Acetylcholine Antagonists Research Articles

Infusions of scopolamine in dorsal hippocampus reduce anticipatory responding in an appetitive trace conditioning procedure.

IntroductionTrace conditioning is impaired by lesions to dorsal hippocampus, as well as by treatment with the muscarinic acetylcholine antagonist scopolamine. However, the role of muscarinic receptors within hippocampus has received little attention.MethodsThe present study examined the effects of intra‐hippocampal infusion of scopolamine (30 µg/side) in an appetitive (2 vs. 10 s) trace conditioning procedure using sucrose pellets as the unconditioned stimulus (US). Locomotor activity (LMA) was examined in a different apparatus.ResultsIntra‐hippocampal scopolamine reduced responding to the 2 s trace conditioned stimulus (CS). Intra‐hippocampal scopolamine similarly depressed responding within the inter‐stimulus interval (ISI) at both 2 and 10 s trace intervals, but there was no such effect in the inter‐trial interval. There was also some overall reduction in responding when the US was delivered; significant at the 10 s but not at the 2 s trace interval. A similar pattern of results to that seen in response to the CS during acquisition was shown drug‐free (in the 5 s post‐CS) in the extinction tests of conditioned responding. LMA was increased under scopolamine.ConclusionsThe results suggest that nonspecific changes in activity or motivation to respond for the US cannot explain the reduction in trace conditioning as measured by reduced CS responding and in the ISI. Rather, the findings of the present study point to the importance of associative aspects of the task in determining its sensitivity to the effects of scopolamine, suggesting that muscarinic receptors in the hippocampus are important modulators of short‐term working memory.

A More Sustainable Process for Preparation of the Muscarinic Acetylcholine Antagonist Umeclidinium Bromide.

A more sustainable process for the synthesis of the long-acting muscarinic acetylcholine antagonist umeclidinium bromide is described. Specifically, we report the synthesis of ethyl 1-(2-chloroethyl)-4-piperidinecarboxylate, a key intermediate in the preparation of umeclidinium bromide, in good yields using triethylamine, as well as the identification and characterization of the by-product formed in this reaction. This new method of synthesis leads to an improvement in yield over that of previously reported protocols using potassium carbonate as base (65.6 % versus 38.6 %). Moreover, in the final synthetic step of the process to obtain umeclidinium bromide, we were able to replace the use of toxic solvents (acetonitrile/chloroform) with water. The use of this green solvent allowed precipitation of the active pharmaceutical ingredient (API) from the reaction medium with high purity and in high yield. Overall, we have developed a more efficient and environmentally friendly process for the synthesis of the umeclidinium bromide API with a higher overall yield (37.8 % versus previously reported overall yield of 9.7 %).

Pharmacological properties of revefenacin (TD-4208), a novel, nebulized long-acting, and lung selective muscarinic antagonist, at human recombinant muscarinic receptors and in rat, guinea pig, and human isolated airway tissues.

Revefenacin (TD‐4208) is a novel, long‐acting, and lung‐selective muscarinic cholinergic receptor (mAChR) antagonist in development as a nebulized inhalation solution for the treatment of chronic obstructive pulmonary disease (COPD) patients. This study evaluated the pharmacology of revefenacin at human recombinant mAChRs and in airway tissues from rats, guinea pigs, and humans. At human recombinant mAChRs, revefenacin displayed high affinity (pKI = 8.2‐9.8) and behaved as a competitive antagonist (pKI, apparent = 9.4‐10.9) at the five human recombinant mAChRs. Kinetic studies demonstrated that revefenacin dissociated significantly slower from the hM3 (t 1/2 = 82 minutes) compared to the hM 2 (t 1/2 = 6.9 minutes) mAChR at 37°C, thereby making it kinetically selective for the former subtype. Similarly, in functional studies, revefenacin‐mediated antagonism of acetylcholine (ACh)‐evoked calcium mobilization responses were reversed less rapidly at hM3 compared to the hM2 mAChR. In isolated tracheal tissues from rat and guinea pig and isolated bronchial tissues from humans, revefenacin potently antagonized mAChR‐mediated contractile responses. Furthermore, the antagonistic effects of revefenacin in rat, guinea pig, and human airway tissues were slowly reversible (t 1/2 of 13.3, >16, and >10 hours, respectively). These data demonstrate that revefenacin is a potent, high affinity, and selective functional mAChR antagonist with kinetic selectivity for the hM3 receptor and produces potent and long‐lasting antagonism of mAChR‐mediated contractile responses in rat, guinea pig, and human airway tissue. These data suggest that revefenacin has the potential to be a potent once‐daily dosed inhaled bronchodilator in COPD patients.

