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The brainstem noradrenergic systems in stress, anxiety, and depression.
Itoi K, Sugimoto N (2010) The brainstem noradrenergic systems in stress, anxiety, and depression. J Neuroendocrinol 22(5):355-361. doi: 10.1111/j.1365-2826.2010.01988.x
Summary: In this review the authors examine the relationship between the central noradrenergic system, fear/anxiety states, and depression. The use of anti-DBH-SAP (Cat. #IT-03) to investigate the function of the noradrenergic system in these paradigms is described.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
Recent progress in research on ribosome inactivating proteins.
Ng TB, Wong JH, Wang H (2010) Recent progress in research on ribosome inactivating proteins. Curr Protein Pept Sci 11(1):37-53. doi: 10.2174/138920310790274662
Summary: This review discusses recent literature on ribosome inactivating proteins including the use of saporin-based conjugates in neuroscience and cancer research. Brief descriptions of research done using 192-IgG-SAP (Cat. #IT-01), OX7-SAP (Cat. #IT-02), dermorphin-SAP (Cat. #IT-12), anti-SERT-SAP (Cat. #IT-23), SSP-SAP (Cat. #IT-11), anti-DBH-SAP (Cat. #IT-03), CTB-SAP (Cat. #IT-14), and other conjugates are provided along with basic information about ribosome inactivating proteins.
Related Products: 192-IgG-SAP (Cat. #IT-01), OX7-SAP (Cat. #IT-02), Dermorphin-SAP / MOR-SAP (Cat. #IT-12), Anti-SERT-SAP (Cat. #IT-23), SSP-SAP (Cat. #IT-11), Anti-DBH-SAP (Cat. #IT-03), CTB-SAP (Cat. #IT-14)
Role of brainstem noradrenergic neurons in modulation of operant nocifensive responses to heat: Pharmacology and hyperalgesia.
Chatterjee K, Kline IV RH, Wiley RG (2009) Role of brainstem noradrenergic neurons in modulation of operant nocifensive responses to heat: Pharmacology and hyperalgesia. Neuroscience 2009 Abstracts 855.10/X15. Society for Neuroscience, Chicago, IL.
Summary: Many spinal dorsal horn neurons are under direct modulation from various brainstem nuclei which act to modulate nociceptive activity. Nocifensive reflex response modulation by spinally projecting noradrenergic brainstem nuclei has been extensively categorized. Strong evidence supports a role for these neurons in the modulation of reflex nocifensive responses but the role of noradrenergic neurons in the cerebral component of nociception remains to be defined in rats. In the present study, we sought to determine the effects of selectively destroying noradrenergic rostral brainstem neurons (A5,A6,A7) on operant escape from 44°C floor heat under several conditions: 1-baseline (after i.c.v. toxin/vehicle injection), 2- after s.c. injection of morphine, clonidine or yohimbine, 3- three hours after bilateral dorsal hindpaw application of mustard oil (secondary hyperalgesia), and 3- three hours after bilateral plantar application of 0.9% capsaicin cream (primary hyperalgesia). Rats were tested daily until steady operant escape responding (~1 month), then injected i.c.v. with 10µl of PBS (vehicle control, n=8) or antiDBH-saporin (10µg, n=8). After recovery from toxin injection, escape responses decreased in the antiDBH-sap rats. Morphine (0, 0.5, 1.0, 2.0 mg/kg s.c.) 20 min prior to testing, dose dependently attenuated escape from the noxious thermal plate at 44oC for all treatment groups. antiDBH-sap treated rats, however, showed an enhanced morphine effect (more prolonged occupancy of the noxious thermal plate). Three hours after plantar capsaicin, or mustard oil to the dorsal surface of both hindpaws, PBS but not antiDBH-sap rats showed enhanced escape. Systemic clonidine (0.125mg/kg) decreased escape for both PBS and antiDBH-sap treated rats, but the anti-nociceptive effect was greater in antiDBH-sap rats. Systemic yohimbine (1.0, 2.5, 5.0mg/kg) had no effect on escape in antiDBH-sap rats but enhanced escape in PBS rats. In direct contrast to effects on escape responding, antiDBH-sap did not affect hotplate lick/guard initial latencies to nociceptive heat at 44° or 47oC. Escape responses to aversively bright light were also decreased in antiDBH-sap rats suggesting generally decreased responsiveness to aversive stimuli. These results support a significant role for rostral brainstem noradrenergic neurons in modulation of pain and highlight important differences between reflex nocifensive responses (hotplate) and operant (escape) responses.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
Immunotoxic lesion of hypothalamic noradrenergic/adrenergic input ameliorates the effects of peripheral LPS challenge on sickness behavior and associated brain c-Fos expression
Gaykema RP, Thacker GC, Shapiro NJ, Goehler LE (2009) Immunotoxic lesion of hypothalamic noradrenergic/adrenergic input ameliorates the effects of peripheral LPS challenge on sickness behavior and associated brain c-Fos expression. Neuroscience 2009 Abstracts 570.11/EE120. Society for Neuroscience, Chicago, IL.
