Neural mechanisms underlying nicotine dependence

There is little doubt that many habitual smokers find it difficult to quit the habit because they have become addicted to the nicotine present in the smoke. This paper addresses some of the pharmacological mechanisms underlying this addiction and discusses how an understanding of these mechanisms may contribute to the more effective use of nicotine replacement therapy during smoking cessation. It considers critically the evidence that the "rewarding" properties of nicotine, which serve to reinforce drug-seeking behaviour, are related to stimulation of the mesolimbic dopamine system of the brain. The critique focuses specifically on the evidence that many central nicotinic receptors, including those which mediate the effects of the drug on dopamine secretion, are readily desensitized by chronic exposure to agonist and that hypotheses which assume that nicotine inhaled from tobacco smoke invariably results in stimulation of the receptors must be treated with caution. Nicotinic receptors in the brain are, however, heterogeneous in nature with different molecular structures and pharmacologies. It is concluded that the reinforcing properties of nicotine sought by smokers may reflect both stimulation and desensitization of the different nicotinic receptor populations, and that smokers may adjust their smoking habits to achieve the balance of receptor stimulation and desensitization which they find most reinforcing. It seems likely that the efficacy of the different nicotine formulations during the treatment of smoking cessation may also reflect their ability to stimulate or desensitize brain nicotinic receptors.     

The stereoscopic anisotropy: Individual differences and underlying mechanisms.

Observers are more sensitive to variations in the depth of stereoscopic surfaces in a vertical than in a horizontal direction; however, there are large individual differences in this anisotropy. The authors measured discrimination thresholds for surfaces slanted about a vertical axis or inclined about a horizontal axis for 50 observers. Orientation and spatial frequency discrimination thresholds were also measured. For most observers, thresholds were lower for inclination than for slant and lower for orientation than for spatial frequency. There was a positive correlation between the 2 anisotropies, resulting from positive correlations between (a) orientation and inclination thresholds and (b) spatial frequency and slant thresholds. These results support the notion that surface inclination and slant perception is in part limited by the sensitivity of orientation and spatial frequency mechanisms. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Post-receptor mechanisms underlying striatal long-term depression

Extracellular and intracellular recordings were obtained from striatal neurons in a brain slice preparation in order to characterize the post-receptor mechanisms underlying striatal posttetanic long-term depression (LTD). Striatal LTD was blocked in neurons intracellularly recorded either with 1,2-bis (o-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid (BAPTA) or with EGTA, calcium (Ca2+) chelators. Intracellular injection of QX-314, a lidocaine derivative that has been shown to block voltage-dependent sodium channels, abolished action potential discharge and blocked striatal LTD. However, under this condition, striatal LTD was restored when, immediately before the delivery of the tetanus, the cell was depolarized at a membrane potential ranging between -30 mV and -20 mV by injecting continuous positive current. Nifedipine (10 microM), a blocker of voltage-dependent L-type Ca2+ channels, blocked striatal LTD. Nifedipine by itself altered neither cortically evoked EPSPs nor input resistance and firing properties of most of the recorded cells. Striatal LTD was also reduced or blocked by incubation of the slices in the presence of the following inhibitors of Ca(2+)-dependent protein kinases: staurosporine (10-50 nM), 1-(5-isoquinolinesulfonyl)-2- methylpiperazine (H-7; 10-50 microM), and calphostin C (1 microM). Our findings suggest that generation of striatal LTD requires a Ca2+ influx through voltage-dependent nifedipine-sensitive Ca2+ channels and a sufficient intracellular free Ca2+ concentration. Furthermore, this form of synaptic plasticity seems to involve the activation of Ca(2+)-dependent protein kinases. Different drugs, acting at receptor and/or post-receptor level, may affect this form of synaptic plasticity and might alter the formation of motor memory.     

Estimating multiple temporal mechanisms in human vision

When studying human ability to perceive temporal changes in luminance it is customary to estimate either temporal impulse response shapes or temporal modulation transfer functions, the representation of the impulse response in the frequency domain. The advantages and limitations of previous methods are summarized. We then describe an approach based on use of an impulse response basis set that resolves some of those limitations. We next present psychophysical results for spatiotemporal signal detection in spatiotemporal noise, together with an economical model of performance. The model is based on accepted notions of psychophysical detection mechanisms and the filter basis set described in the first part of the paper. The best-fitting model requires only eight parameters, as opposed to the 198 parameters required to separately fit each psychometric function, and captures both qualitative and quantitative properties of the psychophysical data. Finally, the best-fitting model indicates that only two temporal filters are necessary to describe the performance of each of three subjects under the specific stimulus conditions employed here.     

