Infralimbic kappa opioid and muscarinic M1 receptor interactions in the concurrent modulation of anxiety and memory

RATIONALE: Spontaneous working memory and anxiety-like behaviour can be concurrently influenced following kappa opioid or muscarinic M1 antagonist infusions in the infralimbic (IL) area of the ventromedial prefrontal cortex (vmPFC) in CD-1 mice. Further dose-response analyses of our previous norBNI and pirenzepine data revealed significant dose x drug interactions on trial-1 and -2 anxiety-related elevated plus-maze indices. These data prompted us to evaluate the effects of simultaneous IL norBNI/pirenzepine infusions on anxiety and spontaneous working memory. OBJECTIVE: The present study sought to evaluate whether (a) our previously reported anxiogenic and working memory disruptive effects of norBNI, and anxiolytic and working memory disruptive effects of pirenzepine data could be replicated using the most effective dose (10 nmol) of each drug and (b) IL infusions of mixed kappa/M1 receptor inhibitor drugs might interactively influence these cognitive, behavioural processes. METHODS: Anxiety was evaluated in the elevated plus maze, and spontaneous alternation memory was evaluated in the Y-maze following pirenzepine, norBNI or two levels of norBNI/pirenzepine drug mix infusions in the IL vmPFC. RESULTS: Pretreatment with the M1 antagonist pirenzepine was anxiolytic in trial 1 (10 nmol) and trial 2 (no-injection) in the elevated plus maze 24 h later, and disrupted alternation performance and some aspects of attention in the Y-maze. Pretreatment with the kappa antagonist norBNI was anxiogenic in trial 1 (10 nmol) and trial 2 (no-injection) in the elevated plus maze 24 h later, and also disrupted alternation performance and some aspects of attention in the Y-maze. The norBNI-10 nmol/pirenzepine-10 nmol mixed drug infusion was somewhat anxiogenic in trial 1, exerted no carry-over effects in trial 2 in the elevated plus maze, and disrupted alternation memory and some aspects of attention in the Y-maze. The norBNI-5 nmol/pirenzepine-10 nmol drug mix had no effect on trial-1 or -2 anxiety measures in the elevated plus maze, yet also disrupted Y-maze spontaneous memory performance. CONCLUSIONS: (1) The effects of IL infusions of norBNI or pirenzepine (10 nmol/0.5 microl) alone on anxiety-like behaviour and aversive learning and memory in the elevated plus-maze replicated previously reported data. (2) Mixed M1/kappa receptor inhibition in the IL cortex exerted counteractive effects on anxiety-like behaviour and aversive learning in the elevated plus maze. (3) Mixed M1/kappa receptor inhibition appeared to exert additive disruptive effects on alternation performance and aspects of attention related to active working memory in the Y-maze.     

Health interventions for the metal working industry: which is the most cost-effective? A study from a developing country

This study ranked the cost-effectiveness of health interventions in the metal working industry in a developing country. Data were based on 82 034 workers of the Northern region of Mexico. Effectiveness was measured through 'healthy life years' (HeaLYs) gained. Costs were estimated per worker according to type and appropriate inputs from selected health interventions. 'Hand' was the anatomical region that yielded the most gain of HeaLYs and amputation was the injury that yielded the most gain of HeaLYs. The most effective health intervention corresponded to training, followed by medical care, education, helmets, safety shoes, lumbar supports, safety goggles, gloves and safety aprons. In dollar terms, education presented the best cost-effectiveness ratio (US$637) and safety aprons presented the worst cost-effectiveness ratio (US$1 147 770). Training proved to be a very expensive intervention, but presented the best effectiveness outcome and the second best cost-effectiveness ratio (US$2084). Cost-effectiveness analyses in developing countries are critical. Corporations might not have the same funds and technology as those in developed countries or multinational companies.     