Summary: Caudal medullary catecholamine neurons that innervate the hypothalamus play a major role in the activation of paraventricular neurons that drive pituitary adrenocorticotropin and adrenal corticosteroid release in response to peripheral pro-inflammatory challenges with interleukin-1 or lipopolysaccharide (LPS). Pro-inflammatory challenges also lead to marked behavioral changes, including fatigue, loss of social interest, anorexia, somnolence, but the precise neuronal mechanisms that underlie sickness behavior remain elusive. We reasoned that the medulla-hypothalamic catecholaminergic pathway may also contribute to the behavioral manifestations in illness. To investigate such possible role, we applied a targeted lesion approach in rats to determine whether or not caudal brainstem catecholaminergic neurons that innervate the hypothalamus are also necessary for the expression of sickness behavior. Anti-dopamine beta hydroxylase antibodies conjugated to saporin (DSAP), when injected into a target region, selectively poisons and destroy noradrenergic/adrenergic neurons that innervate the target. DSAP was micro-injected bilaterally into the hypothalamic paraventricular nucleus (PVN), whereas control rats received unconjugated saporin (SAP controls). Fourteen days later the animals were injected intraperitoneally with either LPS or saline, and 2h later were submitted to the open field to record their exploratory behavior, 1h after which the rats were sacrificed for brain immunohistochemical analyses. LPS-treated SAP control rats showed drastic reduction in exploratory behavior (reduced locomotion distance and velocity). Prior DSAP microinjections largely reversed the LPS-induced reduction in locomotor behavior. The brains of these DSAP rats showed a dramatic loss of noradrenergic innervation of the PVN but also in other parts of the medial, tuberal and tuberomammilary regions of the hypothalamus. The behavioral resilience to LPS coincided with diminished LPS-related c-Fos staining in the PVN, and increased c-Fos staining in the lateral and tuberomammillary regions related to behavior and/or arousal. In summary, our findings support the hypothesis that hypothalamic catecholaminergic projections originating in the lower brainstem play a critical role in the expression of sickness behavior in the context of novelty-induced exploratory activity, but we cannot determine with precision in which part of the hypothalamus the noradrenergic/adrenergic input contributes to the expression of sickness behavior due to extensive collateralization of the ascending projections throughout the hypothalamus.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
The role of limbic norepinephrine in cannabinoid-induced aversion.
Carvalho AF, Reyes AS, Van Bockstaele EJ (2009) The role of limbic norepinephrine in cannabinoid-induced aversion. Neuroscience 2009 Abstracts 449.3/V29. Society for Neuroscience, Chicago, IL.
Summary: The endocannabinoid system has been implicated in diverse physiological mechanisms including modulation of pain and analgesia, learning and memory and feeding, among others. Thus, targeting the cannabinoid system has risen to the forefront in the development of novel treatments for a number of pathophysiological processes. Consistent with this, agonists of the cannabinoid receptor type 1 (CB1R) have been successfully used in the treatment of severe anorexia in patients with AIDS and in alleviating nausea and vomiting in patients undergoing chemotherapy. However, significant side effects have been observed in clinical trials raising concerns regarding the potential clinical utility of cannabinoid-based agents. Disturbances in mood and affect, including paranoia, anxiety and nervousness, have been reported in patients. Understanding the neural circuits and neurochemical substrates impacted by cannabinoids will provide a better means of gauging their actions within the central nervous system that contribute to the expression of unwanted side effects. We have previously shown an increase in anxiety-like behaviors in rats receiving repeated administration of cannabinoid agonists. This increase in anxiety was accompanied by increases in indices of noradrenergic activity. In the present study, we investigated whether norepinephrine in the limbic forebrain of rats is required for cannabinoid-induced aversion using an immunotoxin lesion approach combined with behavioral analysis using a place conditioning paradigm. Male Sprague Dawley rats received bilateral injections of a ribosomal toxin, saporin (SAP) conjugated to an antibody that specifically recognizes the enzyme dopamine-beta-hydroxylase (DSAP), into the limbic forebrain. Control rats received saporin alone. As previously reported, administration of the synthetic cannabinoid receptor agonist, WIN 55,212-2 (3.0mg/kg), induced aversion in a place conditioning paradigm in SAP-only treated rats. The rats’ spatial memory was also evaluated using the Morris Water Maze. Depletion of norepinephrine using DSAP in specific limbic regions impaired cannabinoid-induced aversion to WIN 55,212-2 without affecting learning and memory processes. Taken together, noradrenergic projections to the limbic forebrain may be critical in the manifestation of aversive behaviors associated with cannabinoid agonist exposure.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
Role of A2 noradrenergic neurons and angiotensinergic mechanisms on hypotension induced by hemorrhage.