Genetic alterations and molecular mechanisms underlying colorectal tumorigenesis

Tumor cells are cells that have acquired damage to genes that directly regulate their cell cycles. In the multistep process leading to colorectal carcinoma, the adenoma-carcinoma sequence is characterized by progressive accumulation of genetic abnormalities (K-ras oncogene mutation, allelic deletion on chromosome 5q, 18q, 17p). In a hereditary non-polyposis syndrome (Lynch syndrome II) and in about a quarter of the cases of sporadic colorectal cancer there is a DNA micro-instability which contributes to the acquisition of mutations that cause loss of tumor-suppressor function. The p53 tumor-suppressor gene is the most frequently mutant gene in human cancer. In colorectal cancer cells missense p53 mutations and allelic deletion on chromosomal locus 17p13.1 are found with very high frequency. One of biological roles of p53 gene is to ensure that, in response to genotoxic damage, cells arrest in G1 and attempt to repair their DNA before it is replicated. In addition, p53 is required for apoptosis in response to severe DNA damage, included the damage induced by chemotherapeutics drugs and ionizing radiation. The loss of p53 function results in genomic instability and has been implicated in the evolution of normal cells into cancer cells.     

Effects and underlying mechanisms of self-adapted testing.

Undergraduates participated in 3 experiments related to self-adapted testing. Experiment 1 demonstrated that, in comparison with computerized adaptive testing, self-adapted testing reduced the influence of anxiety on performance but took longer and was less efficient. Experiment 2 indicated that benefits of self-adapted testing cannot be attributed solely to item ordering. Instead, active choice of item difficulty seems to be necessary. Experiment 3 demonstrated that the provision of feedback increased the efficiency of the test but had no effect on estimates of ability derived. The potential of self-adapted testing to reduce the influence of extraneous sources of variation in test performance is discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neural mechanisms of emotion.

When viewed from an evolutionary perspective, the neural mechanisms of emotion can be seen to be distributed across the brainstem, limbic, paralimbic, and neocortical regions. Descending and ascending connections among these levels are discussed in relation to 3 types of emotional processes: peripheral effects on patterned bodily responses, central effects on cognitive processing, and subjective emotional experience. Descending influences from the higher to the lower levels allow for an increasing coordination and flexibility of emotional responses, culminating in patterned activity across the peripheral endocrine, autonomic, and motor systems. Ascending influences from lower to higher levels provide preparatory modulation of cortical pathways, thus enabling perceptual and cognitive processing that is adaptive given the current emotional state. The bodily feelings of emotion are a function of cortical interoceptive sensory fields, activated by centrally generated signals or peripheral inputs from the body. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neutrophil priming: pathophysiological consequences and underlying mechanisms

1. Neutrophil priming by agents such as tumour necrosis factor-alpha, granulocyte/macrophage colony-stimulating factor and lipopolysaccharide causes a dramatic increase in the response of these cells to an activating agent; this process has been shown to be critical for neutrophil-mediated tissue injury both in vitro and in vivo. 2. The principle consequence of priming, aside from a direct effect on cell polarization, deformability and integrin/selectin expression, is to permit secretagogue-induced superoxide anion generation, degranulation and lipid mediator (e.g. leukotriene B4 and arachidonic acid) release. It is now recognized that most priming agents also serve an additional function of delaying apoptosis and hence increasing the functional longevity of these cells at the inflamed site. 3. The potential mechanisms underlying priming are discussed; current data suggest a dissociation between priming and changes in receptor number and/or affinity, G-protein expression, phospholipase C and phospholipase A2 activation and changes in intracellular Ca2+ concentration. However, more recent studies support a key role for protein tyrosine phosphorylation and enhanced phospholipase D and phosphoinositide 3-kinase activity in neutrophil priming. 4. Recent work has also revealed the potential for neutrophils to spontaneously and fully 'de-prime' after an initial challenge with platelet-activating factor. This ability of neutrophils to undergo a complete cycle of priming-de-priming (and re-priming) reveals a previously unrecognized flexibility in the control of neutrophil behaviour at an inflamed site.     

