Psychopharmacological Analysis of Central Muscarinic and Nicotinic Receptors

Arecoline and nicotine are two psychoactive cholinergic alkaloids. Arecoline is primarily a muscarinic agonist while nicotine, at low doses, is a nicotinic agonist. The experiments in this dissertation investigated two major areas: (1) the role of different factors in the development of tolerance to the behavioral effects of arecoline and nicotine, and (2) the possible mechanism and site of action of the discriminative stimulus (DS) effects of arecoline and nicotine. The role of dispositional and physiological factors comfiared to behavioral factors in the development of tolerance to the effects of arecoline and nicotine on operant behavior was assessed in Experiments I and II, respectively. In part one of Experiment I, rats were trained to respond (M1 a variable-interval 15 second (VI-15) schedule for milk reinforcement. Dose-effect relationships were assessed prior to and during chronic arecoline (1.74 mg/kg/day) treatment. After 21 days Of arecoline administration prior to the session, the dose-effect relationship for total responses was not shifted. However, the dose-effect relationship for total reinforcements was shifted to the right. In part two of Experiment I, rats were trained to respond on a fixed-ratio 20 (FR-ZG) schedule for milk reinforcement. Dose-effect relationships were assessed prior to and during chronic arecoline (0.87 mg/kg/day) administration. One group of rats received daily injections of arecoline prior to the seSsion and a second group received arecoline injections after the session. Daily administration of arecoline resulted in a greater shift to the right of the dose-effect relationship in the pre-session group compared to the post-session group. These data demonstrate the importance cflf behavioral factors in the development of tolerance to arecoline. In Experiment II, rats were trained to respond on a VI-15 second schedule of milk reinforcement. Dose-effect relationships were determined prior to and during chronic nicotine (2.28 mg/kg/day) administration. One group of rats received daily injections Of nicotine prior to the session, another group received nicotine injections after the session. After 36 days of chronic treatment, similar degrees of tolerance were observed in both groups, however the group receiving post-session nicotine developed tolerance at a faster rate. The data suggested that 21 complex interaction of nicotine and the experimental environment affected the rate of tolerance development. Experiment III characterized the DS effect of arecoline. Using a two-lever operant paradigm, rats were trained to discriminate arecoline from saline on a VI-12 second schedule of milk reinforcement. Rats could learn to discriminate 1.74 mg/kg arecoline from saline, but not 0.58 mg/kg from saline. Agonist and antagonist studies demonStrated that the DS effect of arecoline is mediated through central muscarinic receptors. In Experiment IV, the ability of physostigmine to interact fiith the DS effect of nicotine (1.14 mg/kg) and arecoline (1.74 mg/kg) was assessed. Physostigmine (0.125 mg/kg) pretreatment shifted the dose-effect relationship for arecoline to the left but did not affect that of nicotine. Physostigmine (0.25 mg/kg) almost completely generalized to the DS effect of arecoline but not to the DS effect of nicotine. These data suggest an interaction of endogenous acetylcholine with muscarinic receptors but not with nicotinic receptors. In Experiment V, the ability hf arecoline and nicotine injected directly into the dorsal hippocampus (DH) and mesencephalic reticular formation (MRF) to generalize to the DS effect of peripherally administered arecoline (1.74 mg/kg) and nicotine (1.14 mg/kg) was assessed; Nicotine injected into these sites generalized in a dose-related manner to nicotine. The MRF was slightly more sensitive than the DH. Arecoline injected into either site did not generalize to the DS effect of, peripherally administered arecoline. However, a decrease in response rates was observed

Recollision as a probe of magnetic-field effects in nonsequential double ionization

Fully accounting for nondipole effects in the electron dynamics, double ionization is studied for He driven by a near-infrared laser field and for Xe driven by a mid-infrared laser field. Using a three-dimensional semiclassical model, the average sum of the electron momenta along the propagation direction of the laser field is computed. If nondipole effects are not accounted for, the average momentum of each electron in the propagation direction of the laser field is zero. When nondipole effects are accounted for the sum of the electron momenta is found to be an order of magnitude larger than twice the average electron momentum along the propagation direction of the laser field in single ionization. This average sum of the electron momenta is found to be maximum at intensities smaller than the intensities satisfying previously predicted criteria for the onset of magnetic-field effects. It is shown that strong recollisions are the reason for this unexpectedly large value of the sum of the momenta along the direction of the magnetic component of the Lorentz force

Primary group size, social support, gender and future mental health status in a prospective study of people living in private households throughout Great Britain