Performance-based reimbursement in health care. Consequences for physicians' cost awareness and work environment

BACKGROUND: The funding and structure of health care is currently undergoing major changes. The impact of such changes on professional behaviour and working conditions have not been widely studied in Europe. The two aims of this study were to prospectively assess the impact of performance-based reimbursement on physicians' attitudes and self-assessed professional behaviour, related to cost awareness, as well as their working conditions. METHOD: Physicians in Stockholm County Council (with a performance-based reimbursement system) and physicians in eleven Swedish councils without performance-based reimbursement were examined simultaneously in 1994. This was a cross-sectional questionnaire study. RESULT: The results show a heightened cost awareness among physicians in Stockholm but also greater discontent with working condition factors such as decision latitude, job satisfaction and personal well-being. CONCLUSION: These results suggest that in order to counteract physicians discontent as a result of altered structure and increased focus on performance-based reimbursement, the autonomy and influence of physicians over the work processes need to be considered.     

Involvement of 5-hydroxytryptamine neuronal system in Delta(9)-tetrahydrocannabinol-induced impairment of spatial memory

The present study investigated the involvement of the serotonin (5-hydroxytryptamine, 5-HT) neuronal system in the Delta(9)-tetrahydrocannabinol-induced impairment of spatial memory in the eight-arm radial maze in rats. Delta(9)-Tetrahydrocannabinol (6 mg/kg, i.p.), which impairs spatial memory, significantly increased the 5-HT content in the ventral hippocampus. A microdialysis study showed that Delta(9)-tetrahydrocannabinol (6 mg/kg, i.p.) decreased 5-HT release in the ventral hippocampus. The 5-HT precursor, 5-hydroxy-L-tryptophan (5-HTP; 50 mg/kg, i.p.), the 5-HT re-uptake inhibitor, clomipramine (0.01 and 0.1 mg/kg, i.p.), the 5-HT receptor agonist, 5-methoxy-N,N-dimethyltryptamine (5-MeODMT; 0.01 and 0.03 mg/kg, i.p.), and the 5-HT(2) receptor agonist, 1-(2,5-dimethoxy 4-iodophenyl)-2-amino propane (DOI; 10 microg/kg, i.p.), significantly attenuated the Delta(9)-tetrahydrocannabinol-induced impairment of spatial memory. These results suggest that the 5-HT neuronal system may be involved in the Delta(9)-tetrahydrocannabinol-induced impairment of spatial memory.     

The acute nootropic effects of Ginkgo biloba in healthy older human subjects: a preliminary investigation

Ginkgo biloba has been shown to have chronic memory enhancing effects in healthy subjects and patients with dementia. There is limited research on the acute nootropic effects of Ginkgo biloba in humans. The current study aimed to examine the acute effects of Ginkgo biloba (120 mg) on memory functioning in healthy older volunteers using the cognitive drug research (CDR) battery of memory tests and the Rey auditory verbal learning task (AVLT). The study was a double-blind placebo-controlled design, with each participant tested under both placebo and Ginkgo biloba treatment conditions. Testing was conducted pre- and 90 min post-drug administration for each treatment condition. Treatment conditions were separated by a 7 day wash out period. No acute effects of Ginkgo biloba were found for any of the memory tests examined. The findings suggest that 120 mg of Ginkgo biloba has no acute nootropic effects in healthy older humans.     

Trans-neuronal regulation of cortical apoptosis in the adult rat olfactory system

Previous work has identified a population of neurons within the anterior piriform cortex that undergo rapid apoptosis following de-afferentation by olfactory bulbectomy in adult rats. The specific initiation signal for apoptosis in this paradigm is unknown, but may include an activity-dependent trans-neuronal cascade. The present report examined the effect of adult-onset unilateral naris occlusion, which reduces olfactory bulb afferent excitation of piriform cortex, on apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling [TUNEL]) in the rat anterior piriform cortex. Adult Long-Evans hooded rats received unilateral naris occlusion or a control manipulation and were sacrificed after 1, 5, 7, 10 or 20 days later. For comparison, a second group of rats received a unilateral bulbectomy and were sacrificed 24 h later. Counts of TUNEL-stained cell profiles were performed for layers I/II and layer III of the anterior piriform cortex ipsilateral and contralateral to the manipulation. The results confirmed that unilateral bulbectomy produced a dramatic increase in TUNEL labeling in layers I/II of the ipsilateral piriform cortex 24 h after bulbectomy. Unilateral naris closure also produced enhanced TUNEL labeling, although the magnitude of the effect was less than that produced by bulbectomy, and enhanced TUNEL labeling was apparent both ipsilateral and contralateral to the sealed naris compared to controls. Deprivation-induced TUNEL labeling was detectable by 24 h post-closure, peaked at 5 days and was no different from controls by 20 days post-closure. Neither bulbectomy nor naris closure affected TUNEL labeling in layer III. Together, these results suggest that there is a population of superficial cells in piriform cortex whose survival is tightly regulated by sensory input.     

