Michael W. Decker

Muscimol injections in the medial septum impair spatial learning

These experiments examined the role of GABAergic systems in modulating septohippocampal cholinergic influences on learning. Microinjections of the GABA(A) agonist muscimol (0.5, 1.0 or 5.0 nmol) or physiological saline were administered (0.5 microliters) into the medial septum of rats via chronically implanted cannulae just prior to daily training in the Morris water maze spatial learning task. The animals received 3 training trials on each of 4 days. The escape latencies of rats trained with a submerged escape platform at a fixed location were significantly shorter than those trained with a randomly located platform. Rate of learning of the fixed location was significantly impaired in rats given pretraining muscimol injections in the medial septum at doses (1.0 and 5.0 nmol) that significantly reduced hippocampal high-affinity choline uptake (HACU). Analyses of responses on a probe trial with no pretraining injections and no platform revealed that, in comparison with controls, animals that had received muscimol prior to each training session were likely to swim in the region where the platform had been located. The finding that muscimol-injected rats were subsequently able to learn the task when trained without muscimol injections indicates that the acquisition impairment was not due to a lasting effect of the drug injections. Our results are consistent with the view that the septal GABAergic modulation of the septohippocampal cholinergic pathway is involved in regulating the acquisition of spatial information.

Concurrent muscarinic and β-adrenergic blockade in rats impairs place-learning in a water maze and retention of inhibitory avoidance

These experiments examined the effects of separate and concurrent muscarinic cholinergic and beta-adrenergic blockade on inhibitory (passive) avoidance performance and spatial learning in the Morris water maze. Pretraining systemic administration of either scopolamine (0.3 or 1.0 mg/kg) or propranolol (3.0 or 10.0 mg/kg) had no significant effect on one-day retention of step-through inhibitory avoidance training. Similarly, pretraining administration of either 0.3 mg/kg scopolamine or 10 mg/kg propranolol did not affect spatial learning in the Morris water maze. However, combined administration of scopolamine and 10.0 mg/kg of propranolol impaired performance on these tasks. These findings further support a role for interactions between norepinephrine and acetylcholine in the modulation of learning and memory and implicate the participation of beta-adrenergic mechanisms in this interaction. Because cholinergic and noradrenergic deterioration is found in aging and Alzheimers disease, these results also have implications regarding the role of age-related noradrenergic and cholinergic dysfunction in cognitive decline.

Effects of concurrent manipulations of cholinergic and noradrenergic function on learning and retention in mice

Interactions between the neuromodulators acetylcholine and norepinephrine (NE) have been reported in both developmental neural plasticity and learning and memory. In a test of the generality of this phenomenon, we assessed the amnestic effects of the muscarinic antagonist scopolamine in normal and NE-depleted mice. Pretraining administration of scopolamine impaired 24-h retention of inhibitory (passive) avoidance training (at doses of 0.1, 0.3 and 1.0 mg/kg) and the acquisition of place-training in a water maze (at a dose of 1.0 mg/kg). NE depletion resulting from systemic administration of DSP-4 did not affect performance on these tasks and did not significantly alter the effects of scopolamine. NE depletion did, however, impair the retention of place learning when mice were retested 16 days after initial training; and this impairment in the retest was additive with one observed in mice originally trained under scopolamine. Normal acquisition but rapid forgetting has also been reported in aged rodents, who display deterioration of the noradrenergic system. Thus, observation of a similar pattern of performance consequent to experimental NE depletion suggests a role for noradrenergic dysfunction in age-related memory decline.

A comparison of the effects of scopolamine and diazepam on acquisition and retention of inhibitory avoidance in mice

Administration of either the muscarinic antagonist scopolamine or the benzodiazepine diazepam prior to training produced a dose-dependent impairment in the retention of one-trial inhibitory avoidance training in mice. To investigate the nature of this drug effect, the effects of scopolamine and diazepam were subsequently assessed on both acquisition and retention of inhibitory avoidance using a multiple-trial, training-to-criterion procedure. The training was conducted using either continuous trials in which the mouse was free to shuttle back and forth between shock and safe compartments or discrete trials in which the mouse was moved from the shock compartment of the safe compartment at the start of each trial. In either case, training continued until the mouse refrained from crossing into the shock compartment for a specified length of time on a single trial. Scopolamine (1.0 mg/kg) administered before training significantly increased the number of trials required to attain criterion, but did not affect retention when these mice were tested 2, 16, or 28 days later. In contrast, diazepam (1.0 mg/kg) did not significantly alter the number of trials necessary to reach criterion, but impaired retention of the inhibitory response in mice trained using discrete trials. The differences in the amnestic effects of scopolamine and diazepam revealed by this detailed analysis suggest that diazepam does not impair inhibitory avoidance performance through an effect on cholinergic function.

Surveillance of colonization and infection with Staphylococcus aureus susceptible or resistant to methicillin in a community skilled-nursing facility.

BACKGROUNDnMethicillin-resistant Staphylococcus aureus (MRSA) is an important nosocomial pathogen in acute care hospitals and long-term care facilities. Few studies have been reported in private skilled nursing facilities (SNFs) not experiencing outbreaks of infections caused by MRSA.nnnMETHODSnFrom a 149-bed SNF with no outbreaks, we report a 1-year prospective surveillance study of S. aureus colonization and infection, with focus on S. aureus phenotypes, both methicillin susceptible (MS) and methicillin resistant (MR). Nasal and stool or rectal screening cultures were done on admission, and all patients underwent screening on at least a quarterly basis for 1 year.nnnRESULTSnOverall, 35% of patients were colonized at least once with S. aureus, (72% MS, 25% MR, and 3% mixed phenotypes), 94% of the MRSA were ciprofloxacin resistant. Nasal colonization with any S. aureus was more frequent, but 13% of patients had positive results only in rectal specimens. Twenty-one percent of the newly admitted and 15% of continuing patients acquired colonization during their stay in the SNE Colonization was transient or persistent, persisted longer in the nares compared with colonization in rectal specimens, and was more stable for methicillin-susceptible S. aureus. Nine percent of patients had development of infection with S. aureus. There was no indication that MRSA colonization led to more infections than methicillin-susceptible S. aureus. Of the 13 infected patients in whom cultures had previously been obtained, seven (54%) had been colonized by the same phenotype strains.nnnCONCLUSIONSnIn this private SNF, endemic S. aureus infections occur at a low frequency, reflecting a moderate level of colonization with S. aureus. However, a trend showing gradual increases in frequencies of colonization and infection is of concern and suggests that in this SNF, future intervention could become warranted.

