Early changes in synaptic and intrinsic properties of dentate gyrus granule cells in a mouse model of Alzheimer’s disease neuropathology and atypical effects of the cholinergic antagonist atropine

ABSTRACTIt has been reported that hyperexcitability occurs in a subset of patients with Alzheimer’s disease (AD) and hyperexcitability could contribute to the disease. Several studies have suggested that the hippocampal dentate gyrus (DG) may be an important area where hyperexcitability occurs. Therefore, we tested the hypothesis that the principal DG cell type, granule cells (GCs), would exhibit changes at the single-cell level which would be consistent with hyperexcitability and might help explain it. We used the Tg2576 mouse, where it has been shown that hyperexcitability is robust at 2-3 months of age. GCs from 2-3-month-old Tg2576 mice were compared to age-matched wild type (WT) mice. Effects of muscarinic cholinergic antagonism were tested because previously we found that Tg2576 mice exhibited hyperexcitability in vivo that was reduced by the muscarinic cholinergic antagonist atropine, counter to the dogma that in AD one needs to boost cholinergic function. The results showed that GCs from Tg2576 mice exhibited increased frequency of spontaneous excitatory postsynaptic potentials/currents (sEPSP/Cs) and reduced frequency of spontaneous inhibitory synaptic events (sIPSCs) relative to WT, increasing the excitation:inhibition (E:I) ratio. There was an inward glutamatergic current that we defined here as a novel synaptic current (nsC) in Tg2576 mice because it was very weak in WT mice. Although not usually measured, intrinsic properties were distinct in Tg2576 GCs relative to WT. In summary, GCs of the Tg2576 mouse exhibit early electrophysiological alterations that are consistent with increased synaptic excitation, reduced inhibition, and muscarinic cholinergic dysregulation. The data support previous suggestions that the DG and cholinergic system contribute to hyperexcitability early in life in AD mouse models.HIGHLIGHTSGranule cells (GCs) in young Tg2576 mice had abnormal synaptic activity.Young Tg2576 GCs had increased excitatory and reduced inhibitory synaptic activity.GC intrinsic properties were altered in young Tg2576 mice.Muscarinic cholinergic regulation of GCs was altered in young Tg2576 mice.Atropine led to a novel spontaneous inward current that was very strong in Tg2576 GCs.

Potentially Inappropriate Prescriptions for Anticholinergic Medications for Patients with Constipation

<b><i>Introduction:</i></b> Constipation is a very common functional gastrointestinal disorder in the general population and can be primary or secondary. <b><i>Objective:</i></b> The aim of this study was to estimate the anticholinergic burden of prescribed drugs in a population diagnosed with constipation in Colombia. <b><i>Methods:</i></b> This was a cross-sectional study that used a population database of 6.5 million people to identify the prescription of cholinergic antagonists and drugs for the management of constipation in outpatient services. The anticholinergic burden was evaluated using the Anticholinergic Drug Scale. Potentially inappropriate prescriptions that increased the risk of constipation were identified. <b><i>Results:</i></b> A total of 3,887 patients with constipation were identified; the identified patients had a mean age of 54.4 ± 21.9 years, and 69.4% were women. Eighty percent received at least one laxative, and the most prescribed laxative was bisacodyl (50.5%). Forty-one percent (<i>n</i> = 1,586) of all patients received drugs with cholinergic antagonist activity, in particular codeine (6.5%) and valproic acid (6.5%). Being over 30 years of age (odds ratio [OR]: 1.79; 95% confidence interval [CI]: 1.24–2.57), being treated in the cities of Manizales (OR: 2.20; 95% CI: 1.50–3.21) and Pereira (OR: 1.49; 95% CI: 1.07–2.09), and having hypothyroidism as a comorbidity (OR: 1.37; 95% CI: 1.08–1.73) were associated with a greater probability of receiving medications with an anticholinergic burden of 3 or more points. <b><i>Conclusions:</i></b> The majority of patients with constipation were women and were using laxatives to manage constipation. A large proportion of patients were prescribed at least one cholinergic antagonist drug, with an increased probability of use after 30 years of age.

