Genetic mediated physiological processes that rely on both pharmacological and nutritional principles hold great promise for the successful therapeutic targeting of reduced carbohydrate craving, body-friendly fat loss, healthy body recomposition, and overall wellness. By integrating an assembly of scientific knowledge on inheritable characteristics and environmental mediators of gene expression, we review the relationship of genes, hormones, neurotransmitters, and nutrients as they correct unwanted weight gain coupled with unhappiness. In contrast to a simple one-locus, one-mechanism focus on pharmaceuticals alone, we hypothesize that the use of nutrigenomic treatment targeting multi-physiological neurological, immunological, and metabolic pathways will enable clinicians to intercede in the process of lipogenesis by promoting lipolysis while attenuating aberrant glucose cravings. In turn, this approach will enhance wellness in a safe and predictable manner through the use of a Genetic Positioning System (GPS) Map. The GPS Map, while presently incomplete, ultimately will serve not only as a blueprint for personalized medicine in the treatment of obesity, but also for the development of strategies for reducing many harmful addictive behaviors and promoting optimal health by using substances compatible with the body’s immune system.
Clostridium difficile is an important, emerging nosocomial pathogen. The transition from harmless colonization to disease is typically preceded by antimicrobial therapy, which alters the balance of the intestinal flora, enabling C. difficile to proliferate in the colon. One of the most perplexing aspects of the C. difficile infectious cycle is its ability to survive antimicrobial therapy and transition from inert colonization to active infection. Toxin-antitoxin (TA) systems have been implicated in facilitating persistence after antibiotic treatment. We identified only one TA system in C. difficile strain 630 (epidemic type X), designated MazE-cd and MazF-cd, a counterpart of the well-characterized Escherichia coli MazEF TA system. This E. coli MazF toxin cleaves mRNA at ACA sequences, leading to global mRNA degradation, growth arrest, and death. Likewise, MazF-cd expression in E. coli or Clostridium perfringens resulted in growth arrest. Primer extension analysis revealed that MazF-cd cleaved RNA at the five-base consensus sequence UACAU, suggesting that the mRNAs susceptible to cleavage comprise a subset of total mRNAs. In agreement, we observed differential cleavage of several mRNAs by MazF-cd in vivo, revealing a direct correlation between the number of cleavage recognition sites within a given transcript and its susceptibility to degradation by MazF-cd. Interestingly, upon detailed statistical analyses of the C. difficile transcriptome, the major C. difficile virulence factor toxin B (TcdB) and CwpV, a cell wall protein involved in aggregation, were predicted to be significantly resistant to MazF-cd cleavage.
Pasteurella multocida is a pathogen of veterinary and medical importance. Here, we report the 1.85 Å resolution crystal structure of the class C acid phosphatase from this organism (denoted rPmCCAP). The structure shows that rPmCCAP exhibits the same haloacid dehalogenase fold and dimeric assembly as the class C enzyme from Haemophilus influenzae. Formation of the dimer in solution is demonstrated using analytical ultracentrifugation. The active site is devoid of a magnesium ion due to the presence of citrate in the crystallization buffer. Absence of the metal ion minimally perturbs the active site structure, which suggests that the main role of the ion is to balance the negative charge of the substrate rather than stabilize the active site structure. The crystal lattice displays unusual crystal packing involving the C-terminal polyhistidine tag mimicking the substrate. Steady-state kinetic constants are determined for the substrates NMN, 5´-AMP, 3´-AMP, 2´-AMP, and p-nitrophenyl phosphate. The highest catalytic efficiency is observed with NMN. The production of polyclonal anti-rPmCCAP antibodies is demonstrated, and these antibodies are shown to cross-react with the H. influenzae class C phosphatase. The antibodies are used to detect PmCCAP in clinical P. multocida and Mannheimia haemolytica strains cultured from infected animals.
