Neurochemical mechanisms mediating the behavioral and cognitive effects of nicotine

Data are reviewed, largely from experiments in the authors'laboratory, that suggest three modes of action of systemic nicotine in producing three different types of effect upon behavior and cognitive function. (1) Preexposure of a stimulus without consequence makes it harder subsequently to form associations to that stimulus, a form of selective attention known as latent inhibition. Latent inhibition is blocked by nicotine, an effect that is apparently mediated by a nicotine-induced increase in dopamine release in the nucleus accumbens. (2) A single dose of nicotine proactively increases the partial reinforcement extinction effect measured several weeks later: that is, resistance to extinction is decreased by nicotine in animals that have been trained on a continuous reinforcement schedule, and increased in animals trained on a partial reinforcement schedule. This effect appears to be due to increased synthesis of tyrosine hydroxylase in the cell bodies of noradrenergic neurons in the locus coeruleus, followed by axonal transport to the hippocampus and increased synthesis and release of noradrenaline in that structure. (3) Nicotine improves vigilance in animals with cognitive deficits due to destruction of the forebrain cholinergic projection system, either as a consequence of excitotoxic lesions of the nuclei of origin of this system or after prolonged alcohol consumption; and also in human subjects with Alzheimer's disease (in which this system undergoes degeneration). This effect is most likely due to an action at denervated cholinergic synapses in the hippocampus and neocortex. © 1994 Wiley-Liss, Inc.     

Cytoprotective actions of 2,4-dimethoxybenzylidene anabaseine in differentiated PC12 cells and septal cholinergic neurons

The potential cytoprotective actions of a novel nicotinic agent 2,4-dimethoxybenzilidene anabaseine (DMXB) were investigated in differentiated PC12 cells and transected rat septal cholinergic neurons in vivo. In NGF-differentiated PC12 cells, removal of both NGF and serum led to cell loss, a reduced % of cells expressing neurites, the release of lactate dehydrogenase, and a decrease in total cellular protein. Cell loss was apparent within 24 h, and remained constant between 4–8 days post-NGF removal. NGF alone (100 ng/ml), DMXB (10 μM), but not nicotine (10 μM), prevented these cell and neurite losses. DMXB-induced cytoprotection was blocked by 1 μM mecamylamine. DMXB (1 mg/kg, ip) injected twice but not once per day protected cholinesterase-staining septal neurons from retrograde degeneration following unilateral fimbrial transections. The twice per day DMXB injection-protocol also decreased cell roundness among cholinesterase-staining cells in the lesioned septal hemisphere compared to saline-injected animals. These studies suggest that DMXB may exert cytoprotective activity in NGF-sensitive neuronal populations. © 1994 Wiley-Liss, Inc.     

Safety pharmacology of the respiratory system: Techniques and study design

The known effects of drugs from a variety of pharmacologic/therapeutic classes on the respiratory system and worldwide regulatory requirements support the need for conducting respiratory evaluations in safety pharmacology. The objective of these studies is to evaluate the potential for drugs to cause secondary pharmacologic or toxicologic effects that influence respiratory function. Changes in respiratory function can result either from alterations in the pumping apparatus that controls the pattern of pulmonary ventilation or from changes in the mechanical properties of the lung that determine the transpulmonary pressures (work) required for lung inflation and deflation. Defects in the pumping apparatus are classified as hypo- or hyperventilation syndromes and are evaluated by examining ventilatory parameters in a conscious animal model. The ventilatory parameters include respiratory rate, tidal volume, minute volume, peak (or mean) inspiratory flow, peak (or mean) expiratory flow, and fractional inspiratory time. Defects in mechanical properties of the lung are classified as obstructive or restrictive disorders and can be evaluated in animal models by performing flow-volume and pressure-volume maneuvers, respectively. The parameters used to detect airway obstruction include peak expiratory flow, forced expiratory flow at 25 and 75% of forced vital capacity, and a timed forced expiratory volume, while the parameters used to detect lung restriction include total lung capacity, inspiratory capacity, functional residual capacity, and compliance. Measurement of dynamic lung resistance and compliance, obtained continuously during tidal breathing, is an alternative method for evaluating obstructive and restrictive disorders, respectively, and is used when the response to drug treatment is expected to be immediate (within minutes post-dose). The species used in the safety pharmacology studies conducted in our laboratory are the same as those used in toxicology studies since pharmacokinetic and toxicologic/pathologic data are available in these species. These data can be used to help select test measurement intervals and doses and to aid in the interpretation of functional change. The techniques and procedures for measuring respiratory function parameters are well established in guinea pigs, rats, and dogs.     