Effects of Scopolamine on Conditioning of Lever Pressing

The aim of this work was to determine the effects of scopolamine, a cholinergic antagonist, on the conditioning of an instrumental response and the contextual conditioning of this response. Five groups of rats were trained to lever-press on a Variable Interval 30 s schedule in context A. Scopolamine was administered 15 min before each conditioning session to AB 0.01 mg/kg, AB 0.10 mg/kg and AB 1.00 mg/kg groups. The AA Saline and AB Saline groups received saline injections.Contextual conditioning of the lever-pressing response was assessed in one extinction session. The AA group received this extinction session in the conditioning context (A), while the AB groups received this session in a different context (B). Results showed that scopolamine impaired the conditioning of the lever-pressing response but no effects on contextual conditioning were found.

Ketamine and rapid-acting antidepressants: a new era in the battle against depression and suicide

Therapeutic medications for the treatment of depression have serious limitations, particularly delayed onset and low rates of efficacy. However, the discovery that a single subanesthetic dose of ketamine, a glutamate NMDA receptor channel blocker, can produce a rapid (within hours) antidepressant response that is sustained (about 1 week), even in patients considered treatment-resistant, has invigorated the field. In addition to these remarkable actions, ketamine has proven effective for the treatment of suicidal ideation. Efforts are under way to develop ketamine-like drugs with fewer side effects as well as agents that act at other sites within the glutamate neurotransmitter system. This includes ketamine metabolites and stereoisomers, drugs that act as NMDA allosteric modulators or that block mGluR2/3 autoreceptors. In addition, targets that enhance glutamate neurotransmission or synaptic function (or both), which are essential for the rapid and sustained antidepressant actions of ketamine in rodent models, are being investigated; examples are the muscarinic cholinergic antagonist scopolamine and activators of mechanistic target of rapamycin complex 1 (mTORC1) signaling, which is required for the actions of ketamine. The discovery of ketamine and its unique mechanisms heralds a new era with tremendous promise for the development of novel, rapid, and efficacious antidepressant medications.

Characterizing the hippocampal theta’s response to carbachol; using a complete septo-hippocampal preparation

The present study describes the pharmacological analysis of the effects of carbachol, a cholinergic agonist, on hippocampal theta activity. Knowing that this activity is critically related to cognitive function and altered in patients with neurodegeneration, pharmacological efforts aiming to directly modulate hippocampal theta activity becomes of central importance. In a recently developed complete septo-hippocampal preparation, carbachol elicited significant theta power enhancement with 1 μM. Concentrations under 1 μM and over 2 μM carbachol caused significant reduction in the power of hippocampal theta activity. Carbachol effects were completely blocked with the cholinergic antagonist scopolamine. At the experimental level, it is the first time the direct action of a cholinergic agonist is evaluated in the septo-hippocampal pathway completely isolated. However, carbachol as a cholinergic agonist is a drug with a certain level of nonspecific response. That is why to correct this experimental limitation, we used scopolamine (cholinergic antagonist) which allowed us to corroborate the effects on the cholinergic pathway. In summary, electrophysiological assays demonstrated an effective concentration range of carbachol specifically modulating hippocampal theta activity.

Characterizing the hippocampal theta’s response to carbachol; using a complete septo-hippocampal preparation

The present study describes the pharmacological analysis of the effects of carbachol, a cholinergic agonist, on hippocampal theta activity. Knowing that this activity is critically related to cognitive function and altered in patients with neurodegeneration, pharmacological efforts aiming to directly modulate hippocampal theta activity becomes of central importance. In a recently developed complete septo-hippocampal preparation, carbachol elicited significant theta power enhancement with 1 μM. Concentrations under 1 μM and over 2 μM carbachol caused significant reduction in the power of hippocampal theta activity. Carbachol effects were completely blocked with the cholinergic antagonist scopolamine. At the experimental level, it is the first time the direct action of a cholinergic agonist is evaluated in the septo-hippocampal pathway completely isolated. However, carbachol as a cholinergic agonist is a drug with a certain level of nonspecific response. That is why to correct this experimental limitation, we used scopolamine (cholinergic antagonist) which allowed us to corroborate the effects on the cholinergic pathway. In summary, electrophysiological assays demonstrated an effective concentration range of carbachol specifically modulating hippocampal theta activity.

Correction of urodynamic disturbances in children with neurogenic bladder dysfunctions

The results of a complex urodynamic and psychological examination of 95 children with neurogenic bladder dysfunction are presented in this paper. It has been demonstrated that the degree of the neurogenic urodynamic disturbances has a linear direct dependence upon the marked character of anxiety. The application of dynamic electroneurostimulation in combination with M-cholinergic antagonist causes a potentiated therapeutic effect.