X-ray crystallography; class C acid phosphatase; analytical ultracentrifugation; steady-state kinetics; polyhistidine affinity tag; haloacid dehalogenase fold
Investigation of the Vpu protein of HIV-1 recently uncovered a novel aspect of the mammalian innate response to enveloped viruses: retention of progeny virions on the surface of infected cells by the interferon-induced, transmembrane and GPI-anchored protein BST-2 (CD317; tetherin). BST-2 inhibits diverse families of enveloped viruses, but how it restricts viral release is unclear. Here, immuno-electron microscopic data indicate that BST-2 is positioned to directly retain nascent HIV virions on the plasma membrane of infected cells and is incorporated into virions. Virion-incorporation was confirmed by capture of infectivity using antibody to the ectodomain of BST-2. Consistent with a direct tethering mechanism, we confirmed that proteolysis releases restricted virions and further show that this removed the ectodomain of BST-2 from the cell surface. Unexpectedly, enzymatic cleavage of GPI anchors did not release restricted virions, weighing against models in which individual BST-2 molecules span the virion and host cell membranes. Although the exact molecular topology of restriction remains unsolved, we suggest that the incorporation of BST-2 into viral envelopes underlies its broad restrictive activity, whereas its relative exclusion from virions and sites of viral assembly by proteins such as HIV-1 Vpu may provide viral antagonism of restriction.
The cellular protein BST-2 prevents newly formed particles of HIV-1 and other enveloped viruses from escaping the infected cell by an unclear mechanism. Here, we show that BST-2 is appropriately positioned to directly retain newly formed HIV-1 virions on the cell surface and is incorporated into infectious virions. We suggest that the incorporation of BST-2 into virions is a key aspect of the protein's broadly restrictive activity against enveloped viruses.
Two members of the class C family of bacterial nonspecific acid phosphatases have been cloned, expressed, purified and crystallized. One of the crystal forms exhibited epitaxial twinning.
Class C nonspecific acid phosphatases are bacterial enzymes that are secreted across the cytoplasmic membrane and hydrolyze a variety of phosphomonoesters at acidic pH. These enzymes are of interest for the development of improved vaccines and clinical diagnostic methods. In one case, the category A pathogen Francisella tularensis, the class C phosphatase plays a role in bacterial fitness. Here, the cloning, expression, purification and crystallization methods for the class C acid phosphatases from F. tularensis and Pasteurella multocida are reported. Crystals of the F. tularensis enzyme diffracted to 2.0 Å resolution and belonged to space group C2221, with one enzyme molecule in the asymmetric unit. Crystals of the P. multocida enzyme diffracted to 1.85 Å resolution and belonged to space group C2, with three molecules in the asymmetric unit. Diffraction patterns from crystals of the P. multocida enzyme exhibited multiple interpenetrating reciprocal-space lattices, indicating epitaxial twinning. Despite this aberrance, autoindexing was robust and the data could be satisfactorily processed to 1.85 Å resolution using MOSFLM and SCALA.
acid phosphatases; class C nonspecific acid phosphatases; Francisella tularensis; Pasteurella multocida; epitaxial twinning
In the current study we determined the functional significance of sodium dependent/independent glucose transporters at the neurovasculature during oxygen glucose deprivation (OGD). Confluent brain endothelial cells cocultured with astrocytes were exposed to varying degrees of in vitro stroke conditions. Glucose transporter 1 (GLUT1) and sodium glucose cotransporter (SGLT) activity were investigated by luminal membrane uptake and transport studies using [3H] D-glucose and also by [14C] alpha methyl D-glucopyranoside (AMG), a specific, nonmetabolized substrate of SGLT. In vivo middle cerebral artery occlusion (MCAO) experiments were tested to determine if blood-brain barrier (BBB) SGLT activity was induced during ischemia. Increases in luminal D-glucose and AMG uptake and transport were observed with in vitro stroke conditions. Specific inhibitor experiments suggest a combined role for both SGLT and GLUT1 at the BBB during OGD. A time dependent increase in the uptake of AMG was also seen in mice exposed to permanent focal ischemia and this increase was sensitive to SGLT inhibitor, phlorizin. Infarct and edema ratio during ischemia were significantly decreased by the inhibition of this transporter. These results show that both GLUT1 and SGLT play a role at the BBB in the blood-to-brain transport of glucose during ischemic conditions and inhibition of SGLT during stroke has the potential to improve stroke outcome. Pharmacological modulation of this novel BBB transporter could prove to be a brain vascular target in stroke.
Studies in vascular smooth muscle cells suggest that, angiotenisn II (Ang II)-mediated cellular response requires transactivation of epidermal growth factor receptor (EGF-R), and involves tyrosine phosphorylation of caveolin-1. Here we demonstrate that, exposure of WB rat liver cells to Ang II does not cause transactivation of EGF-R, but did rapidly activate p42/p44 mitogen-activated protein (MAP) kinases suggesting that it activates MAP kinases independent of EGF-R transactivation. We observed that the phospho-specific anti-caveolin-1 antibody detected a tyrosine phosphorylated, 75 kDa protein in Ang II-treated cells which we identified as glucose regulated protein-75 (GRP-75). Phosphoamino acid analysis showed that Ang II induced its phosphorylation at tyrosine, serine and threonine residues and was localized to the cytoplasm. The ability of Ang-II to induce GRP-75 phosphorylation suggests that it may play a role in the protection of cytoplasmic proteins from the damaging effect of oxidative stress known to be produced during Ang-II induced signaling.