178. Dysfunction of Kynurenic Acid in Major Psychiatric Diseases: Causes, Effects and Therapeutic Opportunities

Kynurenic acid (KYNA) is an astrocyte-derived metabolite of the kynurenine pathway of tryptophan degradation and antagonist of alpha7 nicotinic acetylcholine and N-methyl-D-aspartate receptors, and its levels are elevated in the prefrontal cortex of individuals with schizophrenia. Because endogenous KYNA modulates extracellular glutamate, dopamine and GABA levels in the brain, these increases may be pathophysiologically significant. The presentation will review the latest insights into KYNA neurobiology and provide an update on translationally relevant efforts to manipulate KYNA levels in the mammalian brain.

0257 EFFECTS OF ACUTE SLEEP DEPRIVATION IN RATS: SEXUALLY DIMORPHIC INCREASE IN HIPPOCAMPAL KYNURENIC ACID AND IMPAIRED CONTEXTUAL MEMORY

While restful periods at night have been associated with memory consolidation, prolonged periods of poor sleep quality result in neurocognitive dysfunction. Our current experiments were designed to test the hypothesis that kynurenic acid (KYNA), an astrocyte-derived metabolite of the kynurenine pathway (KP) of tryptophan degradation, is elevated in the brain after sleep disturbances. KYNA is an antagonist of α7 nicotinic acetylcholine (α7nACh) and NMDA receptors, and elevations in KYNA negatively impact learning and memory. We investigated the effect of sleep deprivation (SD) on KP metabolism in both male and female adult Wistar rats. Animals were sleep deprived by gentle handling for 6 h from Zeitgeber time (ZT) 0 to ZT6, where ZT 0 is the start of the light-phase. KP metabolites were analyzed in the brain and plasma immediately after SD. In separate adult animals, we tested contextual memory using the passive avoidance paradigm (PAP). Animals were sleep deprived from ZT0 to ZT6 and underwent PAP training at ZT3. Twenty-four hours after training, animals were tested in the retention trial. In the hippocampus, a region that mediates learning and memory, KYNA levels were 1.4-fold elevated in male rats after SD, but not changed after SD in female rats. In the serum, no significant changes in KYNA or its bioprecursor kynurenine were observed in either sex. In male rats, SD induced significant PAP deficits, evidenced as decreased avoidance latency during the retention trial. Conversely, in female animals, the avoidance latency was not significantly reduced after SD. To test our hypothesis that KYNA elevations mediate memory impairments after SD, we have used a KYNA synthesis inhibitor, BFF-816, that targets the enzyme kynurenine aminotransferase (KAT) II and prevents de novo KYNA production. In male rats, BFF-816 treatment (30 mg/kg, p.o. at ZT0 and Z3) attenuated SD-induced contextual memory impairments. Collectively, our results demonstrate a striking sexual dimorphism in the elevation of hippocampal KYNA and contextual memory retention after an acute period of SD. Additionally, we introduce KAT II inhibition as an efficacious strategy to combat cognitive disruption after SD. NIH K12 HD43489.

