Targeting Topics 07q1

Ablation of NK1 receptor bearing neurons in the nucleus of the solitary tract blunts cardiovascular reflexes in awake rats.

Abdala AP, Schoorlemmer GH, Colombari E.

Brain Res 1119(1):165-173, 2006.

Cardiovascular function is largely controlled by the nucleus of the tractus solitarius (NTS). This work focuses on the baroreflex, cardiopulmonary chemoreflex, and arterial chemoreflex. Rats were injected with either 20 nl of 2 µM SP-SAP (Cat. #IT-07) into the subpostremal NTS, or 200 nl into the subpostremal and commissural NTS. Saporin (Cat. #PR-01) was used as a control. It was established that NK-1 receptor-expressing neurons in the NTS are critical for these reflexes.

Noradrenergic inputs to the bed nucleus of the stria terminalis and paraventricular nucleus of the hypothalamus underlie hypothalamic-pituitary-adrenal axis but not hypophagic or conditioned avoidance responses to systemic yohimbine.

Banihashemi L, Rinaman L.

J Neurosci 26(44):11442-11453, 2006.

Yohimbine (YO) is an α2 adrenoceptor antagonist that increases transmitter release from adrenergic/noradrenergic (NA) neurons. The authors investigated whether NA inputs to the bed nucleus of the stria terminalis (BNST) were required for YO effects. After receiving 11 ng of anti-DBH-SAP (Cat. #IT-03) in the left and right BNST, rats displayed a marked decrease in the hypothalamic-pituitary-adrenal axis in response to YO administration.

Effects of hypocretin-1 in 192-IgG-saporin-lesioned rats.

Blanco-Centurion CA, Shiromani A, Winston E, Shiromani PJ.

Eur J Neurosci 24(7):2084-2088, 2006.

The basal forebrain is a major arousal center. Using 6 µg of 192-IgG-SAP (Cat. #IT-01) injected into the lateral ventricle of rats, the role of non-cholinergic neurons in the basal forebrain was investigated. Administration of orexin, also known as hypocretin, to lesioned animals produced sleep/wake patterns identical to non-lesioned animals. The results indicate that non-cholinergic neurons in the basal forebrain are sufficient to promote arousal in response to orexin.

Neurotoxic lesions centered on the perifornical hypothalamus abolish the cardiovascular and behavioral responses of conditioned fear to context but not of restraint.

Furlong T, Carrive P.

Brain Res 1128(1):107-119, 2007.

This work examined the role of orexin-containing neurons in the perifornical hypothalamus (PeF) during stress response. Orexin-SAP (Cat. #IT-20) or the control conjugate Blank-SAP (Cat. #IT-21) was injected into the PeF of pre-conditioned rats. Tests measuring restraint and conditioned fear to context were then performed on the lesioned animals. While the lesioning was not specific enough to connect results to orexin-containing neurons, the data indicate that the PeF is critical for some forms of stress, but not others.

Effect of selective cholinergic denervation on the serotonergic system: implications for learning and memory.

Garcia-Alloza M, Zaldua N, Diez-Ariza M, Marcos B, Lasheras B, Javier Gil-Bea F, Ramirez MJ.

J Neuropathol Exp Neurol 65(11):1074-1081, 2006.

The authors compared two lesioning methods using 192-IgG-SAP (Cat. #IT-01) to examine the role of the serotonergic system in learning and memory. Administration of 0.067 µg of conjugate to each hemisphere of the nucleus basalis of Meynert reduced cholinergic markers in the frontal cortex. One µg of conjugate administered to the ventricle of each hemisphere reduced cholinergic markers in the frontal cortex and hippocampus. Both models reduced serotonin levels in the frontal cortex, but only the ICV injections modified learning.

Up-regulation of cation-independent mannose 6-phosphate receptor and endosomal-lysosomal markers in surviving neurons after 192-IgG-saporin administrations into the adult rat brain.

Hawkes C, Kabogo D, Amritraj A, Kar S.

Am J Pathol 169(4):1140-1154, 2006.

The cation-independent mannose 6-phosphate receptor (CI-MPR) plays a major role in the endosomal-lysosomal (EL) system. One of the tasks carried out by the EL system is clearance of abnormal proteins after injury. By administering 2.0 µg bilateral injections of 192-IgG-SAP (Cat. #IT-01) to rats, the researchers were able to increase CI-MPR expression levels, as well as other EL markers in response to the lesion. The up-regulation of EL components suggests that the EL system may be able to repair neuronal abnormalities induced by injury.