Freiria-Oliveira AH, Blanch GT, De Paula PM, Colombari E, Menani JV, Colombari DS (2009) Role of A2 noradrenergic neurons and angiotensinergic mechanisms on hypotension induced by hemorrhage. Neuroscience 2009 Abstracts 467.18/DD70. Society for Neuroscience, Chicago, IL.
Summary: The A2 catecholaminergic neurons in the commissural subdivision of the nucleus tractus solitarii (cNTS) are activated by hemorrhage. However, the role of these neurons on the cardiovascular adjustments to hemorrhage is not fully understood. In the present study we investigated the effects of A2 noradrenergic neuron lesion alone or combined with the blockade of angiotensinergic mechanisms on the recovery of blood pressure after hemorrhage. Male Holtzman rats (280-320 g) anesthetized with ketamine combined with xylazine were submitted to lesions of dopamine-beta-hydroxilase (DβH)-containing neurons in the cNTS achieved with injections of anti-DβH-saporin (12.6 ng/60 nl, n=6-8) or sham lesions (injection of immunoglobulin-G-saporin, 12.6 ng/60 nl, n=6). Changes in blood pressure to hemorrhage were tested 30 days after lesions. Immunohistochemistry for tyrosine-hydroxilase was performed to confirm the efficacy of DβH neuron lesion in the cNTS. Two days before tests, femoral artery and vein were cannulated under ketamine and xylazine anesthesia. Hemorrhage consisted in four blood withdrawals (2 ml/300 g body weight, every 10 min) in conscious rats. Immediately after the 4th blood withdrawal, the hypotension was similar in A2-lesioned and sham-lesioned rats (-62 ± 7 mmHg and -73±7 mmHg, respectively). However, A2-lesioned rats rapidly (20 min) recovered from hypotension (-7±2 mmHg), while sham rats did not completely recover from hypotension until the end of experiment (60 min after the 4th blood withdrawn, -20±3 mmHg). The pre-treatment with losartan (angiotensin type 1 receptor antagonist, 10 mg/kg of body weight, iv) impaired the recovery of blood pressure by A2-lesioned rats (-29 ± 4 mmHg and -28 ± 3 mmHg, 20 and 60 min after the 4th blood withdrawal). In sham rats, the treatment with losartan also reduced the partial recovery of blood pressure at the end of the test (-39±6 mmHg, vs. sham control: -20±3mmHg), however, losartan did not affect the hypotension 20 min after the 4th blood withdrawal (-30± 6 mmHg vs. sham control: -35 ± 9 mmHg). The results suggest that A2 noradrenergic neuron lesion in the cNTS facilitates the recovery of hypotension after hemorrhage, probably increasing the action of angiotensinergic mechanisms.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
Caudal hindbrain catecholaminergic projection to the ventrolateral bed nucleus of the stria terminalis (vlBNST): Assessment of role in glucoprivic and CCK feeding responses and corticosterone secretion.
Dinh TT, Huston NJ, Ritter S (2009) Caudal hindbrain catecholaminergic projection to the ventrolateral bed nucleus of the stria terminalis (vlBNST): Assessment of role in glucoprivic and CCK feeding responses and corticosterone secretion. Neuroscience 2009 Abstracts 87.16/CC80. Society for Neuroscience, Chicago, IL.
