targeted-toxins

Sarter M, Bruno JP (2000) Cortical cholinergic inputs mediating arousal, attentional processing and dreaming: Differential afferent regulation of the basal forebrain by telencephalic and brainstem afferents. Neuroscience 95(4):933-952. doi: 10.1016/s0306-4522(99)00487-x

Objective: To examine the cortical cholinergic inputs mediating arousal, specific attentional functions and rapid eye movement sleep-associated dreaming.

Summary: The incorporation of persistent changes in cortical information processing as a result of paired stimulation of cholinergic and sensory inputs into current theories about the cognitive functions of cortical ACh awaits more information, particularly with reference to the temporal dynamic properties of the effects of endogenously released ACh on cortical information processing.

Related Products: 192-IgG-SAP (Cat. #IT-01)

See Also:

• McGaughy J et al. Behavioral vigilance following infusions of 192 IgG-saporin into the basal forebrain: selectivity of the behavioral impairment and relation to cortical AChE-positive fiber density. Behav Neurosci 110:247-265, 1996.
• McGaughy J et al. Sustained attention performance in rats with intracortical infusions of 192 IgG-saporin-induced cortical cholinergic deafferentation: effects of physostigmine and FG 7142. Behav Neurosci 112(6):1519-1525, 1998.

Wiley RG, Lappi DA (1999) Targeting neurokinin-1 receptor-expressing neurons with [Sar9, Met(O2)11] substance P-saporin. Neurosci Lett 277(1):1-4. doi: 10.1016/s0304-3940(99)00846-0

Related Products: SSP-SAP (Cat. #IT-11)

Wrenn C, Lappi DA, Wiley RG (1999) Threshold relationship between lesion extent of the cholinergic basal forebrain in the rat and working memory impairment in the radial maze. Brain Res 847(2):284-298. doi: 10.1016/s0006-8993(99)02099-5

Related Products: 192-IgG-SAP (Cat. #IT-01)

Nichols ML, Allen BJ, Rogers SD, Ghilardi JR, Honore P, Luger NM, Finke MP, Li J, Lappi DA, Simone DA, Mantyh PW (1999) Transmission of chronic nociception by spinal neurons expressing the substance P receptor. Science 286:1558-1561. doi: 10.1126/science.286.5444.1558

Related Products: SP-SAP (Cat. #IT-07)

Kwok KHH, Law KB, Wong RNS, Yung KKL (1999) Immunolesioning of nerve growth factor p75 receptor-containing neurons in the rat brain by a novel immunotoxin: anti-p75-anti-mouse IgG-trichosanthin conjugates. Brain Res 846:154-163. doi: 10.1016/s0006-8993(99)01999-x

Related Products: 192-IgG-SAP (Cat. #IT-01)

Hart S, Sarter M, Berntson GG (1999) Cholinergic inputs to the rat medial prefrontal cortex mediate potentiation of the cardiovascular defensive response by the anxiogenic benzodiazepine receptor partial inverse agonist FG 7142. Neuroscience 94(4):1029-1038. doi: 10.1016/s0306-4522(99)00269-9

Related Products: 192-IgG-SAP (Cat. #IT-01)

Hartlage-Ruebsamen M, Lippe WR, Schliebs R (1999) Cholinergic basal forebrain lesion results in reduced activity of neuronal NO synthase in hippocampal and neocortical areas of the rat brain. Neuroscience 1999 Abstracts 847.3. Society for Neuroscience, Miami, FL.

Summary: Nitric oxide (NO) released by cortical neurons expressing the neuronal form of NO synthase (nNOS) is known to stimulate regional cerebral blood flow and is implicated in the formation of long term potentiation in the hippocampus. Cortical nNOS containing neurons express M] muscarinic acetylcholine receptors and receive cholinergic input from the basal forebrain (BF). Consequently, it has been shown that stimulation of BF cholinergic neurons leads to increased cortical perfusion. Cholinergic cell loss in the BF, reduced cortical blood flow and memory’ dysfunction are characteristics of Alzheimer’s disease. In the present study, we investigated the impact of a selective lesion of BF cholinergic neurons by the cholinergic toxin 192IgG-saporin on the expression and substrate binding activity of nNOS in selected regions of neocortex and hippocampus in the rat. While Western blot analysis yielded no significant changes in total nNOS protein levels 7 days post lesion, nNOS catalytic and substrate binding activity was reduced in a number of hippocampal and neocortical subregions as revealed by NADPH- diaphorase enzyme histochemistry and by quantitative autoradiography using [3H]L-A,’G-nitro-arginine binding. The data suggest that cholinergic mechanisms control, at least in part, neocortical and hippocampal nNOS activity providing further evidence for an NO-mediated influence of the BF cholinergic system on memory function and cortical perfusion. Contract grant sponsor: Deutsche Forschungsgemeinschaft, SCHL 363/4-1.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Silveira DC, Holmes GL, Schachter SC, Geula C, Schomer DL (1999) Increased susceptibility to flurothyl-induced generalized seizures after immunolesions to cholinergic neurons in the basal forebrain. Neuroscience 1999 Abstracts 643.7. Society for Neuroscience, Miami, FL.