Background. Structural characteristics of social networks such as primary group size have received less attention than measures of perceived social support. Previous research suggests that associations between social network size and later common mental disorder status may differ according to sex and initial mental state. Method. Adults participating in the 2000 British National Household Survey of psychiatric morbidity were randomly selected for follow-up 18 months later. The revised Clinical Interview Schedule (CIS-R) and the Interview Measure of Social Relations (IMSR) were administered at baseline and follow-up. Primary group size was defined as the total number of close relatives and friends. A four-level scale of common mental disorder was modelled with ordinal logistic regression, based on weighted data (n=2413). Findings. After adjusting for confounders, a primary group size of three or less at time 1 predicted worse mental health at time 2. This effect was greatest in men who were initially non-cases at baseline (averaged odds 4.5) and in women who were initially cases at baseline (average odds 2.9). Primary group size at time 2 was significantly predicted by level of common mental disorder at time 1 in women but not in men. Thus, confounding by baseline disorder does not explain risk of developing poor mental health in socially isolated men. Conclusion. This study replicates the strong effects of primary group size on future mental health that emerge when men and women are studied separately and when subjects are categorized according to baseline mental health status

The population impact of common mental disorders and long-term physical conditions on disability and hospital admission

Background: Long-term physical conditions (LTCs) consume the largest share of healthcare budgets. Although common mental disorders (CMDs) and LTCs often co-occur, the potential impact of improved mental health treatment on severe disability and hospital admissions for physical health problems remains unknown. Method: A cross-sectional study of 7403 adults aged 16–95 years living in private households in England was performed. LTCs were ascertained by prompted self-report. CMDs were ascertained by structured clinical interview. Disability was assessed using questions about problems with activities of daily living. Population impact and potential preventive gain were estimated using population-attributable fraction (PAF), and conservative estimates were obtained using ‘treated non-cases’ as the reference group. Results: Of the respondents, 20.7% reported at least one LTC. The prevalence of CMDs increased with the number of LTCs, but over two-thirds (71.2%) of CMD cases in people with LTCs were untreated. Statistically significant PAFs were found for CMDs and recent hospital admission [13.5%, 95% confidence intervals (CI) 6.6–20.0] and severe disability (31.3%, 95% CI 27.1–35.2) after adjusting for LTCs and other confounders. Only the latter remained significant when using the most conservative estimate of PAF (21.8%, 95% CI 14.0–28.9), and this was reduced only slightly when considering only participants with LTCs (18.5%, 95% CI 7.9–27.9). Conclusions: Better treatments for CMDs in people with LTCs could achieve almost the same population health gain in terms of reducing severe disability as those targeted at the entire population. Interventions to reduce the prevalence of CMDs among people with LTCs should be part of routine medical care

Costs and benefits of a subtype-specific surveillance system for identifying Escherichia coli O157:H7 outbreaks.

We assessed the societal costs and benefits of a subtype-specific surveillance system for identifying outbreak-associated Escherichia coli O157:H7 infections. Using data from Colorado, we estimated that if it averted five cases annually, the system would recover all its costs

Debt income and mental disorder in the general population

Background The association between poor mental health and poverty is well known but its mechanism is not fully understood. This study tests the hypothesis that the association between low income and mental disorder is mediated by debt and its attendant financial hardship. Method The study is a cross-sectional nationally representative survey of private households in England, Scotland and Wales, which assessed 8580 participants aged 16–74 years living in general households. Psychosis, neurosis, alcohol abuse and drug abuse were identified by the Clinical Interview Schedule – Revised, the Schedule for Assessment in Neuropsychiatry (SCAN), the Alcohol Use Disorder Identification Test (AUDIT) and other measures. Detailed questions were asked about income, debt and financial hardship. Results Those with low income were more likely to have mental disorder [odds ratio (OR) 2.09, 95% confidence interval (CI) 1.68–2.59] but this relationship was attenuated after adjustment for debt (OR 1.58, 95% CI 1.25–1.97) and vanished when other sociodemographic variables were also controlled (OR 1.07, 95% CI 0.77–1.48). Of those with mental disorder, 23% were in debt (compared with 8% of those without disorder), and 10% had had a utility disconnected (compared with 3%). The more debts people had, the more likely they were to have some form of mental disorder, even after adjustment for income and other sociodemographic variables. People with six or more separate debts had a six-fold increase in mental disorder after adjustment for income (OR 6.0, 95% CI 3.5–10.3). Conclusions Both low income and debt are associated with mental illness, but the effect of income appears to be mediated largely by debt