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In this study, the effect of intraseptal injection of specific cholinotoxin 192-IgG saporin (SAP) +/- intraperitoneal injection of N-[chloroethyl]-N-ethyl-2-bromobenzylamine (DSP-4) (noradrenergic fiber neurotoxin) was examined in rat hippocampus. Medial septal lesions resulted not only in selective cholinergic denervation of hippocampus (Medial septal lesion + ganglionectomy; SAP + Gx) but also in hippocampal sympathetic ingrowth (IG) of adrenergic fibers (Medial septal lesion + sham ganglionectomy; SAP + IG). Saporin-induced septal lesions produced a significant reduction in hippocampal choline acetyltransferase activity in all tested groups (SAP + IG +/- DSP-4 and SAP + Gx +/- DSP-4), and an increase in noradrenaline concentration in the SAP + IG group. Visualization of noradrenergic fibers by histofluorescence revealed a mixture of fine and thick varicosities in the SAP + IG but only fine fibers in control and SAP + Gx animals. SAP + IG + DSP-4 lesions produced significant reduction in noradrenaline concentration in all groups with a concomitant decrease in visualization of central noradrenergic fibers in dorsal and ventral hippocampus. Treatment of SAP + IG animals with DSP-4 left mostly thick fibers, probably derived from peripheral sympathetic ingrowth. No fluorescence was seen in either the control + DSP-4 or SAP + Gx + DSP-4 animals. Apoptotic-like changes, using in situ oligonucleotide ligation techniques, were also assessed. Proapoptotic changes were seen in the SAP + Gx +/- DSP-4 group as compared to CON +/- DSP-4 groups. SAP + IG regardless of DSP-4 treatment protected hippocampal cells from apoptotic cell death when compared to positive control and SAP + Gx +/- DSP-4 groups. In summary, elevated noradrenaline concentration following specific cholinergic denervation probably reflects compensatory hippocampal ingrowth originating from the peripheral sympathetic system which may be responsible for neuroprotective effects, i.e., antiapoptosis-like effect. Since cholinergic and noradrenergic systems are known to be involved in Alzheimer's disease and related cognitive function, knowing how these neurotransmitters work after specific lesions may be of importance as an animal model of Alzheimer's disease and as a potential target for Alzheimer's disease drug therapies.

Hippocampal sympathetic ingrowth (HSI), a form of neuronal plasticity, is induced by medial septal lesions and consists of the sprouting of peripheral sympathetic fibers, arising from the superior cervical ganglion, into the dentate gyrus and CA3 region of the hippocampus. HSI has been previously shown to alter learned and spontaneous behaviors, phosphatidyl inositide hydrolysis, and the antagonist binding kinetics of both muscarinic cholinergic receptors and phorbol ester receptors. We now report that sympathetic sprouting reverses decreases in membrane-associated activity of protein kinase C (PKC) following septohippocampal denervation of the rat hippocampus. Further, no changes were found in alpha, beta or gamma PKC isoenzymes among experimental groups, suggesting that the group A PKC isoforms do not mediate the observed changes in activity and phorbol ester binding.

After cholinergic denervation of the hippocampus, via medial septal (MS) lesions, peripheral sympathetic fibers, originating from the superior cervical ganglia, grow into the hippocampus. In this study, we sought to determine the effect of hippocampal sympathetic ingrowth (HSI) on the M2 subtype of muscarinic cholinergic receptors, by examining the membrane binding of [3H]AF-DX 384 in hippocampal tissue from control rats, rats with HSI and rats with MS lesions + concurrent ganglionectomy (CD group). In dorsal hippocampus, Kd was found to be increased while Bmax was decreased in the CD group as compared with both the HSI and control group which did not differ from one another. In ventral hippocampus, Kd was found to be increased while Bmax was decreased in the CD group when compared only with the control group. These results suggest that sympathetic ingrowth, which has its greatest concentration in dorsal hippocampus, can 'normalize' the M2 receptor in hippocampus.