Propantheline

Propantheline

Molecular and Cellular Mechanisms of Rapid-Acting Antidepressants Ketamine and Scopolamine

Major depressive disorder (MDD) is a prevalent neuropsychiatric disease that causes profound social and economic burdens. The impact of MDD is compounded by the limited therapeutic efficacy and delay of weeks to months of currently available medications. These issues highlight the need for more efficacious and faster-acting treatments to alleviate the burdens of MDD. Recent breakthroughs demonstrate that certain drugs, including ketamine and scopolamine, produce rapid and long-lasting antidepressant effects in MDD patients. Moreover, preclinical work has shown that the antidepressant actions of ketamine and scopolamine in rodent models are caused by an increase of extracellular glutamate, elevated BDNF, activation of the mammalian target of rapamycin complex 1 (mTORC1) cascade, and increased number and function of spine synapses in the prefrontal cortex (PFC). Here we review studies showing that both ketamine and scopolamine elicit rapid antidepressant effects through converging molecular and cellular mechanisms in the PFC. In addition, we discuss evidence that selective antagonists of NMDA and muscarinic acetylcholine (mACh) receptor subtypes (i.e., NR2B and M1-AChR) in the PFC produce comparable antidepressant responses. Furthermore, we discuss evidence that ketamine and scopolamine antagonize inhibitory interneurons in the PFC leading to disinhibition of pyramidal neurons and increased extracellular glutamate that promotes the rapid antidepressant responses to these agents. Collectively, these studies indicate that specific NMDA and mACh receptor subtypes on GABAergic interneurons are promising targets for novel rapid-acting antidepressant therapies.

Synthesis of Epibatidine Analogues by Pyrrole Diels–Alder Reactions: Rapid Access to Azabicyclo[2.2.1]heptane and 3,8‐Diazabicyclo[3.2.1]octane Scaffolds for Library Synthesis

Analogues of the nicotinic acetylcholine antagonist epibatidine, suitable for diversification, were synthesized by application of a pyrrole Diels–Alder strategy, allowing rapid generation of azabicyclo[2.2.1]heptane bicyclic cores. Further molecular complexity could be accessed by using intramolecular Diels–Alder reactions, or ring expansion by ozonolysis–reductive amination chemistry. Scaffolds were designed such that they could be orthogonally deprotected, yielding three points of diversity for library synthesis, exemplified by 24 compounds synthesized from four cores.

Adaptive and Behavioral Changes in Kynurenine 3-Monooxygenase Knockout Mice: Relevance to Psychotic Disorders

BackgroundKynurenine 3-monooxygenase converts kynurenine to 3-hydroxykynurenine, and its inhibition shunts the kynurenine pathway—which is implicated as dysfunctional in various psychiatric disorders—toward enhanced synthesis of kynurenic acid, an antagonist of both α7 nicotinic acetylcholine and N-methyl-D-aspartate receptors. Possibly as a result of reduced kynurenine 3-monooxygenase activity, elevated central nervous system levels of kynurenic acid have been found in patients with psychotic disorders, including schizophrenia. MethodsIn the present study, we investigated adaptive—and possibly regulatory—changes in mice with a targeted deletion of Kmo (Kmo–/–) and characterized the kynurenine 3-monooxygenase–deficient mice using six behavioral assays relevant for the study of schizophrenia. ResultsGenome-wide differential gene expression analyses in the cerebral cortex and cerebellum of these mice identified a network of schizophrenia- and psychosis-related genes, with more pronounced alterations in cerebellar tissue. Kynurenic acid levels were also increased in these brain regions in Kmo–/– mice, with significantly higher levels in the cerebellum than in the cerebrum. Kmo–/– mice exhibited impairments in contextual memory and spent less time than did controls interacting with an unfamiliar mouse in a social interaction paradigm. The mutant animals displayed increased anxiety-like behavior in the elevated plus maze and in a light/dark box. After a D-amphetamine challenge (5 mg/kg, intraperitoneal), Kmo–/– mice showed potentiated horizontal activity in the open field paradigm. ConclusionsTaken together, these results demonstrate that the elimination of Kmo in mice is associated with multiple gene and functional alterations that appear to duplicate aspects of the psychopathology of several neuropsychiatric disorders.

A case of aquagenic urticaria successfully treated with omalizumab

A case of aquagenic urticaria successfully treated with omalizumab

Enteric Inhibitory Neurotransmission, Starting Down Under.

