Abstract
It is generally believed that the cholinergic system plays an important role in normal cognitive functioning. Botulinum toxin is the most potent toxin of the peripheral cholinergic system and today it is used in the treatment of a variety of neurological disorders. However, it is surprising that its effect on cognitive processes has been investigated in only two publications. Short-term effects of the central application of botulinum toxin (BTX) type B have been associated with cognitive impairment in animals, while results with type A are ambiguous. In the present study, we have investigated the duration of memory impairment after an intracerebroventricular administration of BTX-A in rats. Two experiments were performed, lasting 12 and 5 months, respectively. In both experiments, the same dose of BTX-A was applied (2 U/kg) and the Morris water maze test was used in the assessment of memory performance. Results show that a single icv injection of a small dose of BTX-A significantly impairs the water maze performance. In both experiments, impairment was apparently of a slow onset and long lasting (up to 12 months). The length and pattern of attenuation suggest development of dementia-like deficits. In addition to providing a potentially new experimental model of memory impairment, these results question the idea of an intracranial application of BTX in the treatment of CNS disorders.
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Ando S, Kobayashi S, Waki H, Kon K, Fukui F, Tadenuma T, Iwamoto M, Takeda Y, Izumiyama N, Watanabe K, Nakamura H (2002) Animal model of dementia induced by entorhinal synaptic damage and partial restoration of cognitive deficits by BDNF and carnitine. J Neurosci Res 70:519–527
Antonucci F, Rossi C, Gianfranceschi L, Rossetto O, Caleo M (2008) Long-distance retrograde effects of botulinum neurotoxin A. J Neurosci 28:3689–3696
Aoki R (2002) Botulinum neurotoxin serotypes A and B preparations have different safety margins in preclinical models of muscle weakening efficacy and systemic safety. Toxicon 40:923–928
Ashton AC, Dolly JO (1988) Characterization of the inhibitory action of botulinum neurotoxin type A on the release of several transmitters from rat cerebrocortical synaptosomes. J Neurochem 50:1808–1816
Bach-Rojecky L, Relja M, Lacković Z (2005) Botulinum toxin type A in experimental neuropathic pain. J Neural Transm 112:215–219
Bach-Rojecky L, Relja M, Filipović B, Lacković Z (2007) Botulinum toxin type A and cholinergic system. Lijec Vjesn 129:407–414
Bergquist F, Niazi HS, Nissbrandt H (2002) Evidence for different exocytosis pathways in dendritic and terminal dopamine release in vivo. Brain Res 950:245–253
Birks J (2006) Cholinesterase inhibitors for Alzheimer’s disease, Cochrane Database Syst Rev 1, p CD005593
Bozzi Y, Costantin L, Antonucci F, Caleo M (2006) Action of botulinum neurotoxins in the central nervous system: antiepileptic effects. Neurotox Res 9:197–203
Braak H, Rüb U, Schultz C, Del Tredici K (2006) Vulnerability of cortical neurons to Alzheimer’s and Parkinson’s diseases. J Alzheimers Dis 9(3):35–44
Cozzolino R, Guaraldi D, Giuliani A, Ghirardi O, Ramacci MT, Angelucci L (1994) Effects of concomitant nicotinic and muscarinic blockade on spatial memory disturbance in rats are purely additive: evidence from the Morris water task. Physiol Behav 56:111–114
D’Hooge R, De Deyn PP (2001) Applications of the Morris water maze in the study of learning and memory. Brain Res Brain Res Rev 36:60–90
Davies P, Maloney AJ (1976) Selective loss of central cholinergic neurons in Alzheimer’s disease. Lancet 2:1403
Everitt BJ, Robbins TW (1997) Central cholinergic systems and cognition. Annu Rev Psychol 48:649–684
Fishkin RJ, Ince ES, Carlezon WA Jr, Duun RW (1993) D-Cycloserine attenuates scopolamine-induced learning and memory deficits in rats. Behav Neural Biol 59:150–157
Gage FD (1985) Performance of hippocampectomized rats in a reference/working memory task: effects of preoperative versus postoperative training. Physiol Psychol 13:235–242
Garcia-Alloza M, Zaldua N, Diez-Ariza M et al (2006) Effect of selective cholinergic denervation on the serotonergic system: implications for learning and memory. J Neuropathol Exp Neurol 65:1074–1081
Gold PE (2003) Acetylcholine modulation of neural systems involved in learning and memory. Neurobiol Learn Mem 80:194–210
Handelmann GE, Olton DS (1981) Spatial memory following damage to the hippocampal CA3 pyramidal cells with kainic acid: Impairment and recovery with preoperative training. Brain Res 217:41–58
Herrera-Morales W, Mar I, Serrano B, Bermúdez-Rattoni F (2007) Activation of hippocampal postsynaptic muscarinic receptors is involved in long-term spatial memory formation. Eur J Neurosci 25:1581–1588
Itoh A, Nitta A, Katono Y, Usui M, Naruhashi K, Iida R, Hasegawa T, Nabeshima T (1997) Effects of metrifonate on memory impairment and cholinergic dysfunction in rats. Eur J Pharmacol 322:11–19
