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PubMed2006

Structures of omega repressors bound to direct and inverted DNA repeats explain modulation of transcription.

Repressor omega regulates transcription of genes required for copy number control, accurate segregation and stable maintenance of inc18 plasmids hosted by Gram-positive bacteria. omega belongs to homodimeric ribbon-helix-helix (RHH2) repressors typified by a central, antiparallel beta-sheet for DNA major groove binding. Homodimeric omega2 binds cooperatively to promotors with 7 to 10 consecutive non-palindromic DNA heptad repeats (5'-(A)/(T)ATCAC(A)/(T)-3', symbolized by -->) in palindromic inverted, converging (--><--) or diverging (<---->) orientation and also, unique to omega2 and contrasting other RHH2 repressors, to non-palindromic direct (-->-->) repeats. Here we investigate with crystal structures how omega2 binds specifically to heptads in minimal operators with (-->-->) and (--><--) repeats. Since the pseudo-2-fold axis relating the monomers in omega(2) passes the central C-G base pair of each heptad with approximately 0.3 A downstream offset, the separation between the pseudo-2-fold axes is exactly 7 bp in (-->-->), approximately 0.6 A shorter in (--><--) but would be approximately 0.6 A longer in (<---->). These variations grade interactions between adjacent omega2 and explain modulations in cooperative binding affinity of omega2 to operators with different heptad orientations.

Bacterial Proteins↗
PubMed1997

Cardiolipin synthase from Escherichia coli.

Escherichia coli cardiolipin synthase catalyzes reversible phosphatidyl group transfer from one phosphatidylglycerol molecule to another to form cardiolipin (CL) and glycerol. The enzyme is specified by the cls gene, located at min 28.02 of the E. coli genetic map. Cells with mutations in cls have longer doubling times, tend to lose viability in the stationary phase, are more resistant to 3,4-dihydroxybutyl-1-phosphonate, and have an altered sensitivity to novobiocin. Although cls null mutants appear to lack CL synthase activity, they are still able to form trace quantities of CL. The enzyme appears to be regulated at both the genetic and enzymatic levels. CL synthase's molecular mass is 45-46 kDa, or about 8 kDa less than the polypeptide predicted by the gene sequence, suggesting that posttranslational processing occurs. CL synthase can use various polyols such as mannitol and arabitol to convert CL to the corresponding phosphatidylglycerol analog. When the amino acid sequences of four bacterial CL synthases are compared, three highly conserved regions are apparent. One of these regions contains a conserved pentapeptide sequence, RN(Q)HRK, and another has a conserved HXK sequence. These two sequences may be part of the active site. E. coli CL synthase has been studied by using a mixed micelle assay. The enzyme is inhibited by CL, the product of the reaction, and by phosphatidate. Phosphatidylethanolamine partially offsets inhibition caused by CL but not by phosphatidate. CDP-diacylglycerol does not appear to affect the activity of the purified enzyme but does stimulate the activity associated with crude membrane preparations.

Amino Acid Sequence↗
PubMed1998

Characterization of the closed complex intermediate formed during transcription initiation by Escherichia coli RNA polymerase.

We have carried out detailed DNase I footprinting studies of the closed complex formed on the phage lambda prmup-1 Delta265 promoter under reaction conditions such that the contribution of the open complex to the footprint was negligible. Detailed quantification shows that the closed complex detected has the same binding constant as that determined in kinetic studies. The footprinting pattern of the closed complex shows major differences from that of the open complex. Not only is it about 20 base pairs shorter, there are also many fewer positions being protected around and upstream of the -35 region. We have derived potential contact regions in the closed and open complexes based on the DNase I footprinting patterns, and confirmed the contact region for the open complex by hydroxyl radical footprinting. One important finding is that most of the essential contacts with the phosphate groups in the -35 region are formed during the isomerization step, a conclusion consistent with our kinetic data showing that this step is salt dependent on this promoter. In addition, we found that the derived contact regions for the closed and open complexes are offset by about three base pairs in the -35 region, which suggests a shift of the contact during isomerization. Finally, we found that the footprinting pattern of the complex formed at 4 degreesC has some similarities to as well as differences from the closed complex formed under standard transcription conditions.

Bacterial Proteins↗
PubMed2006

Analysis of referrals to a multi-disciplinary breast cancer genetics clinic: practical and economic considerations.