The idea of an inhibitory innervation in the gut came from Geoff Burnstock's group at the University of Melbourne in the 1960s. Being resistant to antagonists of norepinephrine and acetylcholine, enteric inhibitory neurotransmission became known as non-cholinergic, non-adrenergic (NANC) neurotransmission. ATP (or a closely related nucleotide) was proposed as the inhibitory neurotransmitter based on release of purines during nerve stimulation and similarities between responses to ATP and transmural nerve stimulation in several gut preparations. Apamin was found to block purinergic responses, providing evidence that small-conductance Ca(2+)-activated K(+) (SK) channels were responsible for inhibitory junction potentials (IJPs). Actually the IJPs in GI muscles are composed of multiple components, and later studies discovered nitric oxide (NO) to be the other major mediator of NANC inhibitory neurotransmission. The purinergic component of enteric inhibitory neurotransmission is mediated by P2Y1 receptors, and this component is absent in P2Y1(-/-) mice. The criteria for a neurotransmitter are better met by β-nicotinamide adenine dinucleotide (β-NAD) or its immediate metabolite ADP-ribose (ADPR) than by ATP. The cells mediating post-junctional responses have been identified. In addition to smooth muscle cells, two classes of interstitial cells express receptors and effectors for NANC neurotransmitters and are electrically coupled to smooth muscle cells. This integrated structure has been named the SIP syncytium. Interstitial cells of Cajal are involved in transduction of cholinergic and nitrergic inputs to GI muscles, and PDGFRα(+) cells mediate purinergic effects. This short symposium report summarizes major historical points of interest and some of the more recent findings related to enteric inhibitory neurotransmission.

Aqueous fraction of Beta vulgaris ameliorates hyperglycemia in diabetic mice due to enhanced glucose stimulated insulin secretion, mediated by acetylcholine and GLP-1, and elevated glucose uptake via increased membrane bound GLUT4 transporters.

BackgroundThe study was designed to investigate the probable mechanisms of anti-hyperglycemic activity of B. Vulgaris.Methodology/Principal FindingsAqueous fraction of B. Vulgaris extract was the only active fraction (50mg/kg). Plasma insulin level was found to be the highest at 30 mins after B. Vulgaris administration at a dose of 200mg/kg. B. Vulgaris treated mice were also assayed for plasma Acetylcholine, Glucagon Like Peptide-1 (GLP-1), Gastric Inhibitory Peptide (GIP), Vasoactive Intestinal Peptide, Pituitary Adenylate Cyclase-Activating Peptide (PACAP), Insulin Like Growth Factor-1 (IGF-1), Pancreatic Polypeptides (PP), and Somatostatin, along with the corresponding insulin levels. Plasma Acetylcholine and GLP-1 significantly increased in B. Vulgaris treated animals and were further studied. Pharmacological enhancers, inhibitors, and antagonists of Acetylcholine and GLP-1 were also administered to the test animals, and corresponding insulin levels were measured. These studies confirmed the role of acetylcholine and GLP-1 in enhanced insulin secretion (p<0.05). Principal signaling molecules were quantified in isolated mice islets for the respective pathways to elucidate their activities. Elevated concentrations of Acetylcholine and GLP-1 in B. Vulgaris treated mice were found to be sufficient to activate the respective pathways for insulin secretion (p<0.05). The amount of membrane bound GLUT1 and GLUT4 transporters were quantified and the subsequent glucose uptake and glycogen synthesis were assayed. We showed that levels of membrane bound GLUT4 transporters, glucose-6-phosphate in skeletal myocytes, activity of glycogen synthase, and level of glycogen deposited in the skeletal muscles all increased (p<0.05).ConclusionFindings of the present study clearly prove the role of Acetylcholine and GLP-1 in the Insulin secreting activity of B. Vulgaris. Increased glucose uptake in the skeletal muscles and subsequent glycogen synthesis may also play a part in the anti-hyperglycemic activity of B. Vulgaris.

Alternative kynurenic acid synthesis routes studied in the rat cerebellum.