Angiotensin II; GRP-75; Phosphorylation; Signal transduction; Oxidative stress; Mitochondria; Chaperone; EGF-R transactivation
We describe a system that permits the automated analysis of reporter gene expression in Caenorhabditis elegans with cellular resolution continuously during embryogenesis and demonstrate its utility by defining the expression patterns of reporters for several embryonically expressed transcription factors. The invariant cell lineage permits the automated alignment of multiple expression profiles, allowing the direct comparison of the expression of different genes' reporters. We have also used the system to monitor perturbations to normal development involving changes both in cell division timing and in cell fate. Systematic application could reveal the gene activity of each cell throughout development.
A review of the literature in both animals and humans reveals that changes in sex hormone have often been associated with changes in behavioral and mental abilities. Previously published research from our laboratory, and others, provides strong evidence that P300 (latency) event-related potential (ERP), a marker of neuronal processing speed, is an accurate predictor of early memory impairment in both males and females across a wide age range. It is our hypothesis, given the vast literature on the subject, that coupling growth hormones (insulin-like growth factor-I, (IGF-I) and insulin-like growth factor binding protein 3 (IGF-BP3)), P300 event-related potential and test of variables of attention (TOVA) are important neuroendocrinological predictors of early cognitive decline in a clinical setting. To support this hypothesis, we utilized structural equation modeling (SEM) parameter estimates to determine the relationship between aging and memory, as mediated by growth hormone (GH) levels (indirectly measured through the insulin-like growth factor system), P300 latency and TOVA, putative neurocognitive predictors tested in this study. An SEM was developed hypothesizing a causal directive path, leading from age to memory, mediated by IGF-1 and IGF-BP3, P300 latency (speed), and TOVA decrements. An increase in age was accompanied by a decrease in IGF-1 and IGF-BP3, an increase in P300 latency, a prolongation in TOVA response time, and a decrease in memory functioning. Moreover, independent of age, decreases in IGF-1 and IGF-BP3, were accompanied by increases in P300 latency, and were accompanied by increases in TOVA response time. Finally, increases in P300 latency were accompanied by decreased memory function, both directly and indirectly through mediation of TOVA response time. In summary, this is the first report utilizing SEM to reveal the finding that aging affects memory function negatively through mediation of decreased IGF-1 and IGF-BP3, and increased P300 latency (delayed attention and processing speed).
Structural equation modeling (SEM); P300 latency; TOVA; IGF-1; IGF-BP3; Age and memory
As socioeconomic status (SES) increases, the incidence of low birthweight and preterm birth decreases irrespective of social class. However, low birthweight remains twice as high for African-American women as for white women even when SES is controlled. This study examines to what extent second generation high SES African-American women experience improvement in birthweight and gestational age. One hundred eighty-nine former Meharry students were surveyed. Identified were 934 births that are the children and grandchildren of these students who matriculated at Meharry. These infants are compared with a cohort of white mothers from a study in the School of Public Health at Yale University. Low birthweight was reduced in the third generation high SES African-American children (6.9%) from the second generation (11.4%) but remained higher than white children (3.3%). Results showed that African-American third generation children remained at higher risk for low birthweight than were white children (relative risk [RR], 1.78; 95% confidence interval [CI], 1.03, 3.09). Similar results were observed for preterm delivery where the increased risk to third generation African-American children was 3.16 (1.89, 5.27). Persistent strong ethnic differences in birthweight in this high SES cohort (OR = 3.16, 95% CI, 1.89-5.27) support a conclusion that African-American women have birthweight distributions that are somewhat lighter than white women. This may explain a portion of current ethnic differences in birthweight. It is also possible that persistent psychosocial and behavioral factors continue to negatively influence birthweight, even in second generation high SES African-American mothers. This explanation will require identification of powerful risk factors, which are largely unrelated to those presently under investigation.