Following cholinergic denervation of the hippocampus by medial septal (MS) lesions, an unusual neuronal reorganization occurs in which peripheral sympathetic fibers, originating from the superior cervical ganglia, grow into the hippocampus (hippocampal sympathetic ingrowth; HSI). Previously, we have found that with MS lesions, animals with (the HSI(+) group) and without (HSI(-) group) ingrowth differed in carbachol stimulated PI hydrolysis, in PKC activity, and in muscarinic cholinergic receptors (mAChR). In this study, performed in hippocampal slices obtained four weeks after MS lesions, we utilized the hydrophilic muscarinic antagonist [3H]N-methylscopolamine ([3H]NMS) and hydrophobic muscarinic antagonist [3H]quinuclidinyl benzilate ([3H]QNB) in the presence of either 4-alpha-phorbol or phorbol 12,13-dibutyrate (PDBu) to determine the effect of MS lesions with and without ingrowth on PKC-mediated mAChR internalization. In the presence of PDBu, a group effect was observed in [3H]NMS binding, with control groups > HSI(+) group > HSI(-) group. However, [3H]QNB binding was similar across groups. These results suggest that the cholinergic denervation of the hippocampus enhances the internalization of mAChRs, which is modified in the presence of HSI.

Following cholinergic denervation of the hippocampus by medial septal lesions, and unusual neuronal reorganization occurs, in which peripheral sympathetic fibers, originating from the superior cervical ganglia, grow into the hippocampus. Previously, we have found that both hippocampal sympathetic ingrowth (HSI) and cholinergic denervation (CD), alone, altered the total number and affinity of muscarinic cholinergic receptors (mAChR). In this study, we utilized the muscarinic antagonist [3H]Pirenzepine, in combination with membrane radioligand binding techniques, to determine the effects of HSI and CD on hippocampal M1 and M1 + M3 mAChR subtypes, 4 weeks after MS lesions. In both the dorsal and ventral hippocampus, HSI was found to markedly diminish the number of M1 AChRs, while CD was found to increase the number of M1 AChRs. Neither treatment affected the affinity of the M1 AChR. However, when M1 + M3 binding was assessed, CD was found to decrease the affinity in both hippocampal regions, without altering the number of receptors. Neither affinity nor number of M1 + M3 receptors was altered by HSI. The results of this study suggest that both cholinergic denervation and hippocampal sympathetic ingrowth uniquely affect hippocampal muscarinic receptors.

Following cholinergic denervation of the neocortex by nucleus basalis magnocellularis (NBM) lesions, peripheral sympathetic fibers grow into the neocortex. Two experiments were performed to determine the behavioral effects of this neuronal rearrangement. Group I animals underwent training on a standard radial-8-arm maze task, while Group II animals learned a modified version (i.e. 4 arms baited). Following acquisition, NBM lesions were performed. Animals with lesions but without sympathetic ingrowth performed consistently better in both behavioral paradigms, than animals with NBM lesions and sympathetic ingrowth. These studies suggest that cortical sympathetic ingrowth can alter behavior and is detrimental to the learning of a spatial memory paradigm.

Following medial septal (MS) lesions peripheral sympathetic fibers, originating from the superior cervical ganglia (SCG), grow into the hippocampus and habenula. To assess their effect on regulatory behaviors, body weight, and food and water consumption were studied under ad libitum and pharmacological stress conditions, after MS lesions, superior cervical ganglionectomy (Gx) or MS lesion + ganglionectomy (MSGx). Twenty-two animals completed the study: control (n = 7), MS lesion (n = 5), Gx (n = 6), MSGx (n = 4). No differences were observed preoperatively. Postoperatively, body weight fell but over time all groups gained weight. However, animals with MSGx were lighter than MS or Gx animals (which were equivalent), which in turn were lighter than controls (P less than 0.0001). Hypophagia was observed in the Gx and MSGx animals when compared to the MS and control groups (P less than 0.05), while hyperdipsia was seen in the MS and Gx groups (P less than 0.001). Administration of both 1 M NaCl and isoproterenol (25 micrograms/kg) increased drinking in all animals (P less than 0.001), with the MSGx group consuming significantly less than all others (P less than 0.025). Food intake increased following 2-deoxy-D-glucose (500 mg/kg) (P less than 0.0001), while epinephrine (120 micrograms/kg) treatment produced anorexia only in the MS group (P less than 0.05). Hyperthermia was found in the Gx and MSGx groups. The results of this study suggest that both the MS region and SCG contribute to the maintenance of normal regulatory behaviors, with combined loss of these neural systems resulting in severe disturbances, both qualitatively and quantitatively different from either MS lesion or Gx. Although the MS lesion group clearly regulated better than the MSGx group, it is unclear whether this is due to ingrowth or just the presence of the SCG.