Kynurenic acid (KYNA), an astrocyte-derived, endogenous antagonist of α7 nicotinic acetylcholine and excitatory amino acid receptors, regulates glutamatergic, GABAergic, cholinergic and dopaminergic neurotransmission in several regions of the rodent brain. Synthesis of KYNA in the brain and elsewhere is generally attributed to the enzymatic conversion of L-kynurenine (L-KYN) by kynurenine aminotransferases (KATs). However, alternative routes, including KYNA formation from D-kynurenine (D-KYN) by D-amino acid oxidase (DAAO) and the direct transformation of kynurenine to KYNA by reactive oxygen species (ROS), have been demonstrated in the rat brain. Using the rat cerebellum, a region of low KAT activity and high DAAO activity, the present experiments were designed to examine KYNA production from L-KYN or D-KYN by KAT and DAAO, respectively, and to investigate the effect of ROS on KYNA synthesis. In chemical combinatorial systems, both L-KYN and D-KYN interacted directly with peroxynitrite (ONOO−) and hydroxyl radicals (OH•), resulting in the formation of KYNA. In tissue homogenates, the non-specific KAT inhibitor aminooxyacetic acid (AOAA; 1 mM) reduced KYNA production from L-KYN and D-KYN by 85.1 ± 1.7% and 27.1 ± 4.5%, respectively. Addition of DAAO inhibitors (benzoic acid, kojic acid or 3-methylpyrazole-5-carboxylic acid; 5 μM each) attenuated KYNA formation from L-KYN and D-KYN by ~35% and ~66%, respectively. ONOO− (25 μM) potentiated KYNA production from both L-KYN and D-KYN, and these effects were reduced by DAAO inhibition. AOAA attenuated KYNA production from L-KYN + ONOO− but not from D-KYN + ONOO−. In vivo, extracellular KYNA levels increased rapidly after perfusion of ONOO− and, more prominently, after subsequent perfusion with L-KYN or D-KYN (100 μM). Taken together, these results suggest that different mechanisms are involved in KYNA production in the rat cerebellum, and that, specifically, DAAO and ROS can function as alternative routes for KYNA production.

Interaction of rocuronium with human liver cytochromes P450

Rocuronium is a neuromuscular blocking agent acting as a competitive antagonist of acetylcholine. Results of an inhibition of eight individual liver microsomal cytochromes P450 (CYP) are presented. As the patients are routinely premedicated with diazepam, possible interaction of diazepam with rocuronium has been also studied.Results indicated that rocuronium interacts with human liver microsomal CYPs by binding to the substrate site. Next, concentration dependent inhibition of liver microsomal CYP3A4 down to 42% (at rocuronium concentration 189 μM) was found. This effect has been confirmed with two CYP3A4 substrates, testosterone (formation of 6β-hydroxytestosterone) and diazepam (temazepam formation). CYP2C9 and CYP2C19 activities were inhibited down to 75–80% (at the same rocuronium concentration). Activities of other microsomal CYPs have not been inhibited by rocuronium.To prove the possibility of rocuronium interaction with other drugs (diazepam), the effect of rocuronium on formation of main diazepam metabolites, temazepam (by CYP3A4) and desmethyldiazepam, (also known as nordiazepam; formed by CYP2C19) in primary culture of human hepatocytes has been examined. Rocuronium has caused inhibition of both reactions by 20 and 15%, respectively.The results open a possibility that interactions of rocuronium with drugs metabolized by CYP3A4 (and possibly also CYP2C19) may be observed.

Tumor Necrosis Factor Alpha Induces a Serotonin Dependent Early Increase in Ciliary Beat Frequency and Epithelial Transport Velocity in Murine Tracheae