Summary: Catecholamine neurons in the caudal hindbrain provide a significant innervation of the vlBNST and some of these neurons co-innervate the paraventricular nucleus of the hypothalamus (PVH). We previously found that PVH injections of the retrogradely-transported immunotoxin, anti-dopamine beta hydroxylase (DBH) saporin (anti-DBH-sap), profoundly reduced feeding and corticosterone responses to glucoprivation, but did not alter CCK-induced satiety, which has been linked to catecholamine neurons in the A2 cell group. In this experiment, we examined the origin of the vlBNST/PVH catecholamine projection and assessed its role in responses to glucoprivation and CCK. Retrograde tracing from vlBNST and PVH revealed dually-projecting DBH-ir (norepinephrine or epinephrine) neurons primarily in A2, A1 and caudal C1, with a few cells also present in C2. Dually-projecting PNMT-ir (epinephrine) were also present in C1 and in small numbers in C2. Overall, the relative numbers of DBH- and PMNT-ir neurons with projections to both vlBNST and PVH and the locations of these triply-labeled neurons indicate that the dually-projecting neurons are predominantly noradrenergic. Injections of anti-DBH-sap into the vlBNST produced cell losses in the hindbrain that were anatomically consistent in distribution and number with the tracing results. This immunotoxin caused a loss of DBH neurons in the dorsal hindbrain that was concentrated in the A2 cell group (14.6 – 13.68 mm caudal to bregma), where a maximum of 50% of DBH neurons were lesioned: 50% loss at 14.6 mm caudal to bregma, 25% at 13.24 mm and 0% at 11.96 mm. In ventral hindbrain, loss of DBH cell bodies was predominantly in the A1 cell group (14.6 – 12.8 mm caudal to bregma), where a maximum of 60% of DBH-ir neurons were lesioned: 60% loss at 14.6 and 13.68 mm, 22% at 13.24 and and 0% at 12.8 mm. In the dorsal hindbrain nearly all cells retrogradely labeled from the vlBNST were ipsilateral and DBH-ir. In ventral hindbrain there was a significant contralateral projection to vlBNST that was not DBH-ir. Anti-DBH-sap lesions did not impair the feeding, blood glucose or corticosterone responses to 2-deoxy-D-glucose (250 mg/kg) and did not impair the suppression of feeding by CCK-8 (4 ug/kg), indicating that the catecholamine projection to the vlBNST, including the dually-projecting neurons that innervate both the vlBNST and the PVH, is not required for these responses.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
Nitrous oxide-induced analgesia does not influence nitrous oxide’s immobilizing requirements.
Jinks SL, Carstens E, Antognini JF (2009) Nitrous oxide-induced analgesia does not influence nitrous oxide’s immobilizing requirements. Anesth Analg 109:1111-1116. doi: 10.1213/ANE.0b013e3181b5a2a7
Summary: Noradrenergic neurons in the locus coeruleus (LC) are involved with the analgesic action of nitrous oxide (N2O). In order to examine whether these neurons are also involved with the immobilizing effects of N2O, rats received 4 µg intracerebroventricular injections of anti-DBH-SAP (Cat. #IT-03). Mouse IgG-SAP (Cat. #IT-18) was used as a control. Lesioned animals did not experience the analgesic effects of N2O, but the immobilizing effects were still present. The data demonstrate that the immobilizing mechanism of N2O is independent from its analgesic effects.
Related Products: Anti-DBH-SAP (Cat. #IT-03), Mouse IgG-SAP (Cat. #IT-18)
Photostimulation of retrotrapezoid nucleus phox2b-expressing neurons in vivo produces long-lasting activation of breathing in rats.
Abbott SB, Stornetta RL, Fortuna MG, Depuy SD, West GH, Harris TE, Guyenet PG (2009) Photostimulation of retrotrapezoid nucleus phox2b-expressing neurons in vivo produces long-lasting activation of breathing in rats. J Neurosci 29:5806-5819. doi: 10.1523/JNEUROSCI.1106-09.2009
Summary: The retrotrapezoid nucleus (RTN) contains a subpopulation of cells that are thought to function as central respiratory chemoreceptors. The authors used bilateral 22-ng injections of anti-DBH-SAP (Cat. #IT-03) into the lateral horn of the second thoracic segment to investigate this hypothesis. Coupled with data generated by lentivirus-driven transgenic expression of a light-activated cationic channel, it is demonstrated that noncatecholaminergic neurons in the RTN function as central respiratory chemoreceptors.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
Noradrenergic neurons in the locus coeruleus contribute to neuropathic pain.
Brightwell JJ, Taylor BK (2009) Noradrenergic neurons in the locus coeruleus contribute to neuropathic pain. Neuroscience 160:174-185. doi: 10.1016/j.neuroscience.2009.02.023
Summary: Noradrenergic neurons were eliminated with 5 µg intracerebroventricular injections of anti-DBH-SAP (Cat. #IT-03). Mouse IgG-SAP (Cat. #IT-18) was used as a control. Animals lesioned with anti-DBH-SAP displayed a reduction in behavioral signs of several kinds of allodynia.
Related Products: Anti-DBH-SAP (Cat. #IT-03), Mouse IgG-SAP (Cat. #IT-18)