Neuroendocrine and autonomous mechanisms underlying thermoregulation in cold environment

This review focuses on the central regulation of thermoregulatory responses with special attention to the participation of thyrotropin-releasing hormone (TRH) in both autonomous and endocrine responses to a cold environment. Besides a direct projection of TRH neurons from paraventricular nuclei (PVN) to the median eminence, and the subsequent activation of the thyroid axis, there are direct projections from the PVN to the autonomic preganglionic neurons controlling autonomous responses. There projections convey information to peripheral targets involved in thermogenesis through the dorsal vagal complex and the spinal cord, for parasympathetic and sympathetic neurotransmissions respectively. Furthermore, cold exposure increases TRH mRNA levels in the PVN but also in dorsal motor and caudal raphe nuclei, thus providing strong evidence for a functional link between autonomous and neuroendocrine systems involved in thermoregulation. The review also focuses on neuroendocrine regulation of cold-induced TRH/TSH release associated with modifications in somatostatin release, with special reference to the participation of several central neurotransmitters (catecholamines, serotonin or GABA) or the influence of sex steroids.     

Processing mechanisms underlying use of the balance schema.

Three experiments contrasted 2 procedures for processing information about sentiment relations: (a) use of the balance schema as a mental model and (b) propositional processing. Ss read short stories that described some of the like–dislike relations in 4-person groups. Stories were presented on a computer terminal, 1 sentence at a time, at a rate controlled by Ss. Later, Ss took a computer-administered retrieval test of all relations in each group. Analysis of reading times, inferences from the given information, and response latencies supported use of the balance schema in processing these relations. This schema enables Ss to construct a complete model of relations in a group without reasoning propositionally and provides a stable configuration in the permanent memory store. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cellular and biochemical mechanisms underlying circadian rhythms in vertebrates

Circadian clocks organize neural processes, such as motor activities, into near 24-hour oscillations and adaptively synchronize these rhythms to the solar cycle. Recently, the first mammalian clock genes have been found. Unpredicted diversity in signaling pathways and clock-controlled gating of signals that modulate timekeeping has been discovered. A diffusible clock output has been found to control some behavioral rhythms. Consensus is emerging that circadian mechanisms are conserved across phylogeny, but that mammals have developed a great complexity of controls.     

Possible mechanisms underlying the antiaging actions of caloric restriction

Restricting the food intake of mice and rats to well below that of ad libitum-fed animals markedly slows the aging processes. This action is reflected in an increase in longevity, a decrease in the age-associated increase in age-specific mortality rate, the maintenance of the physiological processes in a youthful state even at advanced ages, and the delaying of the onset or slowing of the progression or both of most age-associated diseases. The dietary factor responsible is the reduction in energy (caloric) intake. Many hypotheses have been proposed regarding mechanisms underlying this antiaging action. Hypotheses relating the antiaging action to the retardation of growth and development, the reduction of adipose mass, and the reduction of metabolic rate have been found to be wanting. Two of the proposed hypotheses have some evidence in their support. One involves the altered metabolic characteristics of glucose fuel use and of oxidative metabolism. The other relates to the enhanced ability of the rodents restricted in food intake to cope with challenges, which in turn has been linked to the glucocorticoid system and to the heat-shock protein system.     

Multiple molecular mechanisms underlying subdiagnostic variants of Marfan syndrome

Mutations in the FBN1 gene, which encodes fibrillin-1, cause Marfan syndrome (MFS) and have been associated with a wide range of milder, overlap phenotypes. The factors that modulate phenotypic severity, both between and within families, remain to be determined. This study examines the relationship between the FBN1 genotype and phenotype in families with extremely mild phenotypes and in those that show striking clinical variation among apparently affected individuals. In one family, clinically similar but etiologically distinct disorders are segregating independently. In another, somatic mosaicism for a mutant FBN1 allele is associated with subdiagnostic manifestations, whereas germ-line transmission of the identical mutation causes severe and rapidly progressive disease. A third family cosegregates mild mitral valve prolapse syndrome with a mutation in FBN1 that can be functionally distinguished from those associated with the classic MFS phenotype. These data have immediate relevance for the diagnostic and prognostic counseling of patients and their family members.     

Post-receptoral mechanisms of colour vision in New World primates

Diurnal platyrrhines, both di- and trichromats, have magnocellular (M-) and parvocellular (P-) retinal ganglion cells which are morphologically very similar to those found in catarrhines. Catarrhine central P ganglion cells contact single midget bipolar cells, which contact single cones. Physiological recordings of retinal ganglion cells of dichromatic Cebus monkeys showed very similar cell properties to the catarrhine macaque, except that P ganglion cells lacked colour-opponency. We describe the presence of single-headed midget bipolar cells in the Cebus retina. These midget bipolar cells have axon terminal sizes in the same range as the dendritic tree sizes of P ganglion cells as far as 2 mm of retinal eccentricity. This result supports the view that, as in catarrhines, central P ganglion cells of platyrrhines receive input from single midget bipolar cells which in turn, receive input from single cones. This finding is consistent with the idea that a P pathway with one-to-one connectivity was present in the anthropoid ancestor before the divergence between catarrhines and platyrrhines.     

