cholinergic receptors. Muscarinic receptors exist in five subtypes. They are expressed across the entire central system, but are richly represented on the periphery as well. These G¬protein bonded receptors provide the trans¬mission of a signal through a system of second messengers, by which changes occur within the cell in ion concentrations, enzyme conformations, or changes up to the level of cellular expression. All five subtypes cover the full range of varied functions associated with ensuring the correct physiological course of the entire body. After activation of the receptor induced by acetylcholine binding, the signal is transmitted to the cell via G¬proteins located on the plasma membrane, where even muscarinic receptor subtypes are bond¬ed to Gi/o proteins, odd to Gq proteins. In the central nervous system, all muscarinic receptor subtypes occur in different proportions. Muscarinic receptors have a variety of regulatory functions, as well as a variety of behavioural and cognitive processes discussed in this review article.

• MeSH
• acetylcholin metabolismus   MeSH
• centrální nervový systém chemie   fyziologie   MeSH
• lidé MeSH
• receptory muskarinové * fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

Acetylcholine (ACh)-mediated vagal transmission as well as nonneuronal ACh release are considered cardioprotective in pathological situations with increased sympathetic drive such as ischemia-reperfusion and cardiac remodeling. ACh action is terminated by hydrolysis by the cholinesterases (ChEs), acetylcholinesterase, and butyrylcholinesterase. Both ChEs exist in multiple molecular variants either soluble or anchored by specific anchoring proteins like collagen Q (ColQ) anchoring protein and proline-rich membrane anchoring protein (PRiMA). Here we assessed the expression of specific ChE molecular forms in different heart compartments using RT-qPCR. We show that both ChEs are expressed in all heart compartments but display different expression patterns. The acetylcholinesterase-T variant together with PRiMA and ColQ is predominantly expressed in rat atria. Butylcholinesterase is found in all heart compartments and is accompanied by both PRiMA and ColQ anchors. Its expression in the ventricular system suggests involvement in the nonneuronal cholinergic system. Additionally, two PRiMA variants are detected throughout the rat heart.

• MeSH
• acetylcholin metabolismus   MeSH
• acetylcholinesterasa analýza   metabolismus   MeSH
• butyrylcholinesterasa analýza   metabolismus   MeSH
• GPI-vázané proteiny analýza   metabolismus   MeSH
• izoenzymy analýza   metabolismus   MeSH
• kolagen analýza   metabolismus   MeSH
• krysa rodu rattus MeSH
• kvantitativní polymerázová řetězová reakce MeSH
• membránové proteiny analýza   metabolismus   MeSH
• myokard enzymologie   MeSH
• potkani Wistar MeSH
• proteiny nervové tkáně analýza   metabolismus   MeSH
• stanovení celkové genové exprese MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• acetylcholin metabolismus   MeSH
• acetylcholinesterasa metabolismus   MeSH
• acetylthiocholin metabolismus   MeSH
• Electrophorus metabolismus   MeSH
• hydrolýza MeSH
• katalýza MeSH
• kinetika MeSH
• koncentrace vodíkových iontů MeSH
• rybí proteiny metabolismus   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Current options for Alzheimer's disease (AD) treatment are based on administration of cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and/or memantine, acting as an N-methyl-D-aspartate (NMDA). Therapeutic approaches vary and include novel cholinesterase inhibitors, modulators of NMDA receptors, monoamine oxidase (MAO) inhibitors, immunotherapeutics, modulators of mitochondrial permeability transition pores (mPTP), amyloid-beta binding alcohol dehydrogenase (ABAD) modulators, antioxidant agents, etc. The novel trends of AD therapy are focused on multiple targeted ligands, where mostly ChE inhibition is combined with additional biological properties, positively affecting neuronal energy metabolism as well as mitochondrial functions, and possessing antioxidant properties. The present review summarizes newly developed drugs targeting cholinesterase and MAO, as well as drugs affecting mitochondrial functions.

• MeSH
• acetylcholin metabolismus   MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• biogenní monoaminy metabolismus   MeSH
• energetický metabolismus účinky léků   MeSH
• látky ovlivňující centrální nervový systém chemie   farmakologie   terapeutické užití   MeSH
• lidé MeSH
• nervový přenos účinky léků   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Extramural MeSH

In nature, proteins have evolved sophisticated cavities tailored for capturing target guests selectively among competitors of similar size, shape, and charge. The fundamental principles guiding the molecular recognition, such as self-assembly and complementarity, have inspired the development of biomimetic receptors. In the current work, we report a self-assembled triple anion helicate (host 2) featuring a cavity resembling that of the choline-binding protein ChoX, as revealed by crystal and density functional theory (DFT)-optimized structures, which binds choline in a unique dual-site-binding mode. This similarity in structure leads to a similarly high selectivity of host 2 for choline over its derivatives, as demonstrated by the NMR and fluorescence competition experiments. Furthermore, host 2 is able to act as a fluorescence displacement sensor for discriminating choline, acetylcholine, L-carnitine, and glycine betaine effectively.The choline-binding protein ChoX exhibits a synergistic dual-site binding mode that allows it to discriminate choline over structural analogues. Here, the authors design a biomimetic triple anion helicate receptor whose selectivity for choline arises from a similar binding mechanism.