This study provides a set of nutritional and environmental parameters suitable for the growth of morel (Morchella crassipes) sclerotia in the laboratory, using a modification of the jar method of Ower et al. (U.S. patent 4,594,809, June 1986). The optimum nutritional and environmental conditions for morel sclerotium formation and maturation as determined in this study consist of a layer of rye grain supplemented with peptone, yeast extract, trace elements, and Casamino Acids overlaid with perforated aluminum foil and covered with a layer of nutrient-poor soil medium in an 8-oz. (ca. 237-ml) glass jar in the dark. We noted that addition of asparagine or aspartic acid as a nitrogen source to the rye also had a beneficial effect on sclerotium formation, while addition of carbon sources had no significant effect.
Thienopyridine-derivatives (ticlopidine, clopidogrel, and prasugrel) are the primary antiplatelet agents. Thrombotic thrombocytopenic purpura (TTP) is a rare drug-associated syndrome, with the thienopyridines being the most common drugs implicated in this syndrome. We reviewed 20 years of information on clinical, epidemiologic, and laboratory findings for thienopyridine-associated TTP. Four, 11, and 11 cases of thienopyridine-associated TTP were reported in the first year of marketing of ticlopidine (1989), clopidogrel (1998), and prasugrel (2010), respectively. As of 2011, the FDA received reports of 97 ticlopidine-, 197 clopidogrel-, and 14 prasugrel-associated TTP cases. Severe deficiency of ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) was present in 80% and antibodies to 100% of these TTP patients on ticlopidine, 0% of the patients with clopidogrel-associated TTP (p < 0.05), and an unknown percentage of patients with prasugrel-associated TTP. TTP is associated with use of each of the three thienopyridines, although the mechanistic pathways may differ.
thrombotic thrombocytopenic purpura; ticlopidine; clopidogrel; prasugrel; adverse event
thrombotic thrombocytopenic purpura; ticlopidine; ADAMTS13; ADAMTS13 inhibitor; Japan
When conducting optical imaging experiments, in vivo, the signal to noise ratio and effective spatial and temporal resolution is fundamentally limited by physiological motion of the tissue. A 3-dimensional motion tracking scheme, using a multi-photon excitation microscope with a resonant galvanometer, (512×512 pixels at 33 frames/sec) is described to overcome physiological motion, in vivo. The use of commercially available graphical processing units permitted the rapid 3-dimensional cross-correlation of sequential volumes to detect displacements and adjust tissue position to track motions in near real-time. Motion phantom tests maintained micron resolution with displacement velocities of up to 200 μm/min, well within the drift observed in many biological tissues under physiologically relevant conditions. In vivo experiments on mouse skeletal muscle using the capillary vasculature with luminal dye as a displacement reference revealed an effective and robust method of tracking tissue motion to enable (1) signal averaging over time without compromising resolution, and (2) tracking of cellular regions during a physiological perturbation.
Burnout is prevalent in residency training and practice and is linked to medical error and suboptimal patient care. However, little is known about how burnout affects clinical reasoning, which is essential to safe and effective care. The aim of this study was to examine how burnout modulates brain activity during clinical reasoning in physicians. Using functional Magnetic Resonance Imaging (fMRI), brain activity was assessed in internal medicine residents (n = 10) and board-certified internists (faculty, n = 17) from the Uniformed Services University (USUHS) while they answered and reflected upon United States Medical Licensing Examination and American Board of Internal Medicine multiple-choice questions. Participants also completed a validated two-item burnout scale, which includes an item assessing emotional exhaustion and an item assessing depersonalization. Whole brain covariate analysis was used to examine blood-oxygen-level-dependent (BOLD) signal during answering and reflecting upon clinical problems with respect to burnout scores. Higher depersonalization scores were associated with less BOLD signal in the right dorsolateral prefrontal cortex and middle frontal gyrus during reflecting on clinical problems and less BOLD signal in the bilateral precuneus while answering clinical problems in residents. Higher emotional exhaustion scores were associated with more right posterior cingulate cortex and middle frontal gyrus BOLD signal in residents. Examination of faculty revealed no significant influence of burnout on brain activity. Residents appear to be more susceptible to burnout effects on clinical reasoning, which may indicate that residents may need both cognitive and emotional support to improve quality of life and to optimize performance and learning. These results inform our understanding of mental stress, cognitive control as well as cognitive load theory.