Analysis of activity was undertaken in an established regional clinic providing risk assessment, counselling, screening and management for women with a family history of breast or ovarian cancer. The objectives were to determine: (1) how closely the route and pattern of referrals matched official guidelines (2) whether the previously recorded socio-economic imbalance among clinic clientele persisted and (3) the economic and practical consequences of committing resources to verification and extension of reported family histories. The findings were: (1) after some years of operation, the proportion of referrals direct from primary care had increased from less than 50% to over 75%, with a concomitant slight decrease in overall referral rate; (2) the socio-economic distribution of patients referred had become less selective and (3) extension and verification of reported family histories led to a redistribution of risk categories, increasing the proportion of referrals judged to be in the "low risk" category, from 25% (based on referral letter alone) to 41% (at the end of the process). The costs associated with this approach are offset by the savings generated and it allows specialised counselling and screening services to be targeted more efficiently.

Breast Neoplasms↗
PubMed1999

The tetramerization domain of the Mnt repressor consists of two right-handed coiled coils.

The tetrameric Mnt repressor is involved in the genetic switch between the lysogenic and lytic growth of Salmonella bacteriophage P22. The solution structure of its C-terminal tetramerization domain, which holds together the two dimeric DNA-binding domains, has been determined by NMR spectroscopy. This structure reveals an assembly of four alpha-helical subunits, consisting of a dimer of two antiparallel coiled coils with a unique right-handed twist. The superhelical winding is considerably stronger and the interhelical separation closer than those found in the well-known left-handed coiled coils in fibrous proteins and leucine zippers. An unusual asymmetry arises between the two monomers that comprise one right-handed coiled coil. A difference in the packing to the adjacent monomer of the other coiled coil occurs with an offset of two helical turns. The two asymmetric monomers within each coiled coil interconvert on a time scale of seconds. Both with respect to symmetry and handedness of helical packing, the C2 symmetric four-helix bundle of Mnt differs from other oligomerization domains that assemble DNA-binding modules, such as that in the tumor suppressor p53 and the E. coli lac repressor.

Amino Acid Sequence↗
PubMed2001

Social stress exacerbates stroke outcome by suppressing Bcl-2 expression.

The relationship between stressful life events and the onset of disease is well documented. However, the role of psychological stress as a risk factor for life-threatening cerebrovascular insults such as stroke remains unspecified, but could explain individual variation in stroke outcome. To discover the mechanisms through which psychological stress may alter stroke outcome, we modeled the effects of chronic social intimidation and stress on ischemia-induced bcl-2 expression and early neuronal cell loss resulting from cerebral artery occlusion in mice (C57BL/6). The bcl-2 protooncogene promotes cell survival and protects against apoptosis and cellular necrosis in numerous neurodegenerative disorders, including stroke. In our study, male mice were chronically exposed to aggressive social stimuli before induction of a controlled, mild ischemic insult. Stressed mice expressed approximately 70% less bcl-2 mRNA than unstressed mice after ischemia. In addition, social stress greatly exacerbated infarct in wild-type mice but not in transgenic mice that constitutively express increased neuronal bcl-2. Despite similar postischemic concentrations of corticosterone, the major stress hormone in mice, high corticosterone concentrations were significantly correlated with larger infarcts in wild-type mice but not bcl-2 transgenic mice. Thus, enhanced bcl-2 expression offsets the potentially deleterious consequences of high postischemic plasma corticosterone concentrations. Taken together, these data demonstrate that stressful prestroke social milieu strongly compromises an endogenous molecular mechanism of neuroprotection in injured brain and offer a new behavioral target for stroke therapy.

Animals↗
PubMed2002

Cow-calf and feedlot performances of Brahman-derivative breeds.

A study was conducted to compare Brangus, Beefmaster, Gelbray, and Simbrah breed influences for economically important traits. Brangus (9), Beefmaster (12), Gelbray (10), and Simbrah (7) sires were used in purebred and crossbred (Brahman x Hereford F1 cows) matings to generate calves (326) in eight breed groups. Beefmaster cows were of similar size (448 kg), Brangus and Gelbray cows were 11% heavier (501 and 503 kg), and Simbrah cows were 21% heavier (548 kg) compared to Brahman x Hereford F1 cows (452 kg). Calves sired by Brangus and Beefmaster bulls had lower birth weights (35 vs 38 kg; P < 0.05), preweaning growth rates (0.87 vs 0.91 kg x d(-1); P < 0.01), and weaning weights (206 vs 219 kg; P < 0.01) than Gelbray- and Simbrah-sired calves. Birth weights, preweaning ADG, and weaning weight and hip heights were similar between Brangus- and Beefmaster-sired calves. Simbrah-sired calves had greater preweaning growth rates (0.94 vs 0.88 kg x d(-1); P < 0.05), weaning weights (227 vs 211 kg; P < 0.01), and adjusted 205-d hip heights (126 vs 122 cm; P < 0.05) than Gelbray-sired calves. Straightbred Angus steers were introduced in the postweaning portion of the study. Steer calves were placed on feed at an average age of 14.5 mo. Steers were removed from the feedlot upon attaining a targeted 10 mm of backfat. Feedlot ADG did not differ among sire breeds. Brahman-derivative sired steers required an additional 54 d on feed (P < 0.01) and were 86 kg heavier (P < 0.01) at harvest than Angus steers. Continental-Brahman steers spent an additional 25 d on feed (P < 0.05) and were 35 kg heavier (P < 0.01) at harvest than British-Brahman steers. Simbrah-sired steers were 52 kg heavier (P < 0.01) at harvest than Gelbray-sired steers when fed for a similar number of days (211 vs 203 d). However, straightbred Simbrah steers required an additional 12 d on feed (P < 0.01) and weighed 47 kg more (P < 0.01) than Simbrah-sired crossbred steers. The economic value of the heavier calf weaning weights may be offset by the attendant larger cow size of the Continental-Brahman compared to the British-Brahman breeds. Similarly, the heavier weights of Continental-Brahman compared to British-Brahman steers, when harvested at a prescribed level of fatness may be viewed as a benefit, but the increased number of requisite days in the feedlot is a disadvantage.

Animal Feed↗
PubMed2005

Sexually dimorphic expression of the X-linked gene Eif2s3x mRNA but not protein in mouse brain.

Higher expression of X-linked genes in females might contribute to brain sexual differentiation. Although X-inactivation is thought to balance gene dosage between the two sexes, some X-linked genes escape X inactivation and therefore are expressed from both X chromosomes in females. Eif2s3x encodes subunit three of eukaryotic translation initiation factor 2, which regulates the rate of protein translation, and escapes X-inactivation in both humans and mice. By Northern blot analysis, we found Eif2s3x to be expressed higher in females than in males in developing and adult brains as well as adult liver. Gonadally intact XX mice had a higher level of Eif2s3x mRNA expression than XY mice regardless of whether they had testes or ovaries, suggesting that sexually dimorphic gene expression arises as a consequence of sex chromosome complement. In situ hybridization indicated that Eif2s3x mRNA was expressed preferentially in specific brain regions including the habenula, anterodorsal thalamic nucleus, hippocampus, hypothalamus, and cerebellum. Females had significantly higher levels of Eif2s3x mRNA expression than males in cortex, hippocampus and paraventricular nucleus but not in the habenula. The effect of a sex difference in Eif2s3x transcription, however, could potentially be offset by the additional expression in male brains of its Y-linked homologue Eif2s3y which was found in similar brain regions. The sex difference in Eif2s3x transcript appears not to be preserved at the protein level, since no difference in the levels of Eif2s3 protein was found between (1) males and females (2) XX and XY mice, or (3) XO and XX females.

Animals↗
PubMed2003

Hypobaric biology: Arabidopsis gene expression at low atmospheric pressure.

As a step in developing an understanding of plant adaptation to low atmospheric pressures, we have identified genes central to the initial response of Arabidopsis to hypobaria. Exposure of plants to an atmosphere of 10 kPa compared with the sea-level pressure of 101 kPa resulted in the significant differential expression of more than 200 genes between the two treatments. Less than one-half of the genes induced by hypobaria are similarly affected by hypoxia, suggesting that response to hypobaria is unique and is more complex than an adaptation to the reduced partial pressure of oxygen inherent to hypobaric environments. In addition, the suites of genes induced by hypobaria confirm that water movement is a paramount issue at low atmospheric pressures, because many of gene products intersect abscisic acid-related, drought-induced pathways. A motivational constituent of these experiments is the need to address the National Aeronautics and Space Administration's plans to include plants as integral components of advanced life support systems. The design of bioregenerative life support systems seeks to maximize productivity within structures engineered to minimize mass and resource consumption. Currently, there are severe limitations to producing Earth-orbital, lunar, or Martian plant growth facilities that contain Earth-normal atmospheric pressures within light, transparent structures. However, some engineering limitations can be offset by growing plants in reduced atmospheric pressures. Characterization of the hypobaric response can therefore provide data to guide systems engineering development for bioregenerative life support, as well as lead to fundamental insights into aspects of desiccation metabolism and the means by which plants monitor water relations.