Summary: Intracerebroventricular (icv) injections of toxin 192 IgG-saporin produce almost complete loss of cholinergic neurons in the basal forebrain (BF) with extensive dennervation throughout the neocortex and hippocampus. The association among epilepsy and BF cholinergic neurons, which are involved in learning and memory processes, remains unclear. Intraperitoneal injections of pilocarpine, a cholinergic agonist, elicit seizures. Seizures alter the expression of hippocampal muscarinic receptors in human epilepsy. Immunolesions to BF cholinergic neurons increase the number of generalized seizures induced by rapid amygdaloid kindling. We investigated whether BF cholinergic neurons influence the expression of generalized seizures in model of generalized epilepsy. Adult male rats received icv injections of toxin 192-IgG-saporin (lesioned group) or saline (control group). Following 30 days of icv injections both lesioned and control rats were submitted to flurothyl administration. The latency of onset for the first myoclonic jerk, bilateral forelimb clonus, and tonic seizures were recorded. In addition, the hidden platform version of the Morris water maze was used to assess spatial learning and memory. Brain tissue was processed for acetylcholinesterase activity using sensitive histochemical method. Lesioned rats had significantly (p<0.05) shorter latency of onset of tonic seizures than control rats. Spatial learning and memory was significantly (p<0.05) reduced in lesioned animals compared to controls. These preliminary results indicate that immunolesions to cholinergic neurons in the BF increase the susceptibility to seizures induced by flurothyl. Thus, it appears that BF cholinergic neurons participate in the modulation of generalized seizures in both limbic and generalized epilepsy in rats.

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Janni G, Lappi DA, Ohara PT, Jasmin L (1999) CTB-saporin induced demyelinating myelopathy in the rat. Neuroscience 1999 Abstracts 731.2. Society for Neuroscience, Miami, FL.

Summary: In designing a rat model of demyelinating disease, we have used a newly developed neurotoxin, the B fragment of cholera toxin (CTB) linked to the potent ribosome inactivating protein saporin. Saporin linked to CTB targets cell expressing ganglioside GM1 on their surface, mainly Schwann cells, oligodendrocytes, and to a lesser degree neurons. After binding to GM1, CTB-Saporin is rapidly endocytosed and induces cell death. We demonstrate that intrathecal injection of 1 µg in 5 µl of CTB-Saporin at the lumbar level produces a demyelinating disease of the spinal cord. Behaviorally, this disease is characterized by an ascending paralysis that progresses most prominently from day 7 to day 14 post-treatment. In approximately half of the animals, the disease progresses to the brainstem, while in the others the disease regresses spontaneously, leaving these animals with only a moderate residual neurologic deficit. Histologically and ultrastructurally, the spinal pathology is characterized by a loss of myelin and oligodendroglyocytes as well as an immune response involving circulating leukocytes. Immunostaining shows the presence of CD8 immunopositive T lymphocytes but not CD4 T lymphocytes. We therefore conclude that CTB-Saporin induced demyelination involves an immune, but not an autoimmune mediated component in addition to the direct cytotoxic effect. Supported by Georgetown University.

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Waite JJ (1999) Cholinergic deafferentation of the hippocampus or cortex produces differential modulation of attentional processing. Neuroscience 1999 Abstracts 754.4. Society for Neuroscience, Miami, FL.

Summary: Dissociation of attentional changes produced by lesion of the cholinergic neurons in the medial septum (MS) and nucleus basalis magnocellularis (NBM) was investigated by selective lesion with the immunotoxin 192 IgG-saporin followed by testing in the multiple choice serial reaction time task. Male F-344 rats were trained in the 5-choice reaction time task. After criterion performance was attained, the toxin was administered intraparenchymally into the MS (75 ng/site bilateral) and/or NBM (150 ng/site bilateral) to selectively destroy cholinergic neurons projecting to hippocampus and cortex, respectively. Residual ChAT activity, expressed as percent of PBS-infused control, was: in frontal cortex, 28% (NBM); 88% (MS); and 21% (NBM+MS); in hippocampus, 103% (NBM); 18% (MS); and 19% (NBM+ MS). Animals reacquired the baseline task to equivalent levels among groups, based on both accuracy and omissions within ten sessions. MS rats performed with greatest accuracy when the intertrial interval (ITI) was short. They always had fewest omissions. Accuracy for this group suffered when the ITI was long and when a noise was presented just before the light stimulus. NBM rats had the most omissions, but accuracy was generally as good or better than controls and the MS group. Rats with both MS and NBM lesions were frequently between MS and NBM performance curves, putting them close to controls in many tests. They performed worse than all groups in terms of accuracy when the ITI was short and when the light intensity was reduced. Thus, the double lesion had an additive effect when the salience of stimulus was reduced and when the frequency of trials was faster. Supported by NIH NS33371.

Related Products: 192-IgG-SAP (Cat. #IT-01)