expertise; burnout; clinical reasoning; cognitive load; fMRI
The evolution of minimal DNA tumor virus’ genomes has selected for small oncoproteins that hijack critical cellular protein interaction networks. The structural basis for the dominant interactions of adenovirus oncoproteins has remained elusive as no full-length structures have been solved. Adenovirus E4-ORF3 forms a nuclear scaffold and simultaneously inactivates p53, PML, TRIM24 and MRE11/RAD50/NBS1 (MRN) tumor suppressors. We identify oligomerization mutants and solve the crystal structure of an E4-ORF3 dimer. The structure of E4-ORF3 is unrelated to known polymers or oncogenes. E4-ORF3 dimers have a central β-core and co-assemble in multiple configurations by exchanging their C-terminal tails. The resulting polymers are disordered weaves of linear and branched oligomer threads that form a 3D network that partitions the nucleus. The assembly of E4-ORF3 creates avidity driven interactions with PML and an emergent MRN binding interface. This study unveils an elegant solution whereby a small domain forms a multivalent polymer to disrupt multiple protein complexes.
Phosphate (Pi) deficiency induces a multitude of responses aimed at improving the acquisition of Pi, including an increased density of root hairs. To understand the mechanisms involved in Pi deficiency-induced alterations of the root hair phenotype in Arabidopsis (Arabidopsis thaliana), we analyzed the patterning and length of root epidermal cells under control and Pi-deficient conditions in wild-type plants and in four mutants defective in the expression of master regulators of cell fate, CAPRICE (CPC), ENHANCER OF TRY AND CPC 1 (ETC1), WEREWOLF (WER) and SCRAMBLED (SCM). From this analysis we deduced that the longitudinal cell length of root epidermal cells is dependent on the correct perception of a positional signal (‘cortical bias’) in both control and Pi-deficient plants; mutants defective in the receptor of the signal, SCM, produced short cells characteristic of root hair-forming cells (trichoblasts). Simulating the effect of cortical bias on the time-evolving probability of cell fate supports a scenario in which a compromised positional signal delays the time point at which non-hair cells opt out the default trichoblast pathway, resulting in short, trichoblast-like non-hair cells. Collectively, our data show that Pi-deficient plants increase root hair density by the formation of shorter cells, resulting in a higher frequency of hairs per unit root length, and additional trichoblast cell fate assignment via increased expression of ETC1.
This investigator-initiated study explores the safety, maximum tolerated dose (MTD), clinical response, and pharmacokinetics (PK) of hydroxychloroquine (HCQ) with and without erlotinib in patients with advanced non-small cell lung cancer (NSCLC).
Patients with prior clinical benefit from an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor were randomized to HCQ or HCQ plus erlotinib in a 3+3 dose escalation schema.
Twenty-seven patients were treated, 8 with HCQ (arm A) and 19 with HCQ plus erlotinib (arm B). EGFR mutations were detected in 74% of patients and 85% had received ≥2 prior therapies. Arm A had no dose-limiting toxicities (DLTs), but the MTD was not reached as this arm closed early to increase overall study accrual. In arm B, 1 patient each experienced grade 3 rash, nail changes, skin changes, nausea, dehydration, and neutropenia, 1 had grade 4 anemia, and 1 developed fatal pneumonitis, all considered unrelated to HCQ. There were no DLTs, therefore the highest tested dose for HCQ with erlotinib 150mg was 1000mg daily. One patient had a partial response (PR) to erlotinib/HCQ, for an overall response rate of 5% (95% CI, 1–25). This patient had an EGFR mutation and remained on therapy for 20 months. Administration of HCQ did not alter the PK of erlotinib.
HCQ with or without erlotinib was safe and well-tolerated. The recommended phase 2 dose of HCQ was 1000mg when given in combination with erlotinib 150mg.
To examine the neuropathological substrates of cognitive dysfunction and dementia in Parkinson’s disease (PD).
140 patients with a clinical diagnosis of PD and either normal cognition or onset of dementia two or more years after motor symptoms (PDD) were studied. Patients with a clinical diagnosis of dementia with Lewy bodies were excluded.
Autopsy records of genetic data and semi-quantitative scores for the burden of neurofibrillary tangles (NFTs), senile plaques (SPs), Lewy body (LB/LN) and other pathologies were used to develop a multivariate logistic regression model to determine the independent association of these variables with dementia. Correlates of co-morbid Alzheimer’s disease (PDD+AD) were also examined.
92 PD patients developed dementia and 48 remained cognitively normal. Severity of cortical LB/LN (CLB/LN) pathology was positively associated with dementia (p<0.001), with an odds-ratio (OR) of 4.06 (CI95%1.87–8.81), as was Apolipoprotein E4 (APOE4) genotype (p=0.018,OR4.19 CI95% 1.28–13.75). 28.6% of all PD cases had sufficient pathology for co-morbid AD, of which 89.5% were demented. The neuropathological diagnosis of PDD+AD correlated with an older age of PD onset (p=0.001,OR1.12 CI95%1.04–1.21), higher CLB/LN burden (p=0.037,OR 2.48 CI95%1.06–5.82), and cerebral amyloid angiopathy severity (p=0.032, OR4.16 CI95%1.13–15.30).
