Clemastine induces an impairment in developmental myelination

Abnormalities in myelination are associated to behavioral and cognitive dysfunction in neurodevelopmental psychiatric disorders. Thus, therapies to promote or accelerate myelination could potentially ameliorate symptoms in autism. Clemastine, a histamine H1 antagonist with anticholinergic properties against muscarinic M1 receptor, is the most promising drug with promyelinating properties (Mei et al., 2014). Clemastine penetrates the blood brain barrier efficiently and promotes remyelination in different animal models of neurodegeneration including multiple sclerosis, ischemia and Alzheimer's disease. However, its role in myelination during development is unknown. We showed that clemastine treatment during development increase oligodendrocyte differentiation in both white and gray matter. However, despite the increase in the number of oligodendrocytes, conduction velocity of myelinated fibers of corpus callosum decreased in clemastine-treated mice. Confocal and electron microscopy showed a reduction in the number of myelinated axons and nodes of Ranvier and a reduction of myelin thickness in corpus callosum. To understand the mechanisms leading to myelin formation impairment in the presence of an excess of myelinating oligodendrocytes, we focused on microglial cells which also express muscarinic M1 receptors. Importantly, the population of CD11c+ microglia cells, necessary for myelination, as well as the levels of insulin growth factor-1 decrease in clemastine-treated mice. Altogether, these data suggest that clemastine impact on myelin development is more complex than previously thought and could be dependent on microglia-oligodendrocyte crosstalk. Further studies are needed to clarify the role of microglia cells on developmental myelination.

Effects of prenatal ethanol exposure on choline-induced long-term depression in the hippocampus

Choline is an essential nutrient that is being explored as a nutritional treatment for many neurological disorders. Indeed, choline has already moved to being used in clinical trials for Fetal Alcohol Spectrum Disorders (FASD), and there is increased pressure to better understand its therapeutic mechanism(s) of action. This is particularly true given its potential to directly effect synaptic mechanisms that are believed important for cognitive processes. In the current work we study how the direct application of choline can affect synaptic transmission in hippocampal slices obtained from adolescent (post-natal days 21-28) Sprague-Dawley rats (Rattus norvegicus). The acute administration of choline chloride (2 mM) reliably induced a long-term depression (LTD) of field excitatory postsynaptic potentials (fEPSP) in the DG in vitro. The depression required the involvement of M1-receptors, and the magnitude of the effect was similar in slices obtained from male and female animals. To further study the impact of choline in an animal model of FASD, we examined offspring from dams fed an ethanol-containing diet (35.5% ethanol-derived calories) throughout gestation. In slices from the adolescent animals that experienced prenatal ethanol exposure (PNEE), we found that the choline induced an LTD that uniquely involved the activation of NMDA and M1 receptors. This study provides a novel insight into how choline can modulate hippocampal transmission at the level of the synapse and that it can have unique effects following PNEE.

Efficacy and safety of lurasidone in children and adolescents: Recommendations for clinical management and future research

: Lurasidone is a novel azapirone derivative, and atypical antipsychotic agent with a high binding affinity for dopaminergic (D2), serotoninergic (5-HT2A), and 5-HT7 receptors (antagonist), a moderate affinity for 5-HT1A receptors (partial agonist), and no appreciable affinity for histaminergic (H1) and muscarinic (M1) receptors. It was recently included by the European Medication Agency among the in-label pharmacological treatments for children and adolescents affected by early onset schizophrenia. As a dopamine and serotonin antagonist, lurasidone acts on a variety of receptors and showed its efficacy both as an antipsychotic and an activating compound. Administered with food or within 30 minutes from a meal, it presents sufficient bioavailability and does not interact ith most of the other drugs during metabolism. With little effects on hormones and weight gain, potential procognitive profile due to its 5-HT7 antagonism, and reduced extrapyramidal side effects, lurasidone could be a good choice in terms of both effectiveness and tolerability, particularly for patients headed towards a long-term treatment. This article aims to summarize the available scientific evidence from the literature on the use of lurasidone in children and adolescents and to provide recommendations for clinical management and future research.

Activation of M1 muscarinic receptors reduce pathology and slow progression of neurodegenerative disease.

The most prevalent types of dementias, including Alzheimer's disease, are those that are propagated via the spread of 'prion-like' misfolded proteins. Despite considerable effort, no treatments are available to slow or stop the progression of these dementias. Here, we investigate the possibility that activation of the M1-muscarinic receptor (M1-receptor), which is highly expressed in the brain and that shows pro-cognitive properties, might present a novel disease modifying target. We demonstrate that the progression of murine prion disease, which we show here displays many of the pathological, behavioural and biochemical hallmarks of human neurodegenerative disease, is slowed and normal behaviour maintained by the activation of the M1-receptor with a highly tolerated positive allosteric modulator (VU846). This correlates with a reduction in both neuroinflammation and indicators of mitochondrial dysregulation, as well as a normalisation in the expression of markers associated with neurodegeneration and Alzheimer′s disease. Furthermore, VU846 preserves expression of synaptic proteins and post-synaptic signalling components that are altered in disease. We conclude that allosteric regulation of M1-receptors has the potential to reduce the severity of neurodegenerative diseases caused by the ″prion-like″ propagation of misfolded protein in a manner that extends life span and maintains normal behaviour.