Marine biodiversity as a source of chemical diversity

Total global biodiversity is estimated at between 3 and 500 × 10⁶ species of prokaryote and eukaryote organisms spread across 70 or more phyla. The marine macrofauna alone are estimated between 0.5 and 30 × 10⁶ species and represents a broader range of taxonomic diversity than that found in the terrestrial environment, which has been the traditional source of natural products. With a typical eukaryote possessing 50,000 genes, the global marine macrofauna are the source of 2.5 × 10¹⁰ to 1.5 × 10¹² primary products and an associated extensive range of secondary products. However, only a few thousand novel compounds from marine organisms have been described. These compounds have proven unique in chemical and pharmacological terms but, as yet, no therapeutic agents have resulted. Given a broader drug discovery strategy, and facilitated by technological advances, it is predicted that the characterisation of marine chemical diversity will be accelerated. Strategies for drug discovery from the virtually untapped chemical diversity of marine organisms are discussed. © 1994 Wiley-Less, Inc.     

An Assessment of Recent Pharmacy Graduates' Knowledge and Competency,Professional Practice Functions,and Involvement in Pharmacy Teaching Programs

Study Objectives . To determine self-evaluated professional knowledge and competency, functions, demographic information, lifelong learning, degree and training status, practice sites, involvement in pharmacy teaching programs, and salary for recent pharmacy graduates. Design . A survey of recent Bachelor of Science (B.S.) pharmacy graduates of the University of Wisconsin School of Pharmacy. Measurements and Main Results . A total of 371 B.S. pharmacy graduates (55% response rate) provided information. Graduates who had an advanced degree or training (from many programs) after completing their B.S. pharmacy degree, and those who were teaching in pharmacy programs generally had higher self-rated levels of knowledge and competencies. Hospital pharmacists spent less of their work time in dispensing activities (33.82% ± 30.39%) than community pharmacists (61.04% ± 19.97%; t =8.78, df = 288, p<0.001); community pharmacists spent twice as much of their work time counseling and educating patients (16.65% ± 10.47% vs 7.13% ± 7.39%; t = 9.06, df = 288, p<0.001). The amount of time pharmacists spent in dispensing functions had a negative association with knowledge and competencies in the sections on pharmacokinetic and disease process (r=−0.277, p<0.01), patient communications (r=−0.272, p<0.01), and administrative and economic aspects of practice (r=−0.210, p<0.01) for all respondents. Pharmacists reported that they spent 13.78 ± 14.06 hours per month outside work in professional lifelong learning. There was a negative association between the time pharmacists spent dispensing and the time they spent in professional lifelong learning (r=−0.239, p<0.001), and a positive relationship between the time spent in such learning and the time providing information to prescribers and other health care professionals (r=0.214, p<0.001), monitoring patients (r=0.216, p<0.001), and performing primary care activities (r=0.176, p<0.001). Graduates reported a mean yearly salary of $46,879 ± $8183. More hospital pharmacists were involved in teaching (48, 37%) than those practicing in a community setting (19, 12%). Conclusions . Practice site, advanced degree or training, lifelong learning, involvement in teaching programs, and time spent in various professional functions were associated with pharmacists' self-rated knowledge and competencies. (Pharmacotherapy 1994;14(6):712–723)     

RENIN GENE POLYMORPHISM ASSOCIATED WITH ALDOSTERONE RESPONSIVENESS TO THE RENINANGIOTENSIN SYSTEM IN PATIENTS WITH ALDOSTERONE-PRODUCING ADENOMAS

1. Aldosterone levels in patients with unilateral aldosterone-producing adenomas may be responsive or unresponsive to the renin-angiotensin system, with the former often previously misdiagnosed as bilateral adrenal hyperplasia. 2. In tumours from patients in the responsive subgroup, renin mRNA is expressed in greater amounts than in tumours from patients in the unresponsive subgroup, or in normal adrenals. 3. We compared the frequency of four renin gene polymorphisms in peripheral blood DNA from the two subgroups and found significant associations between BglI, TaqI and HinfI restriction fragment length polymorphisms (RFLP) and aldosterone responsiveness. 4. Allelic variation in the constitutive renin gene was associated with a specific cause of hypertension.     