CLB/LN pathology is the most significant correlate of dementia in PD. Additionally, APOE4 genotype may independently influence the risk of dementia in PD. AD pathology was abundant in a subset of patients, and may modify the clinical phenotype. Thus, therapies that target α-synuclein, tau, or Aβ could potentially improve cognitive performance in PD.
Endocannabinoids are key modulators of synaptic function. By activating cannabinoid receptors expressed in the central nervous system, these lipid messengers can regulate several neural functions and behaviors. As experimental tools advance, the repertoire of known endocannabinoid-mediated effects at the synapse, and their underlying mechanism, continues to expand. Retrograde signaling is the principal mode by which endocannabinoids mediate short- and long-term forms of plasticity at both excitatory and inhibitory synapses. However, growing evidence suggests that endocannabinoids can also signal in a non-retrograde manner. In addition to mediating synaptic plasticity, the endocannabinoid system is itself subject to plastic changes. Multiple points of interaction with other neuromodulatory and signaling systems have now been identified. Synaptic endocannabinoid signaling is thus mechanistically more complex and diverse than originally thought. In this review, we focus on new advances in endocannabinoid signaling and highlight their role as potent regulators of synaptic function in the mammalian brain.
Understanding relationships between heart failure and arrhythmias, important causes of suffering and sudden death, remains an unmet goal for biomedical researchers and physicians. Evidence assembled over the last decade supports a view that activation of the multifunctional Ca2+ and calmodulin-dependent protein kinase II (CaMKII) favors myocardial dysfunction and cell membrane electrical instability. CaMKII activation follows increases in intracellular Ca2+ or oxidation, upstream signals with the capacity to transition CaMKII into a Ca2+ and calmodulin-independeant, constitutively active enzyme. Constitutively active CaMKII appears poised to participate in disease pathways by catalyzing the phosphorylation of classes of protein targets important for excitation-contraction coupling and cell survival, including ion channels and Ca2+ homeostatic proteins, and transcription factors that drive hypertrophic and inflammatory gene expression. This rich diversity of downstream targets helps to explain the potential for CaMKII to simultaneously affect mechanical and electrical properties of heart muscle cells. Proof of concept studies from a growing number of investigators show that CaMKII inhibition is beneficial for improving myocardial performance and reducing arrhythmias. Here we review the molecular physiology of CaMKII, discuss CaMKII actions at key cellular targets and results of animal models of myocardial hypertrophy, dysfunction and arrhythmias that suggest CaMKII inhibition may benefit myocardial function while reducing arrhythmias.
CaMKII; Arrhythmias; Heart Failure; Ion channels; Remodeling
This review article focuses on the impact that the presence of pain has on drug self-administration in rodents, and the potential for using self-administration to study both addiction and pain, as well as their interaction. The literature on the effects of noxious input to the brain on both spinal and supraspinal neuronal activity is reviewed, as well as the evidence that human and rodent neurobiology is affected similarly by noxious stimulation. The convergence of peripheral input to somatosensory systems with limbic forebrain structures is briefly discussed in the context of how the activity of one system may influence activity within the other system. Finally, the literature on how pain influences drug-seeking behaviors in rodents is reviewed, with a final discussion of how these techniques might be able to contribute to the development of novel analgesic treatments that minimize addiction and tolerance.
The effects of nicotine on cognitive processes such as learning and memory may play an important role in the addictive liability of tobacco. However, it remains unknown whether genetic variability modulates the effects of nicotine on learning and memory. The present study characterized the effects of acute, chronic, and withdrawal from chronic nicotine administration on fear conditioning, somatic signs, and the elevated plus maze in 8 strains of inbred mice. Strain-dependent effects of acute nicotine and nicotine withdrawal on contextual fear conditioning, somatic signs, and the elevated plus maze were observed, but no association between the effects of acute nicotine and nicotine withdrawal on contextual fear conditioning were observed, suggesting that different genetic substrates may mediate these effects. The identification of genetic factors that may alter the effects of nicotine on cognition may lead to more efficacious treatments for nicotine addiction.
Nicotine; Genetics; Addiction; Anxiety; Learning; Withdrawal