An activity-dependent assay for ricin and related RNA N-glycosidases based on electrochemiluminescence.

Keener WK, Rivera VR, Young CC, Poli MA.

Anal Biochem 357(2):200-207, 2006.

The authors use synthetic biotinylated RNA substrates to assay adenine-specific RNA N-glycosidases, one of which is saporin (Cat. #PR-01). The RNA substrates are annealed to a ruthenylated oligodeoxynucleotide, allowing the capture of ruthenium chelate on magnetic beads. The N-glycosidase activity can then be detected by enzyme-linked chemiluminescence. The developed assay provides a robust method for assessing threats involving N-glycosidases.

A putative flip-flop switch for control of REM sleep.

Lu J, Sherman D, Devor M, Saper CB.

Nature 441(7093):589-594, 2006.

The authors propose a REM sleep regulatory system that involves GABA-ergic and glutaminergic neurons in the mesopontine tegmentum. Two µl of 0.1% orexin-SAP (Cat. #IT-20) was injected into the medial medullary reticular formation of rats. The results suggest the sharp transitions into and out of REM sleep are controlled by recipro-cal interactions between GABAergic REM-off and REM-on neuronal populations.

Neuronal nitric oxide synthase is upregulated in a subset of primary sensory afferents after nerve injury which are necessary for analgesia from alpha2-adrenoceptor stimulation.

Ma W, Eisenach JC.

Brain Res 1127(1):52-58, 2007.

Peripheral nerve injury resulting in neuropathic pain often responds poorly to opioid treatment. α2-adrenoreceptor (AR) agonists, however, perform better after this type of injury. After a spinal nerve ligation, rats were treated with a 0.6 µg-intrathecal injection of 192-IgG-SAP (Cat. #IT-01). The increase of neuronal nitric oxide synthase (nNOS) caused by spinal ligation was abolished in the lesioned animals. The data indicate that AR agonists may reduce sensitization by activating nNOS fibers in the superficial dorsal horn.

Lack of localization of 5-HT6 receptors on cholinergic neurons: implication of multiple neurotransmitter systems in 5-HT6 receptor-mediated acetylcholine release.

Marcos B, Gil-Bea FJ, Hirst WD, Garcia-Alloza M, Ramirez MJ.

Eur J Neurosci 24(5):1299-1306, 2006.

The authors investigated a potential link between 5-HT6 receptors, cholinergic activity, and learning. After 0.067 µg of 192-IgG-SAP (Cat. #IT-01) was injected into each hemisphere of the nucleus basalis magnocellularis in the basal forebrain of rats, 5-HT6 receptor mRNA and protein expression were measured. Results demonstrate the involvement of multiple neurotransmitter systems in neurochemical actions following 5-HT6 receptor blockade.

Selective depletion of cortical noradrenaline by anti-dopamine beta-hydroxylase-saporin impairs attentional function and enhances the effects of guanfacine in the rat.

Milstein JA, Lehmann O, Theobald DE, Dalley JW, Robbins TW.

Psychopharmacology (Berl) 190(1):51-63, 2007.

The authors examined the effect of cortical noradrenalin depletion on a reaction time task. Rats received 0.2 µg-intracortical infusions of anti-DBH-SAP (Cat. #IT-03), then were trained in a reaction time task. The effect of guanfacine, a selective α-2 adrenergic agonist was also tested in these animals. Lesioned rats were not impaired on the baseline task, but were slower and less accurate during high rate conditions. Guanfacine only affected the lesioned animals.

Role of catecholaminergic neurones of the caudal ventrolateral medulla in cardiovascular responses induced by acute changes in circulating volume in rats.

Pedrino GR, Maurino I, de Almeida Colombari DS, Cravo SL.

Exp Physiol 91(6):995-1005, 2006.

Catecholaminergic neurons in the caudal ventrolateral medulla (CVLM) are thought to help regulate body fluid homeostasis and cardiovascular response due to changes in circulating volume. The authors injected 6.3 ng of anti-DBH-SAP (Cat. #IT-03) into the CVLM of rats, and measured several physiological parameters following an injection of hypertonic or isotonic saline. Data from the lesioned rats indicate that catecholaminergic neurons mediate the cardiovascular response to volume expansion or increases in sodium levels.