Rural Hospital Inpatient Surgical Volume: Cutting-edge Service or Operating on the Margin?

Surgical services are an important part of modern health care, but providing them to isolated rural citizens is especially difficult. Public policy initiatives could influence the supply, training, and distribution of surgeons, much as they have for rural primary care providers. However, so little is known about the proper distribution of surgeons, their contribution to rural health care, and the safety of rural surgery that policy cannot be shaped with confidence. This study examined the volume and complexity of inpatient surgery in rural Washington state as a first step toward a better understanding of the current status of rural surgical services. Information about rural surgical providers was obtained through telephone interviews with administrators at Washington's 42 rural hospitals. The Washington State Department of Health's Commission Hospital Abstract Recording System (CHARS) data provided a count of the annual surgical admissions at rural hospitals. Diagnosis-related group (DRG) weights were used to measure complexity of rural surgical cases. Surgical volume varied greatly among hospitals, even among those with a similar mix of surgical providers. Many hospitals provided a limited set of basic surgical services, while some performed more complex procedures. None of these rural hospitals could be considered high volume when compared to volumes at Seattle hospitals or to research reference criteria that have assessed volume-outcome relationships for surgical procedures. Several hospitals had very low volumes for some complex procedures, raising a question about the safety of performing them. The leaders of small rural hospitals must recognize not only the fiscal and service benefits of surgical services--and these are considerable--but also the potentially adverse effect of low surgical volume on patient outcomes. Policies that encourage the proper training and distribution of surgeons, the retention of basic rural surgical services, and the rational regionalization of complex surgery are likely to enhance the convenience and safety of surgery for rural citizens.     

The necessity for sphenoidal electrodes in the presurgical evaluation of temporal lobe epilepsy: pro position.

Whether sphenoidal electrodes should be used in the presurgical evaluation of people with refractory epilepsy has remained controversial. Many studies have been published touting their advantages, or conversely, their lack of benefit. The present paper reviews the evidence supporting the utility of sphenoidal electrodes. In principle, sphenoidal electrodes have an advantage over laterally placed scalp electrodes in detecting inferiorly directed mesial temporal discharges. Published studies demonstrate that sphenoidal electrodes are more sensitive than scalp electrodes and sometimes detect interictal spikes and seizures not seen with scalp electrodes. While the net added yield is relatively low, perhaps 5 to 10%, those patients in whom sphenoidal electrodes provide unique localizing information have much to gain. Sphenoidal electrodes may spare some patients unnecessary intracranial electrode investigation and permit surgery for others.     

A Thalamic Contribution to Arousal-induced, Non-photic Entrainment of the Circadian Clock of the Syrian Hamster

It is well established that the circadian clock of the suprachiasmatic nuclei (SCN) is entrained by light. More recently, the potent effects of arousing, non-photic cues on the clock have been recognized. The neural mediators of non-photic entrainment are yet to be identified. To examine the contribution of the thalamic intergeniculate leaflet (IGL) and its NPY-immunopositive projection, the geniculo-hypothalamic tract to non-photic entrainment by arousal, male Syrian hamsters received lesions of the IGL (IGLX) which ablated NPY-immunoreactivity in the SCN. Their circadian responses to both photic and non-photic cues were then tested. Lesions resulted in a delay in the timing of activity onset following lights out, but had no effect on the behavioural or cellular circadian responses to phase-advancing light pulses presented at circadian time (CT) CT19 (where CT12 represents the time of activity onset). Injection with a benzodiazepine (chlordiazepoxide, 100 mg/kg) at CT6 suppressed wheel-running, increased general locomotion of intact controls and induced large phase advances of the circadian rhythm of wheel-running. Chlordiazepoxide also inhibited wheel-running in lesioned animals, but there was no significant increase in general locomotion and the lesioned animals did not phase advance. Serial arousal by injection of saline at intervals of 23.5 h for 6 days entrained the circadian rhythm of wheel-running of intact hamsters and was associated with an increase in general locomotor activity. Entrainment by serial arousal was abolished by IGLX. However, the lesioned animals did show a clear behavioural response to every presentation of the non-photic cue. These results show that the IGL is a necessary component of the neural pathways mediating both arousal- and benzodiazepine-induced non-photic entrainment.