Intra-dorsal striatal acetylcholine M1 but not dopaminergic D1 or glutamatergic NMDA receptor antagonists inhibit the consolidation of duration memory in interval timing

The striatal beat frequency (SBF) model assumes that striatal medium spiny neurons encode duration via synaptic plasticity. Muscarinic 1 (M1) cholinergic receptors, as well as dopamine and glutamate receptors, are important for neural plasticity in the dorsal striatum. Therefore, we investigated the effect of inhibiting these receptors on the formation of duration memory. After sufficient training in a Peak interval (PI)-20 s procedure, rats were given a single or mixed infusion of a selective antagonist for the dopamine D1 receptor (SCH23390, 0.5 μg per side), the NMDA-type glutamate receptor (D-AP5, 3 μg), or the M1 receptor (pirenzepine, 10 μg) bilaterally in the dorsal striatum, immediately before starting a PI 40 s session (shift session). On the next day, the rats were tested for new duration memory (40 s) in a session in which no lever presses were reinforced (probe session). In the shift session, performance was tie, irrespective of the drug injected. However, in the probe session, the mean peak time (an index of duration memory) of the M1 + NMDA co-blockade group, but not of the D1 + NMDA co-blockade group, was lower than that of the control group (Exp. 1 and 2). In Exp. 3, the effect of the co-blockade of M1 and NMDA receptors was replicated. Moreover, sole blockade of M1 receptors induced the same effect as M1 and NMDA blockade. These results suggest that in the dorsal striatum, the M1 receptor, but not the D1 or NMDA receptors, are involved in the consolidation of duration memory.

Fluctuating NMDA Receptor Subunit Levels in Perirhinal Cortex Relate to Their Dynamic Roles in Object Memory Destabilization and Reconsolidation

Reminder cues can destabilize consolidated memories, rendering them modifiable before they return to a stable state through the process of reconsolidation. Older and stronger memories resist this process and require the presentation of reminders along with salient novel information in order to destabilize. Previously, we demonstrated in rats that novelty-induced object memory destabilization requires acetylcholine (ACh) activity at M1 muscarinic receptors. Other research predominantly has focused on glutamate, which modulates fear memory destabilization and reconsolidation through GluN2B- and GluN2A-containing NMDARs, respectively. In the current study, we demonstrate the same dissociable roles of GluN2B- and N2A-containing NMDARs in perirhinal cortex (PRh) for object memory destabilization and reconsolidation when boundary conditions are absent. However, neither GluN2 receptor subtype was required for novelty-induced destabilization of remote, resistant memories. Furthermore, GluN2B and GluN2A subunit proteins were upregulated selectively in PRh 24 h after learning, but returned to baseline by 48 h, suggesting that NMDARs, unlike muscarinic receptors, have only a temporary role in object memory destabilization. Indeed, activation of M1 receptors in PRh at the time of reactivation effectively destabilized remote memories despite inhibition of GluN2B-containing NMDARs. These findings suggest that cholinergic activity at M1 receptors overrides boundary conditions to destabilize resistant memories when other established mechanisms are insufficient.

Lurasidone – pharmacodynamic and pharmacokinetic properties, clinical potential and interaction risk

Lurasidone is a novel second-generation antipsychotic approved for the treatment of schizophrenia and bipolar depression in adults. It displays high affinity for D2 and 5-HT2A and 5-HT7 receptors, moderate affinity for 5-HT1A and α2C-noradrenergic receptors, and negligible affinity for histamine H1 and muscarinic M1 receptors. It acts as potent D2, 5-HT2A and 5-HT7 antagonist and partial 5-HT1A agonist. Lurasidone taken orally is rapidly absorbed with the time to maximum concentration of 1-3 hours. Lurasidone should be taken with food (at least 350 kcal) due to limited absorption. The mean elimination half-life of lurasidone is 18.1–25.5 hours for doses 20–80 mg/day and 28.8–37.4 hours for doses of 120–160 mg/day. Steady-state is reached within 7 days. The drug is metabolised via CYP 3A4 and excreted mainly in faeces (67–80%) and with urine (about 8–19%). The use of lurasidone with strong inhibitors or inducers of CYP 3A4 (e.g. ketoconazole, erythromycin, or carbamazepine, respectively) is contraindicated. In the case of combined treatment of lurasidone and moderate inhibitors of CYP 3A4, the dose of lurasidone should be decreased to 40 mg/day. Lurasidone is an inhibitor of P-glycoprotein and could increase the level of digoxin and potentate the side effects risk of this drug. Pomelo, grapefruit, or a large amount of oranges should be avoided in the diet during treatment with lurasidone. Pharmacodynamic properties of lurasidone underlie its antipsychotic, antidepressant, precognitive, and sleep-awake rhythm normalising activity.