The role of N-cholinoreceptors in somatovisceral intersystemic interactions in early rat ontogenesis

Interaction of slow-wave rhythmic components of cardiac, respiratory and motor activities was analyzed in non-narcotized of newborn 1-day-old (P1) and 16-day-old (P16) Wistar rat pups under normal and impaired cholinergic regulation. Functional activity of these three systems is rhythmic, and coordination of their functioning is an important element of the mechanism of adaptive rearrangements under changing factors of the external and internal environment. The acetylcholinesterase inhibitor physostigmine (eserine) was used to increase the level of endogenous acetylcholine and enhance cholinergic effects. To reveal the role of N-cholinoreceptors in intersystemic somatovisceral interactions (ISI), we performed blockade of this receptor type with benzohexonium. Administration of physostigmine leads to the development of a number of pathological reactions and a decrease in the level of ISI in all ranges of modulating rhythms in rats of both ages. ISI in younger rats appear to be more resistant to changes in the level of cholinergic activation. Blockade of N-cholinoreceptors causes inhibition of ISI at P1 and partially to their potentialization at P16. The activation of cholinoreactive structures, which occurred against the background of cholinoreceptors blockade, reduces the pathological effects of physostigmine in animals of both ages, but at the same time leads to an attenuation of ISI. This weakening is more pronounced in 16-day old rats, which may indicate the formation of the definitive level of cholinergic regulation in the first weeks of postnatal ontogenesis.

Acetylcholine Signaling Genes are Required for Cocaine-Stimulated Egg Laying in Caenorhabditis elegans

The toxicity and addictive liability associated with cocaine abuse are well known. However, its mode of action is not completely understood, and effective pharmacotherapeutic interventions remain elusive. The cholinergic effects of cocaine on acetylcholine receptors, synthetic enzymes, and degradative enzymes have been the focus of relatively little empirical investigation. Due to its genetic tractability and anatomical simplicity, the egg laying circuit of the hermaphroditic nematode, Caenorhabditis elegans, is a powerful model system to precisely examine the genetic and molecular targets of cocaine in vivo. Here, we report a novel cocaine-induced behavioral phenotype in Caenorhabditis elegans, cocaine-stimulated egg laying. In addition, we present the results of an in vivo candidate suppression screen of synthetic enzymes, receptors, degradative enzymes, and downstream components of the intracellular signaling cascades of the main neurotransmitter systems that control Caenorhabditis elegans egg laying. Our results show that cocaine-stimulated egg laying is dependent on acetylcholine synthesis and synaptic release, functional nicotinic acetylcholine receptors, and the Caenorhabditis elegans acetylcholinesterases.

Inhibition of Recombinant Human Acetylcholinesterase Activity by Antipsychotics

Background/Aims: Extrapyramidal symptoms (EPS) are representative side effects of antipsychotics, caused by their inhibitory action on dopaminergic nerves in nigrostriatal pathways. EPS could be also caused by direct augmentation of cholinergic effects, for example, by acetylcholinesterase (AChE) inhibition. We investigated the potential inhibitory effects of 26 clinically available antipsychotics on the activity of recombinant human AChE (rhAChE) to predict the role of antipsychotic-induced AChE inhibition in EPS onset. Method: The degree of rhAChE activity inhibition was calculated using the 5,5′-dithio-bis-(2-nitrobenzoic acid) method. Results: At a concentration of 10–5 mol/L, haloperidol, bromperidol, timiperone, nemonapride, pimozide, risperidone, blonanserin, aripiprazole, and brexpiprazole inhibited rhAChE activity by >20%. Risperidone, aripiprazole, and brexpiprazole inhibited rhAChE activity in a concentration-dependent manner, and their effects were more potent than those of other antipsychotics. The inhibitory effects of these 3 drugs were evident from 10–6 mol/L, and their pIC50 values were 4.74 ± 0.04, 4.80 ± 0.04, and 4.93 ± 0.06, respectively. Notably, the concentration range in which aripiprazole inhibited rhAChE activity (≥10–6 mol/L) overlapped with its clinically achievable blood levels. Conclusion: Aripiprazole may cause EPS at clinical dosages by augmenting cholinergic effects via AChE inhibition, in addition to its suppressive effect on dopaminergic neurons.

Clozapine efficiency in tardive syndromes induced by anti-psychotic treatment

IntroductionTardive syndromes (TS) resulting from prolonged exposure to dopamine receptor blocking agents are frequent. Clozapine is considered to have a low risk of causing new onset TS and accounts therefore as an interesting option in patients with invalidating TS.ObjectivesOur study aims to describe clozapine indications in patients experiencing TS.MethodsPresentation of the clinical cases of five patients, who experienced different kinds of TS secondary to 1st and 2nd generation anti-psychotic treatment.ResultsWe present the cases of AB aged 41, MJ aged 40, HM aged 31 and AS aged 30, diagnosed with schizophrenia; and FB aged 24,diagnosed with schizoaffective disorder. Adverse side effects to conventional anti-psychotics such as limb and trunk tremors were described for AB, choreic limb movements, axial and segmental dystonia for MJ, AS, FB and oculogyration for FB. All patients were switched to atypical anti-psychotics without improvement of the TS. The switch to clozapine, associated with abotulinum injection for MJ, led to regression of the TS and improvement of clinical signs. In fact, according to several studies, clozapine seems to be an interesting option when invalidating TS occurs. The low prevalence of TS under clozapine can be explained by its low affinity for striatal-D2 receptors, its anti-serotonin and anti-cholinergic effects.ConclusionsClozapine should be considered in symptomatic patients who develop TS while receiving other anti-psychotics. Further research on mechanism of TS and clozapine effect on TS is needed.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Dose and Time-dependent Alterations in Various Cholinergic and Non-cholinergic Markers after Organophosphate Poisoning: Possible Role in Diagnosis

Toxicity of organophosphates (OP) is mainly ascribed to inhibition of acetylcholinesterase (AChE) enzyme at the cholinergic synapses. This results in cholinergic crisis leading to various muscarinic, nicotinic and central effects. Additionally, there are several non-cholinergic effects of OP which are likely to exacerbate the toxicity and complicate diagnosis. The present study reports the dose (0.125 - 4.0 LD50) and time (1 h - 14 d)- dependent acute effect of diisopropyl phosphorofluoridate (DFP) on mice body weight, organ-body weight index (brain), butyrylcholinesterase (BChE) and β-glucoronidase (BG) activity in plasma, AChE activity, reduced glutathione (GSH) and malondialdehyde (MDA) levels in brain, and DNA damage in brain (agarose gel electrophoresis) and blood (comet assay). The study reveals a dose and time- dependent BChE inhibition up to 24 h and AChE inhibition up to 7 d. However, elevated BG levels were observed up to 1 h only after 1.0, 2.0, and 4.0 LD50 DFP. Diminished GSH levels up to 24 h and increased MDA levels at 4 h indicated oxidative stress. None of the treatments produced any DNA damage in soft tissues. In addition to cholinesterase, the study suggests possible relevance of measuring BG levels (non-cholinergic marker) in the diagnosis of OP poisoning.