Intracerebroventricular injection of streptozotocin causes neurotoxicity to myelin that contributes to spatial memory deficits in rats

It has been reported that intracerebroventricular (icv) injection of streptozotocin (STZ) impairs spatial memory by disrupting glucose utilization through an insulin-dependent mechanism in the cerebral cortex and hippocampus. However, evidence of septal damage and microglosis induced by icv STZ suggested that its neurotoxic effects could contribute to the memory impairment. The present study examined the histopathological changes in adult rats following three icv STZ injections (0.25 mg into each lateral ventricle) and their effects on spatial memory in a Morris water maze task. STZ retarded acquisition of reference learning (progressive reduction in escape latency) and disrupted working memory (difference in escape latency between the two swims within a daily session). STZ caused selective injury to myelin and axons in the fornix and hippocampus in association with activation of microglia. The 3rd ventricle was enlarged by 100-150% because of a loss of ependymal cells and damage to hypothalamic periventricular myelin but the process involved in these changes is unclear. Our findings provide an alternative explanation for the decrease in glucose utilization in the hippocampus and cortex and the impairment of spatial memory induced by STZ. These could result from a disruption of the communication through myelinated axons in the fornix connecting the septum and the hippocampus, and through other myelinated axons adjacent to the ventricles. The selective damage to myelin may well result from oxidative stress.     

Involvement of the medial temporal lobe in priming for new associations

This study was addressed to the question of whether the medial temporal lobe (MTL) plays a critical role in implicit memory for new associations. Priming for new associations was examined in two different tasks in 18 patients with focal lesions all involving the MTL. In Experiment 1, following a study phase for pairs of unrelated words, subjects performed a perceptual identification task on old, recombined, and new pairs of words presented at brief exposure durations. In contrast to control subjects, and despite a normal level of item priming, the patients failed to show superior identification of the old pairs relative to the recombined pairs, the measure of associative priming. In Experiment 2, subjects engaged in speeded naming of the print color for previously studied words presented in the original color or in a different old color, and for unstudied words. Again, in contrast to control subjects and despite a normal level of item facilitation on color naming reaction time (RT), the patients failed to show priming for recently experienced new associations between words and colors. Explicit recognition memory by the patients was abnormal in both experiments. This study records an absence of priming for new associations, in two different tasks in which the nature of the stimuli was considerably different, in a large group of patients with lesions in the MTL. Although some previous research has reported significant associative priming in other tasks for patients with MTL lesions, the present results suggest that this region is critical for forming new associations of the types assessed here.     

Competition among multiple memory systems: converging evidence from animal and human brain studies

Research of the neurobiological bases of learning and memory suggest that these processes are not unitary in nature, but rather that relatively independent neural systems appear to mediate different types of memory. Neurobiological studies, for instance, have identified separable cognitive or "declarative" and stimulus-response "habit" memory systems that rely upon the medial temporal lobe (e.g. hippocampus) and basal ganglia (e.g. caudate-putamen), respectively. Evidence indicates that multiple memory systems are activated simultaneously and in parallel in various learning tasks, and recent findings suggest that these systems may interact. One form of interaction between medial temporal lobe and basal ganglia memory systems appears competitive in nature, and has been revealed in non-human animal studies in which damage to a given memory system results in enhanced learning. Recent human neuroimaging research has also provided evidence in favor of competition between memory systems. Thus, converging evidence across species supports the hypothesis of interactive multiple memory systems in the mammalian brain. Potential neurobiological mechanisms mediating such interactions include direct anatomical projections between the medial temporal lobe and basal ganglia, indirect neuromodulatory influences of other brain structures (e.g. basolateral amygdala) and activity of neocortical brain regions involved in top-down response selection.