• MeSH
• acetylcholin chemie   metabolismus   MeSH
• bakteriální proteiny chemie   metabolismus   MeSH
• cholin chemie   metabolismus   MeSH
• fosfáty chemie   metabolismus   MeSH
• kinetika MeSH
• kompetitivní vazba MeSH
• krystalografie rentgenová MeSH
• membránové transportní proteiny chemie   metabolismus   MeSH
• molekulární modely MeSH
• proteinové domény * MeSH
• protonová magnetická rezonanční spektroskopie MeSH
• Sinorhizobium meliloti metabolismus   MeSH
• transportní proteiny chemie   metabolismus   MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

Some rats [sign-trackers (STs)] are prone to attribute incentive salience to reward cues, which can manifest as a propensity to approach and contact pavlovian cues, and for addiction-like behavior. STs also exhibit poor attentional performance, relative to goal-trackers (GTs), which is associated with attenuated acetylcholine (ACh) levels in prefrontal cortex (Paolone et al., 2013). Here, we demonstrate a cellular mechanism, linked to ACh synthesis, that accounts for attenuated cholinergic capacity in STs. First, we found that electrical stimulation of the basal forebrain increased cortical choline transporter (CHT)-mediated choline transport in GTs, paralleled by a redistribution of CHTs to the synaptic plasma membrane. Neither increases in choline uptake nor translocation of CHTs occurred in STs. Second, and consistent with uptake/translocation alterations, STs demonstrated a reduced ability to support cortical ACh release in vivo compared with GTs after reverse-dialysis to elevate extracellular potassium levels. Third, rats were significantly more likely to develop sign-tracking behavior if treated systemically before pavlovian conditioned approach training with the CHT inhibitor VU6001221. Consistent with its proposed mechanisms, administration of VU6001221 attenuated potassium-evoked ACh levels in prefrontal cortex measured with in vivo microdialysis. We propose that loss of CHT-dependent activation of cortical cholinergic activity in STs degrades top-down executive control over behavior, producing a bias for bottom-up or stimulus-driven attention. Such an attentional bias contributes to nonadaptive reward processing and thus identifies a novel mechanism that can support psychopathology, including addiction.SIGNIFICANCE STATEMENT The vulnerability for addiction-like behavior has been associated with psychological traits, such as the propensity to attribute incentive salience to reward cues that is modeled in rats by sign-tracking behavior. Sign-trackers tend to approach and contact cues associated with reward, whereas their counterparts, the goal-trackers, have a preference for approaching the location of the reward. Here, we show that the capacity of presynaptic cholinergic synapses to respond to stimulation by elevating presynaptic choline uptake and releasing acetylcholine is attenuated in sign-trackers. Furthermore, pharmacological inhibition of choline transport induced sign-tracking behavior. Our findings suggest that reduced levels of cholinergic neuromodulation can mediate an attentional bias toward reward-related cues, thereby allowing such cues to exert relatively greater control over behavior.

• MeSH
• acetylcholin metabolismus   MeSH
• biologické markery metabolismus   MeSH
• cholin metabolismus   MeSH
• kauzalita MeSH
• krysa rodu rattus MeSH
• membránové transportní proteiny metabolismus   MeSH
• neurony cholinergní fyziologie   MeSH
• neurotransmiterové látky metabolismus   MeSH
• odklon pozornosti fyziologie   MeSH
• odměna * MeSH
• podněty MeSH
• potkani Sprague-Dawley MeSH
• presynaptické terminály metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Apolipoprotein E4 (apoE4) is the most prevalent genetic risk factor for Alzheimer's disease. We utilized apoE4-targeted replacement mice (approved by the Tel Aviv University Animal Care Committee) to investigate whether cholinergic dysfunction, which increases during aging and is a hallmark of Alzheimer's disease, is accentuated by apoE4. This revealed that levels of the pre-synaptic cholinergic marker, vesicular acetylcholine transporter in the hippocampus and the corresponding electrically evoked release of acetylcholine, are similar in 4-month-old apoE4 and apolipoprotein E3 (apoE3) mice. Both parameters decrease with age. This decrease is, however, significantly more pronounced in the apoE4 mice. The levels of cholinacetyltransferase (ChAT), acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) were similar in the hippocampus of young apoE4 and apoE3 mice and decreased during aging. For ChAT, this decrease was similar in the apoE4 and apoE3 mice, whereas it was more pronounced in the apoE4 mice, regarding their corresponding AChE and BuChE levels. The level of muscarinic receptors was higher in the apoE4 than in the apoE3 mice at 4 months and increased to similar levels with age. However, the relative representation of the M1 receptor subtype decreased during aging in apoE4 mice. These results demonstrate impairment of the evoked release of acetylcholine in hippocampus by apoE4 in 12-month-old mice but not in 4-month-old mice. The levels of ChAT and the extent of the M2 receptor-mediated autoregulation of ACh release were similar in the adult mice, suggesting that the apoE4-related inhibition of hippocampal ACh release in these mice is not driven by these parameters. Evoked ACh release from hippocampal and cortical slices is similar in 4-month-old apoE4 and apoE3 mice but is specifically and significantly reduced in hippocampus, but not cortex, of 12-month-old apoE4 mice. This effect is accompanied by decreased VAChT levels. These findings show that the hipocampal cholinergic nerve terminals are specifically affected by apoE4 and that this effect is age dependent.

• MeSH
• acetylcholin metabolismus   MeSH
• apolipoprotein E3 genetika   MeSH
• apolipoprotein E4 genetika   metabolismus   MeSH
• cholin-O-acetyltransferasa metabolismus   MeSH
• guanosin 5'-O-(3-thiotrifosfát) farmakologie   MeSH
• hipokampus účinky léků   metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši transgenní MeSH
• myši MeSH
• N-methylskopolamin farmakologie   MeSH
• receptory muskarinové metabolismus   MeSH
• tritium metabolismus   MeSH
• věkové faktory MeSH
• vezikulární transportní proteiny acetylcholinu metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH