References

Urquhart M, Reyes BAS, Thomas SA, Mackie K, Van Bockstaele EJ (2016) Diacylglycerol lipase-α expression increases in the coeruleo-cortical pathway in dopamine-β-hydroxylase knockout mice as well as rats treated with DSP-4. Neuroscience 2016 Abstracts 77.09 / AAA24. Society for Neuroscience, San Diego, CA.

Summary: Endocannabinoids are involved in the regulation of many physiological processes including behavioral responses to stress. Endocannabinoids modulate norepinephrine (NE) signaling primarily via involvement of CB1 cannabinoid receptors (CB1r). Our previous studies have shown that acute and repeated administration of a CB1r agonist increases multiple indices of noradrenergic activity involving the locus coeruleus (LC)-frontal cortex (FC) pathway. Diacylglycerol lipase-α (DGL-α), a key enzyme in the biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG) is localized to both the FC and the LC. Using electron microscopy, we have recently shown that in the rat FC DGL-α is localized in postsynaptic profiles that are targeted by dopamine-β-hydroxylase (DβH), the enzyme that converts dopamine to norepinephrine and represents a marker of noradrenergic neurons (Hartman et al., 1972). In this study, we also described interactions between DGL-α, CB1r and DβH in the FC using confocal microscopy. In the present study, we investigated expression levels of DGL-α under two conditions of NE deletion: in a rat model using a systemic injection of saporin conjugated with antibody against DβH (DSP-4) and in a genetically engineered mouse that lacked the enzyme DβH (DβH-knockout, KO). We compared expression levels of DGL-α to either control rats or wild type (WT) mice using Western blot analysis. Protein extracts from micropunches of FC and LC were obtained and probed for DGL-α. Results showed that DGL-α expression was significantly increased in FC (P < 0.05) of both DSP-4 treated rats and DβHKO mice when compared to WT mice. DGL-α expression was also significantly increased in the LC (P < 0.05) of DβHKO when compared to WT mice. These data add to the accumulating evidence that dysregulation of NE transmission results in significant adaptations in the brain endocannabinoid system.

Related Products: Anti-DBH-SAP (Cat. #IT-03)

Naylor R, McGhee C, Cowan C, Davidson A, Holm T, Sherwin T (2016) Derivation of corneal keratocyte-like cells from human induced pluripotent stem cells. PLoS One 11:e0165464. doi: 10.1371/journal.pone.0165464 PMID: 27792791

Summary: Slides containing cryosections were dried overnight at 4°C and then washed twice in Tris Buffered Saline containing 0.1% Triton X100 (TBST). Slides were then placed in block solution (3% BSA, 5% Goat serum in TBST) for at least one hour. The primary antibody was then applied in the same block solution (1:100) and left overnight at 4°C.

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Benn A, Robinson E (2017) Differential roles for cortical versus sub-cortical noradrenaline and modulation of impulsivity in the rat. Psychopharmacology (Berl) 234:255-266.. doi: 10.1007/s00213-016-4458-8

Summary: Atomoxetine is a noradrenaline re-uptake inhibitor licensed for the treatment of adult and childhood attention deficit hyperactivity disorder. Although atomoxetine has established efficacy, the mechanisms which mediate its effects are not well understood. In this study, the authors investigated the role of cortical versus sub-cortical noradrenaline by using focal dopamine beta hydroxylase-saporin-induced lesions, to the prefrontal cortex (PFC) or nucleus accumbens shell (NAcSh). Male Lister hooded rats received bilateral lesions by using stereotaxic injections of the immunotoxin Anti-DβH-SAP (Cat. #IT-03), 0.02 μg in 0.5 μL per injection into the PFC and 0.004 μg in 0.2 μL per injection for NAcSh lesions. The data suggest that noradrenaline in the nucleus accumbens shell plays an important role in the effects of atomoxetine. Under these conditions, prefrontal cortex noradrenaline did not appear to contribute to atomoxetine’s effects suggesting a lack of cortical-mediated “top-down” modulation. Noradrenaline in the prefrontal cortex appears to contribute to the modulation of impulsive responding in amphetamine-treated animals, with a loss of noradrenaline associated with potentiation of its effects. These data demonstrate a potential dissociation between cortical and sub-cortical noradrenergic mechanisms and impulse control in terms of the actions of atomoxetine and amphetamine.

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Nam H, Kerman I (2016) A2 noradrenergic neurons regulate forced swim test immobility. Physiol Behav 165:339-349. doi: 10.1016/j.physbeh.2016.08.020

Summary: Wistar-Kyoto rats are often used as a model of depression, and exhibit high levels of immobility when subjected to a forced swim test (FST). Researchers discovered relative hyperactivation in the locus coeruleus of WKY rats compared to the genetically related Wistar rats when exposed to one- and two-day FSTs. Lesser activation of A2 noradrenergic cell group was seen by diminished levels of FOS after both days of the FST. A2 noradrenergic neurons of Winstar rats were lesioned by injecting 2.2 ug of Anti-DBH-SAP (Cat. #IT-03) into the nucleus tractus solitaris (NTS). Lesioned rats exhibited increased FST immobility on both days of the test, similar to natural WKY behavior in the same test. These data indicate that the A2 noradrenergic cell group regulates FST behavior and that its hypoactivation may contribute to the unique behavioral phenotype of WKY rats.

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Kaushal R, Taylor B, Jamal A, Zhang L, Ma F, Donahue R, Westlund K (2016) GABA-A receptor activity in the noradrenergic locus coeruleus drives trigeminal neuropathic pain in the rat; contribution of NAα1 receptors in the medial prefrontal cortex. Neuroscience 334:148-159. doi: 10.1016/j.neuroscience.2016.08.005

Summary: The goal of this study was to investigate the role of the locus coeruleus (LC) in a rat orofacial pain model of trigeminal neuropathy induced by chronic constrictive injury of the infraorbital nerve (CCI-ION). Mechanical thresholds to von Frey filaments were tested on whisker pads to evaluate neuropathic pain behavior; pain was indicated by development of mechanical hypersensitivity. Noradrenergic (NA) neurons were lesioned with 5-mcg injections of Anti-DBH-SAP (Cat. #IT-03) into the left lateral ventricle. Mouse-IgG-SAP (Cat. #IT-18) was used as a control. After ablation of NA neurons there was a notable increase in the mechanical threshold compared to control animals. They also targeted coeruleotrigeminal NA neurons by injecting Anti-DBH-SAP into the trigeminal brainstem nuclei bilaterally in one animal and saw similar results. Injecting a GABAA receptor antagonist into the LC after injury had an inhibitory effect on nerve injury induced hypersensitivity. Injection of a NAα1 receptor antagonist, but not a NAα2 receptor antagonist, into the medial prefrontal cortex (mPFC) alleviates mechanical hypersensitivity. They conclude that GABAA-mediated activation of NA neurons during CCI-ION can facilitate hypersensitivity through NAα1 receptors in the mPFC, and that the LC is a chronic pain generator.

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Kang BR, Yang SH, Chung BR, Kim W, Kim Y (2016) Cell surface GRP78 as a biomarker and target for suppressing glioma cells. Sci Rep 6:34922. doi: 10.1038/srep34922. PMID: 27713511

Summary: The publication discusses the identification of cell surface GRP78 as a promising biomarker for glioma, a type of brain tumor. Furthermore, it highlights the potential of targeting cell surface GRP78 as a strategy to suppress glioma cells, offering new insights into the development of therapeutic approaches for this challenging disease.

Kumar JR, Rajkumar R, Lee LC, Dawe GS (2016) Featured Article: Targeted lesioning reveals role of nucleus incertus in the anxiogenic effect of buspirone. Targeting Trends 17(4)

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Read the featured article in Targeting Trends.

See Also:

• Kumar J et al. Nucleus incertus contributes to an anxiogenic effect of buspirone in rats: Involvement of 5-HT1A receptors. Neuropharmacology 110:1-14, 2016.

Paban V, Valable S, Baril N, Gilbert V, Chambon C, & Alescio-Lautier B (2016) Neuronal and glial changes in rat hippocampal formation after cholinergic deafferentation. J Biomol Res Ther 5(3):1000147. doi: 10.4172/2167-7956.1000147

Summary: The effects of cholinergic insult were studied in the hippocampal formation of cholinergic lesioned rats at metabolic and cellular levels by in vivo nuclear magnetic resonance spectrometry and immuno-histochemical approaches.

Usage: Cholinergic deafferentation was induced by injection of the cholinergic immunotoxin 192-IgG-SAP into the medial septum (37.5 ng/side).

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Cai Y, Chew C, Muñoz F, Sengelaub D (2017) Neuroprotective effects of testosterone metabolites and dependency on receptor action on the morphology of somatic motoneurons following the death of neighboring motoneurons. Dev Neurobiol 77:691-707.. doi: 10.1002/dneu.22445

Summary: In this study the authors examined whether the protective effects of testosterone could be mediated via its androgenic or estrogenic metabolites and if these neuroprotective effects were mediated through steroid hormone receptors. Analysis was done using receptor antagonists to attempt to prevent the neuroprotective effects of hormones after partial motoneuron depletion. These motoneurons were selectively killed by intramuscular injection of CTB-SAP (2 ul, 0.1%) (Cat. #IT-14). Compared with intact normal animals, partial motoneuron depletion resulted in decreased dendritic length in remaining quadriceps motoneurons. Dendritic atrophy was attenuated with both dihydrotestosterone and estradiol treatment to a degree similar to that seen with testosterone and attenuation of atrophy was prevented by receptor blockade. Together, the results suggest that neuroprotective effects on motoneurons can be mediated by either androgenic or estrogenic hormones and require action via steroid hormone receptors, further supporting a role for hormones as neurotherapeutic agents in the injured nervous system.

Related Products: CTB-SAP (Cat. #IT-14)

Ueki Y, Ramirez G, Salcedo E, Stabio ME, Lefcort F (2016) Loss of Ikbkap causes slow, progressive retinal degeneration in a mouse model of familial dysautonomia. eNeuro 3:ENEURO.0143-0116.2016. doi: 10.1523/eneuro.0143-16.2016 PMID: 27699209

Summary: Familial dysautonomia (FD) is an autosomal recessive congenital neuropathy that is caused by a mutation in the gene for inhibitor of kappa B kinase complex-associated protein (IKBKAP). A classic hallmark of the disease is progressive blindness marked by retinal ganglion cell (RGC) loss and optic nerve atrophy. To investigate the consequences of Ikbkap loss in the retina, we generated Ikbkap conditional knockout mice using TUBA1a-Cre. Our data demonstrate that this is a powerful model system that faithfully recapitulates the phenotype and progression of FD blindness.

Usage: Immunohistochemistry

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