Neonatal 6-hydroxydopa, but not DSP-4, elevates brainstem monoamines and impairs inhibitory avoidance learning in developing rats

The involvement of brain monoamines in learning and memory in developing rats was studied by comparing the effects of 3 different noradrenergic neurotoxin treatments. Two experimental groups of male Sprague-Dawley rat pups were injected systemically with 50 micrograms/g of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) either on the day of birth or on postnatal days 17-18. Rats in the third experimental group were injected systemically with 60 micrograms/g of 6-hydroxydopa (6-OHDOPA) on postnatal days 0 and 2. Control littermates received vehicle. The animals were trained on an inhibitory avoidance task on postnatal days 27-29 and tested for retention 24 h later. The drug treatments produced comparable depletion of norepinephrine in the hippocampus and frontal cortex. 6-OHDOPA, but neither DSP-4 treatment, significantly elevated brainstem concentrations of norepinephrine and serotonin. In addition, 6-OHDOPA, but not DSP-4, significantly impaired retention of the inhibitory avoidance task. The impairment did not reflect insensitivity to the footshock used in training: both neonatal drug treatments tended to lower, not raise, footshock thresholds, as measured by a flinch test. High affinity choline uptake was not affected by either neonatal drug treatment in any of the brain areas examined. Thus, the 6-OHDOPA-induced behavioral deficit did not involve altered acetylcholine function. The results implicate brainstem monoamines in the modulation of learning and memory during development.

Thiazolidinediones and the preservation of β‐cell function, cellular proliferation and apoptosis

The thiazolidinediones (TZDs) or glitazones are pharmaceutical agents that have profound effects on energy expenditure and conservation. They also exert significant anti‐inflammatory effects and influence cell proliferation and cell death. The drugs are primarily used in clinical practice in the treatment of patients with type 2 diabetes mellitus, a disorder of insulin resistance that occurs when the pancreatic β‐cells are unable to produce adequate amounts of insulin to maintain euglycaemia. Loss of pancreatic β‐cell function in type 2 diabetes is progressive and often precedes overt diabetes by 10u2003years or more, as was shown by the United Kingdom Prospective Diabetes Study. Any therapeutic or preventive approach that would limit or reverse loss of β‐cell function in diabetes would have profound effects on the morbidity associated with this widespread disease. Evidence suggesting a potential role of TZDs in preserving β‐cell function in type 2 diabetes as well as the ability of these agents to exert anti‐inflammatory and proapoptotic anticancer effects, and their ability to promote cellular proliferation in various organs is reviewed.

Norepinephrine depletion reduces the effects of social and olfactory experience.

Control juvenile rats adapted normally to a new home-cage bedding odor if they were caged with rats neonatally treated with 6-hydroxydopa, but not DSP-4. Neither social nor olfactory experience influenced preferences of NE-depleted rats. In some forebrain regions of controls caged with DSP-4 rats, monoamine concentrations were depressed and a metabolite elevated, suggesting the situation was stressful. DSP-4 treatment decreased the effect of footshock on hippocampal cholinergic activity, implying that NE depletion reduced sensitivity to stress. Thus, norepinephrine may modulate the biobehavioral effects of the postweaning olfactory and social environment.

ABT-418: A Novel Cholinergic Channel Activator (ChCA) for the Potential Treatment of Alzheimer’s Disease

Evidence is accumulating to suggest that compounds which activate neuronal nicotinic acetylcholine receptors (nAChRs) may have potential benefit in the treatment of dementia, especially Alzheimer’s disease (AD) (for review: Arneric and Williams, 1994). The focus of this chapter is to summarize the preclinical pharmacology of ABT-418 [(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole], a novel analog of (-)-nicotine that is in clinical development for the treatment of AD. ABT-418 is a cholinergic channel activator (ChCA) with cognitive enhancement and anxiolytic-like activity possessing a substantially reduced side-effect profile compared to (-)-nicotine (Americ et al., 1994; Decker et al., 1994a). The enhanced preclinical safety profile and excellent transdermal delivery across species are consistent with the early Phase I clinical studies (Sebree et al., 1993).

ABT-089: An Orally Effective Cholinergic Channel Modulator (ChCM) with Cognitive Enhancement and Neuroprotective Action

Recent evidence suggests the existence of a diversity of neuronal nicotinic acetylcholine receptor (nAChRs) subtypes with a wide distribution in brain, that each subtype may be involved in mediating specific functions/behaviors, and that these subtypes have a defined pharmacology that may be selectively targeted (Arneric et al., 1995a). The pharmacologic diversity of neuronal nAChR subtypes suggests the possibility of developing selective compounds which would have more favorable side-effect profiles than existing agents which generally exhibit low selectivity. This broader class of agents, collectively called cholinergic channel modulators (ChCMs) selectively activate some subtypes of nAChRs (i.e. Cholinergic Channel Activators, ChCAs) or inhibit the function of other subtypes (Cholinergic Channel Inhibitors, ChCIs).