Summary
The present study investigates the effects of a serotonin (5-HT) reuptake inhibitor, alaproclate, on water maze cued navigation performance in serotonin depleted and control rats. Treatment with p-chlorophenylalanine (PCPA), a serotonin synthesis inhibitor, (400 mg/kg/day×3 i.p.) significantly depleted cerebral levels of both 5-HT (about 80% depletion) and its major metabolite 5-HIAA (about 90% depletion) for at least 7 days. PCPA treatment also slightly decreased cerebral noradrenaline and dopamine levels (16% and 22% reductions, respectively). PCPA treatment alone had no effect on the acquisition of the cued navigation version (visible platform) of the water maze task measured as the distance to find the escape platform, but it significantly increased swimming speeds of the rats. Alaproclate (20 mg/kg i.p.) increased escape distance and slightly decreased swimming speeds of the rats. The effects of alaproclate did not differ between PCPA and sham treated (arabic gum 400 mg/kg/day × 3 i.p.) rats. The results demonstrate that alaproclate induced cued navigation behavioral deficit is maintained after a marked depletion of cerebral serotonin.
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Bartus RT, Dean RL, Beer B, Lippa AS (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217: 408–417
Bergman I, Brane G, Gottfries CG, Jostell KG, Karlsson I, Svennerholm L (1983) Alaproclate: a pharmacokinetic and biochemical study in patients with dementia of the Alzheimer type. Psychopharmacology 80: 279–283
Bowen DM, Allen SJ, Benton JS, Goodhardt MJ, Haan EA, Palmer AM, Sims NR, Smith CCT, Spillane JA, Esira GK, Neary D, Snowden JS, Wilcock GK, Davison AN (1983) Biochemical assesment of serotonergic and cholinergic dysfunction and cerebral atrophy in Alzheimer's disease. J Neurochem 41: 266–272
Danielsson E (1986) Muscarinic receptors and cGMP synthesis: studies on human and rat tissues. PhD Thesis, University of Stockholm
Fibiger HC, Campbell BA (1971) The effects of para-chlorophenylalanine on spontaneous locomotor activity in the rat. Neuropharmacology 10: 25–32
Gottfries CG, Adolfsson R, Aquilonius S-M, Carlsson A, Eckernäs S-A, Nordberg A, Oreland L, Svennerholm R, Wiberg A, Winblad B (1983) Biochemical changes in dementia disorders of Alzheimer type (AD/SDAT). Neurobiol Aging 4: 261–271
Hillegaart V, Ahlenius S, Larsson K (1989) Effects of local application of 5-HT into the median and dorsal raphe nuclei on male rat sexual and motor behavior. Behav Brain Res 33: 279–286
Hollander E, Mohs R, Davies K (1986) Cholinergic approaches to the treatment of Alzheimer's disease. Br Med Bull 42(1): 97–100
Höfkelt T, Ljungdahl Å, Steinbusch H, Verhofstad A, Nilsson G, Brodin E, Pernow B, Goldstein M (1978) Immunohistochemical evidence of substance P-like immunoreactivity in some 5-hydroxytryptamine-containing neurons in the rat central nervous system. Neuroscience 3: 517–538
Johansson O, Höfkelt T, Pernow B, Jeffcoate L, White N, Steinbusch W, Verhofstad A, Emson P, Spindel E (1981) Immunohistochemical support for three putative transmitters in one neuron: coexistence of 5-hydroxytryptamine, substance P and thyrotropin releasing hormone-like immunoreactivity in medullary neurons projecting to spinal cord. Neuroscience 6: 1857–1881
Jacobs BL, Trimbach C, Eubanks EE, Trulson M (1974a) Hippocampal mediation of raphe lesion- and pcpa-induced hyperactivity in the rat. Brain Res 94: 253–261
Jacobs BL, Wise WD, Taylor KM (1974b) Differential behavioral and neurochemical effects following lesions of the dorsal or median raphe nuclei in rats. Brain Res 79: 353–361
Mefford IN (1981) Application of high performance liquid chromatography with electrochemical detection to neurochemical analysis: measurements of catecholamines, serotonin and metabolites in rat brain. J Neurochem 34: 741–745
Morris RGM, Garrud P, Rawlins JNP, O'Keefe J (1982) Place navigation impaired in rats with hippocampal lesions. Nature (Lond) 297: 681–683
Ögren SO, Altman HJ, Bartfai T (1987) Alaproclate potentiation of muscarinic, agonist evoked tremor, salivation and enhanced recall. In: Tucek S (ed) Synaptic transmitters and receptors. Wiley, Chichester, pp 34–46
Ögren SO, Carlsson S, Bartfai T (1985a) Serotonergic potentiation of muscarinic agonist evoked tremor and salivation in rat and mouse. Psychopharmacology 86: 258–264
Ögren SO, Holm AC, Hall H, Lindberg U (1984) Alaproclate, a new selective 5-HT uptake inhibitor with therapeutic potential in depression and senile dementia. J Neural Transm 59: 265–288
Ögren SO, Nordström Ö, Danielsson E, Peterson LL, Bartfai T (1985b) In vivo and in vitro studies on the potentiation of muscarinic receptor stimulation by alaproclate, a selective 5-HT uptake blocker. J Neural Transm 61: 1–20
Perry EK (1986) The cholinergic hypothesis-ten years on. Br Med Bull 42: 63–69
Perry EK, Curtis M, Dick DJ, Condy JM, Atack JR, Bloxham CA, Blessed G, Fairbairn A, Tomlinsons BE, Perry RH (1985) Cholinergic correlates of cognitive impairment in Parkinson's disease: comparison with Alzheimer's disease. J Neurol Neurosurg Psychiatry 48: 413–421
Reinikainen KJ, Paljärvi L, Huuskonen M, Soininen H, Laakso M, Riekkinen PJ (1988a) A post-mortem study of noradrenergic, serotonergic and GABAergic neurons in Alzheimer's disease. J Neurol Sci 84: 101–116
Reinikainen KJ, Riekkinen PJ, Paljärvi L, Soininen H, Helkala E-L, Jolkkonen J, Laakso M (1988b) Cholinergic deficit in Alzheimer's disease: a study based on CSF and autopsy data. Neurochem Res 13: 135–146
Riekkinen P Jr, Sirviö, J, Riekkinen PJ (1990) Interaction between raphe dorsalis and nucleus basalis magnocellularis in spatial learning. Brain Res 527: 342–345
Riekkinen P Jr, Jäkälä P, Rirviö J, Riekinen PJ (1991) The effects of increased serotonergic and decreased cholinergic activity on spatial navigation performance in rats. Pharmacol Biochem Behav 39: 25–29
Trulson ME, Jacobs BL (1978) Behavioural evidence for denervation supersensitivity after destruction of central serotonergic nerve terminals. Serotonin neurotoxins. Ann NY Acad Sci: 497–509
Vanderwolf CH (1987) Near total loss of “learning” and “memory” as a result of combined cholinergic and serotonergic blockade in the rat. Behav Brain Res 23: 43–57
Vanderwolf CH, Baker GB (1986) Evidence that serotonin mediates non-cholinergic neocortical low voltage fast activity, non-cholinergic hippocampal rhytmical slow activity and contributes to intelligent behaviour. Brain Res 374: 342–356
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Jäkälä, P., Sirviö, J., Riekkinen, P. et al. The effects of alaproclate and p-chlorophenylalanine on cued navigation performance in rats. J Neural Transm Gen Sect 4, 43–52 (1992). https://doi.org/10.1007/BF02257621
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DOI: https://doi.org/10.1007/BF02257621