Long-term effects of neonatal basal forebrain cholinergic lesions on radial maze learning and impulsivity in rats.

Scattoni ML, Adriani W, Calamandrei G, Laviola G, Ricceri L.

Behav Pharmacol 17(5-6):517-524, 2006.

Work in the last decade has focused on clarifying the role of cholinergic dysfunction in Alzheimer’s disease. Seven-day-old rats received 0.21 µg of 192-IgG-SAP (Cat. #IT-01) administered to the third ventricle, and were tested at 5 months of age in delay tolerance and radial maze. Test results suggest that prolonged basal forebrain cholinergic hypofunction is detectable only during highly complex tasks.

Antisocial and seizure susceptibility phenotypes in an animal model of epilepsy are normalized by impairment of brain corticotropin-releasing factor.

Turner LH, Lim CE, Heinrichs SC.

Epilepsy Behav 10(1):8-15, 2007.

There appears to be an inverse relationship between seizure susceptibility and social interaction. This work examines the role that CRF may play in this system. 2.5 µg of CRF-SAP (Cat. #IT-13) was administered to the lateral ventricle of rats, and the lesioned animals were assessed in terms of social investigation times as well as handling-induced seizures. The results support the involvement of CRF systems in facilitating evoked seizures and suppression of social activity.

Long-term effects of immunotoxic cholinergic lesions in the septum on acquisition of the cone-field task and noncognitive measures in rats.

van der Staay FJ, Bouger P, Lehmann O, Lazarus C, Cosquer B, Koenig J, Stump V, Cassel JC.

Hippocampus 16(12):1061-1079, 2006.

192-IgG-SAP (Cat. #IT-01) has been used to make extremely specific lesions in the septohippocampal cholinergic system of the brain. The specificity of these lesions is allowing researchers to more accurately map the involvement of the septohippocampal cholinergic system in spatial learning and memory. Here, rats received 0.8 µg of 192-IgG-SAP in the medial septum and the vertical limb of diagonal band of Broca. Lesioned animals only exhibited deficits in attentional learning.

Spinal NK-1 receptor expressing neurons mediate opioid-induced hyperalgesia and antinociceptive tolerance via activation of descending pathways.

Vera-Portocarrero LP, Zhang ET, King T, Ossipov MH, Vanderah TW, Lai J, Porreca F.

Pain 129(1-2):35-45, 2007.

Although used for treatment of pain, opioids can induce hyperalgesia. In this work the authors evaluated the role that NK-1 receptor-expressing neurons play in morphine-induced hyperalgesia and spinal antinociceptive tolerance. Rats received a 5-µl intrathecal injection of 10 µM SP-SAP (Cat. #IT-07). Saporin (Cat. #PR-01) was used as a control. The results indicate that NK-1 receptor-expressing neurons play a critical role in morphine-induced neuroplastic changes.

Inhibition within the nucleus tractus solitarius (NTS) ameliorates environmental exploration deficits due to cerebellum lesions in an animal model for autism.

Walker BR, Diefenbach KS, Parikh TN.

Behav Brain Res 176(1):109-120, 2007.

In this work the authors use environmental exploration deficits in rats as a model for autism. Animals received 2 µg of either OX7-SAP (Cat. #IT-02) or 192-IgG-SAP (Cat. #IT-01) into each ventricle. Only the OX7-SAP-treated rats displayed a reduction in exploration behavior, and the anticonvulsant muscimol restored exploration behavior to control levels. This system may have use in controlling behavior deficits seen in autism.

Basal forebrain cholinergic lesions reduce heat shock protein 72 response but not pathology induced by the NMDA antagonist MK-801 in the rat cingulate cortex.

Willis CL, Ray DE, Marshall H, Elliot G, Evans JG, Kind CN.

Neurosci Lett 407(2):112-117, 2006.

The NMDA receptor antagonist MK-801 may have use in establishing a model for schizophrenia. The mechanism by which cortical neurons are damaged by these antagonists is unknown. The authors tested the theory that cholinergic hyperstimulation of cingulate neurons is involved by administering 80 ng of 192-IgG-SAP (Cat. #IT-01) unilaterally to rats. The results indicate that although cholinergic neurons are involved in the heat shock response to MK-801, the pathological effects follow a different pathway.