The tracheal epithelium prevents via its highly effective clearance mechanism the contamination of the lower airways by pathogens. This mechanism is driven by ciliary bearing cells which are not only in contact with the gas phase; in addition they are also influenced by inflammatory mediators. These mediators can alter the protective function of the epithelium. Since the pro-inflammatoric cytokine tumor necrosis factor-α (TNF-α) plays a pivotal role within the inflammatory cascade, we investigated its effect onto the tracheal epithelium measured by its ciliary beat frequency and the particle transport velocity. In organ explant experiments the ciliary beat frequency and the particle transport velocity were measured under the application of TNF-α using tracheae from male C57BL6J mice. We observed a dose dependent TNF-α induced increase of both particle transport velocity and ciliary beat frequency. Knock out mice experiments made evident that the increase was depended on the expression of tumor necrosis factor receptor 1 (TNF-R1). The increases in ciliary beat frequency as well as the accelerated particle transport velocity were either inhibited by the unspecific serotonin antagonist methysergide or by cyproheptadine a specific 5-HT2 receptor antagonist. Thus, acetylcholine antagonists or nitric oxide synthase (NOS) inhibitors failed to inhibit the TNF-α induced activation. In conclusion, TNF-α may play a pivotal role in the protection of lower airways by inducing ciliary activity and increase in particle transport velocity via TNF-R1 and 5-HT2 receptor.

Continuous kynurenine administration during the prenatal period, but not during adolescence, causes learning and memory deficits in adult rats

Cognitive dysfunctions, including deficits in hippocampus-mediated learning and memory, are core features of the psychopathology of schizophrenia (SZ). Increased levels of kynurenic acid (KYNA), an astrocyte-derived tryptophan metabolite and antagonist of α7 nicotinic acetylcholine and N-methyl-D-aspartate receptors, have been implicated in these cognitive impairments. Following recent suggestive evidence, the present study was designed to narrow the critical time period for KYNA elevation to induce subsequent cognitive deficits. KYNA levels were experimentally increased in rats (1) prenatally (embryonic day (ED) 15 to ED 22) or (2) during adolescence (postnatal day (PD) 42 to PD 49). The KYNA precursor kynurenine was added daily to wet mash fed to (1) dams (100 mg/day; control: ECon; kynurenine-treated: EKyn) or (2) adolescent rats (300 mg/kg/day; control: AdCon; kynurenine-treated: AdKyn). Upon termination of the treatment, all animals were fed normal chow until biochemical analysis and behavioral testing in adulthood. On the last day of continuous kynurenine treatment, forebrain KYNA levels were significantly elevated (EKyn +472 %; AdKyn +470 %). KYNA levels remained increased in the hippocampus of adult EKyn animals (+54 %), but were unchanged in adult AdKyn rats. Prenatal, but not adolescent, kynurenine treatment caused significant impairments in two hippocampus-mediated behavioral tasks, passive avoidance and Morris water maze. Collectively, these studies provide evidence that a continuous increase in brain KYNA levels during the late prenatal period, but not during adolescence, induces hippocampus-related cognitive dysfunctions later in life. Such increases may play a significant role in illnesses with known hippocampal pathophysiology, including SZ.

Two receptors are involved in the central functions of kynurenic acid under an acute stress in neonatal chicks

Intracerebroventricular (i.c.v.) injection of kynurenic acid (KYNA) had sedative and hypnotic effects during stress in neonatal chicks. However, its mechanism has not been clarified. KYNA is an endogenous antagonist of the α7 nicotinic acetylcholine (α7nACh) receptor and N-methyl-d-aspartate (NMDA) receptor. Therefore, this study clarified the mechanism of sedative and hypnotic effects of KYNA in the brain during an acute stress. In Experiment 1, to investigate the relationship between KYNA and the α7nACh receptor, KYNA was injected i.c.v. with galantamine, an agonist of the allosteric potentiating site of the α7nACh receptor. Galantamine did not attenuate the effect of KYNA, but higher levels of galantamine caused harmful effects. In Experiment 2, the role of the NMDA receptor was investigated using the NMDA receptor antagonist (+)-MK-801, d-serine which has high affinity to a co-agonist glycine site at the NMDA receptors, NMDA as the NMDA receptor agonist, and 2,3-pyridinedicarboxylic acid (QUIN), an agonist of the NMDA receptor subgroup containing the subunits NR2A and NR2B. The behavioral changes following KYNA were partially attenuated by QUIN alone. In conclusion, we suggest that KYNA functioned via the simultaneous inhibition of the α7nACh receptor and NMDA receptor subgroup containing the subunits NR2A and NR2B.