Jackson JJ, Soliman MR (1996) Effects of tacrine (THA) on spatial reference memory and cholinergic enzymes in specific rat brain navigation task. Life Sci 58:47–54
Jankovic J (2004) Botulinum toxin in clinical practice. J Neurol Neurosurg Psychiatry 75:951–957
Jarrard LE (1978) Selective hippocampal lesions: differential effects on performance by rats of a spatial task with preoperative versus postoperative training. J Comp Physiol Psychol 92:19–27
Kao I, Drachman DB, Price DL (1976) Botulinum toxin: mechanism of presynaptic blockade. Science 193:1256–1258
Kitabatake Y, Hikida T, Watanabe D, Pastan I, Nakanishi S (2003) Impairment of reward-related learning by cholinergic cell ablation in the striatum. Proc Natl Acad Sci USA 100:7965–7970
Leanza G, Nilsson OG, Wiley RG, Björklund A (1995) Selective lesioning of the basal forebrain cholinergic system by intraventricular 192 IgG-saporin: behavioural, biochemical and stereological studies in the rat. Eur J Neurosci 7:329–343
Luvisetto S, Marinelli S, Lucchetti F, Marchi F, Cobianchi S, Rossetto O, Montecucco C, Pavone F (2004) Central injection of botulinum neurotoxins: behavioural effects in mice. Behav Pharmacol 15:233–240
McDonald MP, Overmier JB (1998) Present imperfect: a critical review of animal models of the mnemonic impairments in Alzheimer’s disease. Neurosci Biobehav Rev 22:99–120
Meunier FA, Schiavo G, Molgó J (2002) Botulinum neurotoxins: from paralysis to recovery of functional neuromuscular transmission. J Physiol Paris 96:105–113
Miyamoto M, Narumi S, Nagaoka A, Coyle JT (1989) Effects of continuous infusion of cholinergic drugs on memory impairment in rats with basal forebrain lesions. J Pharmacol Exp Ther 248:825–835
Morris RG, Hagan JJ, Rawlins JN (1986) Allocentric spatial learning by hippocampectomised rats: a further test of the “spatial mapping” and “working memory” theories of hippocampal function. Q J Exp Psychol B 38:365–395
Murray CL, Fibiger HC (1986) Pilocarpine and physostigmine attenuate spatial memory impairments produced by lesions of the nucleus basalis magnocellularis. Behav Neurosci 100:23–32
Myhrer T (2003) Neurotransmitter systems involved in learning and memory in the rat: a meta-analysis based on studies of four behavioral tasks. Brain Res Brain Res Rev 41:268–287
Najib A, Pelliccioni P, Gil C, Aguilera J (1999) Clostridium neurotoxins influence serotonin uptake and release differently in rat brain synaptosomes. J Neurochem 72:1991–1998
Nilsson OG, Leanza G, Rosenblad C, Lappi DA, Wiley RG, Björklund A (1992) Spatial learning impairments in rats with selective immunolesion of the forebrain cholinergic system. NeuroReport 3:1005–1008
Noble EP, Wurtman RJ, Axelrod J (1967) A simple and rapid method for injecting H3-norepinephrine into the lateral ventricle of the rat brain. Life Sci 6:281–291
Opello KD, Stackman RW, Ackerman S, Walsh TJ (1993) AF64A (ethylcholine mustard aziridinium) impairs acquisition and performance of a spatial, but not a cued water maze task: Relation to cholinergic hypofunction. Physiol Behav 54:1227–1233
Puumala T, Sirvio J, Ruotsalainen S, Riekkinen P Sr (1996) Effects of St-587 and prazosin on water maze and passive avoidance performance of scopolamine-treated rats. Pharmacol Biochem Behav 55:107–115
Salmon DP, Butters N (1995) Neurobiology of skill and habit learning. Curr Opin Neurobiol 5:184–190
Sarter M, Bruno JP (1997) Cognitive functions of cortical acetylcholine: toward a unifying hypothesis. Brain Res Brain Res Rev 23:28–46
Sarter M, Bruno JP, Givens B (2003) Attentional functions of cortical cholinergic inputs: What does it mean for learning and memory? Neurobiol Learn Mem 80:245–256
Torres EM, Perry TA, Blockland A, Wilkinson LS, Wiley RG, Lappi DA, Dunett SB (1994) Behavioural, histochemical and biochemical consequences of selective immunolesions in discrete regions of the basal forebrain cholinergic system. Neuroscience 63:95–122
Verderio C, Grumelli C, Raiteri L, Coco S, Paluzzi S, Caccin P, Rossetto O, Bonanno G, Montecucco C, Matteoli M (2007) Traffic of botulinum toxins A and E in excitatory and inhibitory neurons. Traffic 8:142–153
von Linstow Roloff E, Harbaran D, Micheau J, Platt B, Riedel G (2007) Dissociation of cholinergic function in spatial and procedural learning in rats. Neuroscience 146:875–889
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Supported by the Croatian Ministry of Science, Education and Sport and the Deutscher Akademischer Austausch Dienst (DAAD). We thank Bozica Hrzan for her excellent technical assistance.
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Lacković, Z., Rebić, V. & Riederer, P.F. Single intracerebroventricular injection of botulinum toxin type A produces slow onset and long-term memory impairment in rats. J Neural Transm 116, 1273–1280 (2009). https://doi.org/10.1007/s00702-009-0285-y
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DOI: https://doi.org/10.1007/s00702-009-0285-y