Adaptation, Physiological↗
PubMed2004

Compensation of corneal horizontal/vertical astigmatism, lateral coma, and spherical aberration by internal optics of the eye.

Both the anterior surface of the cornea and the internal optics (the posterior cornea, crystalline lens) contribute to the aberration of a wavefront passing through the eye. Artal, Guirao, Berrio, and Williams (2001) reported that the wavefront aberrations produced by the internal optics offset, or compensate for, the aberrations produced by the cornea to reduce ocular wavefront aberrations. We have investigated the wavefront aberrations of the cornea, internal optics, and complete eye on both the population and individual level to determine which aberrations are compensated and probable paths leading to that compensation. The corneal and ocular aberrations of 30 young subjects at relaxed accommodation were measured with the Topcon Wavefront Analyzer, which simultaneously measures refraction, corneal topography (videokeratoscope), and wavefront aberrations (Hartmann-Shack sensor). We found strong evidence for compensation of horizontal/vertical (H/V) astigmatism (Zernike term Z5) lateral coma (Z8) and spherical aberration (Z12). H/V astigmatism compensation is scaled for each individual, suggesting that it is actively determined by a fine-tuning process. Spherical aberration shows no individual compensation, suggesting that is a passive result of genetically determined physiology. Lateral coma shows individually scaled compensation, some of which may be attributable to eccentricity of the fovea.

Accommodation, Ocular↗
PubMed1994

Inferior colliculus neuronal membrane and synaptic properties in genetically epilepsy-prone rats.

Previous studies using single-unit recording techniques have shown that the inferior colliculus is critical for audiogenic seizure initiation in genetically epilepsy-prone rats (GEPR). In order to investigate cellular abnormalities that may be important in causing audiogenic seizure susceptibility, intracellular recordings were made from neurons of inferior colliculus dorsal cortex (ICd) in a GEPR variety that exhibits severe audiogenic seizures (GEPR-9). GEPR neuronal membrane and synaptic properties were compared to those of normal Sprague-Dawley rats (SD), the strain from which GEPR were derived. We found six electrophysiological differences between GEPR and normal SD ICd neurons, all of which could promote seizures in GEPR. (1) Input resistance was higher in GEPR than in normal ICd neurons. (2) Threshold for repetitive action potential firing was closer to resting membrane potential in GEPR ICd neurons. (3) GEPR neurons showed faster repetitive spike firing than normal SD neurons. (4) Anode break spikes occurred at the offset of a hyperpolarizing pulse more often in GEPR than in normal SD neurons. (5) Stimulation of the commissure of the inferior colliculus caused synaptic paired pulse inhibition in normal ICd neurons, but paired pulse facilitation was always observed in GEPR neurons. (6) In GEPR, a large epileptiform depolarizing event could be elicited by strong electrical stimulation of the commissure of the inferior colliculus. In normal SD rats, similar epileptiform activity was seen only after application of bicuculline or NMDA. Our results suggest that both abnormal neuronal membrane properties and altered synaptic transmission are likely to contribute to seizure predisposition and audiogenic seizure initiation in GEPR.

Acoustic Stimulation↗
PubMed1995

Concept of bridging the gap from youth to adulthood.

Clinical atherosclerotic cardiovascular disease reaches substantial incidence beginning at age 45 years in men and age 55 years in women but has its onset in childhood. Lesions progress in relation to exposure to identified risk factors and, once initiated, tend to be self-perpetuating. Because predisposing factors are often initiated in childhood, interventions beginning early in life are optimal for prevention of adult disease. Even genetically predisposed people usually require an unfavorable lifestyle for the atherogenic trait to be expressed. No combination of risk factors entirely accounts for the increase in clinical atherosclerotic events with advancing age. This may be a reflection of longer exposure to risk factors or impaired ability to cope with them in advanced age. The declining risk factor risk ratios with advancing age may be a consequence of the selective early removal of those most susceptible from the population at risk. Risk of major cardiovascular events increases about 2.5-fold with each 10 years of age, even in people without major risk factors who are considered at low risk for atherosclerotic cardiovascular events. However, at any age vulnerability to cardiovascular events is strongly influenced by the burden of risk factors. Decreased risk ratios with advanced age are offset by a greater absolute risk. The female advantage over men erodes with age, with the menopause and with acquisition of an unfavorable lipid profile and glucose intolerance.