Combination Effects of ZSET1446/ST101 With Memantine on Cognitive Function and Extracellular Acetylcholine in the Hippocampus

In the novel object recognition task, ZSET1446 (also coded as ST101) enhanced object recognition memory in mice and ameliorated cognitive impairment caused by scopolamine in rats. The enhancement induced by ZSET1446 in mice was abolished by injection of mechamylamine, a nonselective antagonist of nicotinic acetylcholine (ACh) receptors, or dihydro-β-erythroidine, a selective antagonist against the α4 subunit of nicotinic ACh receptors. These results suggest that the procognitive effect of ZSET146 is probably mediated by stimulation of nicotinic receptors. Memantine was also effective in these tests and concomitant administration of subeffective doses of ZSET1446 and memantine significantly ameliorated the cognitive performance in the novel object recognition task in both mice and rats. Moreover, oral administration of ZSET1446 or memantine increased the extracellular level of ACh in the hippocampus as compared with the control. Further, concomitant administration of subeffective doses of ZSET1446 and memantine significantly increased the extracellular level of ACh as compared with the group of ZSET1446 or memantine alone. These results suggest that these two compounds have a synergistic effect on the cognitive function possibly by synergistic increase in the extracellular level of ACh in the hippocampus, and that the combination therapy of these compounds might be effective in clinical settings.

Biperiden for treatment of somnambulism in adolescents and adults with or without epilepsy: Clinical observations

BackgroundSleepwalking in adolescents and adults may lead to serious injuries and require treatment. Anecdotal treatment recommendations include benzodiazepines (which also work in focal seizures of the frontal lobe that are an important differential diagnosis), imipramine and amitriptyline. MethodsWe assessed in a follow-up study of 4years (medium, range: 2–7years) the usefulness of the antiparkinsonian drug biperiden (Akineton©), an acetylcholine antagonist with high affinity for muscarinic M1-type receptors, in four consecutive cases of arousal disorder with sleepwalking and confusional behavior in adolescents and adults with or without epilepsy who did not respond to diazepam, clonazepam or amitriptyline. FindingsThe adjunctive use of biperiden was associated with reduction or remission of sleepwalking episodes in four consecutive treatment-refractory cases of arousal disorder with sleepwalking and confusional behavior. In contrast, biperiden showed no effect in a patient with REM behavioral disorder. InterpretationAlthough our observations do not and cannot establish the efficacy or safety of biperiden, it may be useful to consider biperiden for treatment of sleepwalking, if needed. A putative cholinergic mechanism of arousal disorders, including sleepwalking, provides a reasonable hypothesis why the anticholinergic agent biperiden might work. Evidence for efficacy and safety from randomized controlled trials is needed to confirm our preliminary observations.

Histaminergic modulation of nonspecific plasticity of the auditory system and differential gating

In the auditory system of the big brown bat (Eptesicus fuscus), paired conditioned tonal (CS) and unconditioned leg stimuli (US) for auditory fear conditioning elicit tone-specific plasticity represented by best-frequency (BF) shifts that are augmented by acetylcholine, whereas unpaired CS and US for pseudoconditioning elicit a small BF shift and prominent nonspecific plasticity at the same time. The latter represents the nonspecific augmentations of auditory responses accompanied by the broadening of frequency tuning and decrease in threshold. It is unknown which neuromodulators are important in evoking the nonspecific plasticity. We found that histamine (HA) and an HA3 receptor (HA3R) agonist (α-methyl-HA) decreased, but an HA3R antagonist (thioperamide) increased, cortical auditory responses; that the HA3R agonist applied to the primary auditory cortex before pseudoconditioning abolished the nonspecific augmentation in the cortex without affecting the small cortical BF shift; and that antagonists of acetylcholine, norepinephrine, dopamine, and serotonin receptors did not abolish the nonspecific augmentation elicited by pseudoconditioning. The histaminergic system plays an important role in eliciting the arousal and defensive behavior, possibly through nonspecific augmentation. Thus HA modulates the nonspecific augmentation, whereas acetylcholine amplifies the BF shifts. These two neuromodulators may mediate differential gating of cortical plasticity.