Cognitive mechanisms underlying implicit negative self concept in dysphoria.

Whereas explicit measures of the self-concept typically demonstrate a negative bias in depressed individuals, implicit measures such as the Implicit Association Test (IAT), revealed an opposite, positive bias. To address this inconsistent pattern, the authors examined, using a novel paradigm, mental set maintenance (i.e., the difficulty of maintaining active a required mental set) and set operation (the efficiency of executing the mental set while it is maintained). Dysphoric (N = 33) and nondysphoric (N = 30) participants alternated between an IAT focusing on self reference and a matched neutral task. Nondysphorics had greater difficulty in maintaining a negative self reference task compared to a neutral task. Conversely, dysphorics did not exhibit such difficulty, and they maintained a negative self-reference task more easily than nondysphorics. No group differences were evinced in smoothness of set operation. These results suggest that the shield protecting nondysphorics from maintaining negative mental sets is absent in dysphorics. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Possible serotonergic mechanisms underlying the antidepressant and anti-obsessive-compulsive disorder responses

Considerable evidence is now available to support the pivotal role of the serotonin (5-HT) system is exerting the antidepressant response in humans. Different type of antidepressant treatments enhance 5-HT neurotransmission via different pre- or postsynaptic mechanisms. The time course for the occurrence of these adaptive changes in the brain of laboratory animals is consistent with the delayed onset of the antidepressant response in humans. The drugs effective in obsessive-compulsive disorder (OCD) also enhance 5-HT neurotransmission in brain regions involved in mediating OCD symptoms but with a more prolonged delay, consistently with the larger time necessary to obtain therapeutic effect in OCD than in depression. The elucidation of these mechanisms of action lead to the development of new pharmacologic strategies to potentiate the therapeutic effect of the drugs currently available and the identification of novel targets to accelerate and further improve treatment response in depression and OCD.     

Cellular mechanisms underlying magnesium sulfate inhibition of phasic myometrial contractions

The neutrophil chemotactic cytokine, IL-8, has been reported to also chemoattract T lymphocytes in vitro and in vivo. Previously we showed that freshly isolated T cells migrated in response to IL-8, but incubation of T cells at 37 degrees C resulted in progressively decreased levels of IL-8 binding sites on T cells in association with reduced chemotactic responses. However, this reduced binding and migration of cultured T cells in response to IL-8 can be prevented by the presence of mononuclear cells in the culture. In order to define the factor(s) responsible for the restoration of T cell binding and migration in response to IL-8, we examined the effects of various cytokines. Addition of IFN-gamma in cultured T cells maintained both the CXC chemokine receptor CXCR1 and CXCR2 binding sites for IL-8 on these cells to the level comparable to that expressed on freshly purified T cells accompanied by an almost complete restoration of their chemotactic response to IL-8. The results suggest that Th1 cytokine, IFN-gamma, produced by mononuclear cells stimulated by proinflammatory signals may play an important role in regulating IL-8 receptor expression on T cells and in sustaining the function of these cells in response to IL-8.     

Neuroendocrine mechanisms underlying the control of gonadotropin secretion by steroids

There is considerable evidence that although estradiol may trigger the preovulatory surge of gonadotropins, progesterone is required for its full magnitude and duration and that glucocorticoids bring about selective follicle-stimulating hormone release. The luteinizing hormone-releasing hormone (LHRH) neuron does not have steroid receptors and is regulated by excitatory amino acid neurotransmission. Steroids do not appear to modulate excitatory amino acid receptors directly but increase release of glutamate in the preoptic area. This may be due to the suppression by steroids of the enzyme glutamatic acid decarboxylase67 that converts glutamate into GABA. NMDA receptors colocalize with nitric oxide synthase-containing neurons that surround the LHRH neurons in the preoptic area and intersect the LHRH fibers in the median eminence. Other potential novel pathways of LHRH release that are currently being explored include carbon monoxide generated by the action of heme oxygenase-2 on heme molecules and bradykinin acting via bradykinin B2 receptors.