Adult↗
PubMedDate not supplied

The impact of requirements for parental consent on minors' abortions in Mississippi.

Mississippi data for 1993 indicate that the state's new parental consent requirement had little effect on the abortion rate among minors. In a comparison of Mississippi residents who had abortions during the five months before and the six months after the law went into effect, the ratio of minors to adults who sought abortions in the state declined by 13%, a decrease offset by a 32% increase in the ratio of minors to adults who obtained abortions out of state. There was also a 28% drop in the ratio of minors to adults from other states who had abortions in Mississippi. The parental consent requirement increased by 19% the ratio of minors to adults who obtained their procedure after 12 weeks of gestation.

Abortion Applicants↗
PubMed2002

Biomechanics of bone: determinants of skeletal fragility and bone quality.

Bone fragility can be defined by biomechanical parameters, including ultimate force (a measure of strength), ultimate displacement (reciprocal of brittleness) and work to failure (energy absorption). Bone fragility is influenced by bone size, shape, architecture and tissue 'quality'. Many osteoporosis treatments build bone mass but also change tissue quality. Antiresorptive therapies, such as bisphosphonates, substantially reduce bone turnover, impairing microdamage repair and causing increased bone mineralization, which can increase the brittleness of bone. Anabolic therapies, such as parathyroid hormone (PTH-(1-84)) or teriparatide (PTH-( 1-34)), increase bone turnover and porosity, which offset some of the positive effects on bone strength. Osteoporosis therapies may also affect bone architecture by causing the redistribution of bone structure. Restructuring of bone during treatment may change bone fragility, even in the absence of drug effects on bone mineral density (BMD). This effect may explain why some drugs can affect fracture incidence disproportionately to changes in BMD. For instance, in a recent clinical trial, PTH-(1-34) therapy caused a dose-related increase in spinal BMD without any dose-dependent effect on the observed decrease in spinal fracture incidence. This apparent disassociation between spinal BMD and bone fragility is probably due to effects of PTH-(1-34) on bone architecture within vertebral bodies. While it has been shown that BMD is highly heritable, bone mineral distribution and architecture are also under strong genetic influence. Recent findings suggest that different genes regulate trabecular and cortical structures within lumbar vertebrae, producing a wide range of bone architectural designs. These findings suggest that there is no single optimal bone architecture; instead many different architectural solutions produce adequate bone strength.

Biomechanical Phenomena↗
PubMed2004

Bile acid-induced negative feedback regulation of the human ileal bile acid transporter.

Ileal expression of the apical sodium-dependent bile acid transporter (ASBT) in the rat is unaffected by bile salts, yet in the mouse it is under negative-feedback regulation. The bile acid responsiveness of human ASBT is unknown. The human ASBT promoter linked to a luciferase reporter was studied in Caco-2 cells treated with chenodeoxycholic acid (CDCA) and transfected with expression plasmids for farnesoid X-receptor (FXR), short heterodimer partner (SHP), and retinoic acid receptor/retinoid X receptor (RAR/RXR). CDCA treatment of Caco-2 cells led to a 75% reduction in steady-state ASBT messenger RNA levels and a 78% reduction in human ASBT promoter activity. A dominant negative FXR abrogated the response to CDCA. Site-directed mutagenesis of an RAR/RXR cis element in the human ASBT promoter reduced its activity by 50% and eliminated the bile acid response. Retinoic acid activated the human ASBT promoter fourfold. SHP repressed the activity of the ASBT promoter and reduced activation by retinoic acid. Antisense mediated knock-down of SHP in Caco-2 cells partially offset the bile acid mediated repression of ASBT promoter activity. In conclusion, the human ASBT is positively regulated by retinoic acid. Bile acids induce a negative feedback regulation of human ASBT via an FXR-mediated, SHP-dependent effect upon RAR/RXR activation of ASBT.

Base Sequence↗
PubMed1997

Effects of aging on the circadian rhythm of wheel-running activity in C57BL/6 mice.

The effects of age on the circadian clock system have been extensively studied, mainly in two rodent species, the laboratory rat and the golden hamster. However, less information is available on how aging alters circadian rhythmicity in a commonly studied rodent animal model, the mouse. Therefore, in the present study we compared the rhythm of wheel-running activity in adult (6-9 mo) and old (19-22 mo) C57BL/6J mice maintained under different lighting conditions for a period of 4 mo. During this period, mice were subjected to phase advances and phase delays of the light-dark (LD) cycle and eventually to constant darkness (DD). In LD (12 h light, 12 h dark), old mice exhibited delayed activity onset relative to light offset and an increase in the variability of activity onset compared with adult mice. After a 4-h phase advance of the LD cycle, old mice took significantly longer to reentrain their activity rhythm when compared with adult animals. Old mice also demonstrated a decline in the number of wheel revolutions per day and a tendency toward a decrease in the length of the active phase. An increase in fragmentation of activity across the 24-h day was obvious in aging animals, with bouts of activity being shorter and longer rest periods intervening between them. No age difference was detected in the maximum intensity of wheel-running activity. In DD, the free-running period was significantly longer in old mice compared with adults. In view of the rapidly expanding importance of the laboratory mouse for molecular and genetic studies of the mammalian nervous system, the present results provide a basis at the phenotypic level to begin to apply genetic methods to the analysis of circadian rhythms and aging in mammals.

Aging↗
PubMed1996

Effects of insulin, epinephrine, and glucose on regulation of transcription of the serine dehydratase gene in newborn dogs.

Our previous investigation showed that hyperinsulinemia incompletely suppressed the transcription of the gene encoding L-serine dehydratase (SDH) (EC 4.2.1.13), a gluconeogenic enzyme, in newborn dogs. To test another hypothesis that insulin resistance in newborn mammals may be partially due to counterregulatory factors, such as epinephrine, euglycemic hyperinsulinemic clamps, hyperglycemic hyperinsulinemic clamps, and hyperglycemic hyperinsulinemic hyperepinephrinemic clamps were performed in newborn dogs in the present study. The infusion rates of insulin and epinephrine were 30 m U/kg/min and 150 ng/kg/min, respectively; the glucose infusion rate was adjustable. The SDH mRNA levels in kidney and liver of newborn dogs were quantitatively analyzed by using rat SDH cDNA probe and by a personal densitometer. The results showed that insulins, glucose, and epinephrine did not change the kidney SDH mRNA level; hyperinsulinemia and hyperglycemia reduced the liver SDH mRNA level by 8.5 and 29.2%, respectively; in the presence of hyperglycemia and hyperinsulinemia, epinephrine was able to increase the liver SDH mRNA by 27.8%, almost offsetting the reduction of the liver SDH mRNA level induced by the combination of insulin and glucose. We conclude that the enhanced regulatory effect of epinephrine counteracting insulin on SDH gene transcription in liver of newborn dogs may be one of the mechanisms responsible for the neonatal insulin resistance which contributes to neonatal hyperglycemia.

Animals↗
PubMed1993

Decrease in locus coeruleus [3H]idazoxan binding site density in genetically epilepsy-prone (GEPR) rats.

Deficits in norepinephrine synthesis, transmitter level, turnover and reuptake have been reported in the brain of genetically epilepsy-prone (GEPR) rats. We investigated the hypothesis that these alterations may trigger a compensatory downregulation of locus coeruleus alpha 2-adrenergic receptors and an upregulation of postsynaptic alpha 2-adrenergic receptor density in forebrain regions of GEPR rat brain. alpha 2-adrenergic receptor density was measured in the locus coeruleus and 7 forebrain regions of control and GEPR rats by in vitro [3H]idazoxan autoradiography. Specific [3H]idazoxan binding site density was decreased significantly in the locus coeruleus of both GEPR-3 and GEPR-9 rats compared to controls. No significant differences in specific [3H]idazoxan binding were observed in the 7 forebrain regions of GEPR-9 rats compared to control. Reduced locus coeruleus alpha 2-adrenergic receptor density in GEPR rats may produce a net increase in locus coeruleus noradrenergic cell firing, an effect which could, in part, offset the impact of reduced noradrenergic influence in GEPR rat forebrain. Additionally, decreased norepinephrine levels in GEPR rat brain may be a long-term consequence of reduced alpha 2-adrenergic receptor-mediated inhibition of locus coeruleus firing activity.

Adrenergic alpha-Antagonists↗