Abstract
Rationale
Nicotine has been shown in many, but not all, studies to improve cognitive function in a number of species including rats, mice, monkeys, and humans. Recently, we have found that nicotine also improves memory in zebrafish. Nicotinic agonists are being developed as novel treatments for Alzheimer's disease and other cognitive impairments.
Objectives
In screening the therapeutic potential of novel nicotinic agonists, it is important to have a rapid assay of cognitive improvement. Zebrafish can help with this effort.
Methods
We have developed a method of rapidly assessing spatial position discrimination learning in zebrafish in one session of seven trials. We used this method to determine the cognitive effects of nicotine.
Results
Nicotine (100 mg/l administered during 3 min of immersion) caused a significant improvement in percent correct performance. This dose was within the effective range we found to improve the choice accuracy performance of zebrafish using the more time-intensive delayed spatial alternation procedure. Interestingly, the positive effect of nicotine was seen at 20–40 min postadministration, but not earlier, and declined at 80 and 160 min posttreatment. At the 40-min postdosing interval, 200 mg/l nicotine was also found to significantly improve choice accuracy. Nicotine-induced accuracy improvement was reversed by the nicotinic antagonist mecamylamine given shortly before testing but not when given concurrently with nicotine.
Conclusions
This position discrimination procedure in zebrafish effectively demonstrated the cognitive-enhancing effects of nicotine. This model may be useful in the early screening of novel nicotinic compounds for treatment of cognitive dysfunction.
Similar content being viewed by others
References
Arthur D, Levin ED (2001) Spatial and non-spatial discrimination learning in zebrafish. Anim Cogn 4:125–131
Behrend ER, Bitterman ME (1964) Avoidance conditioning in the fish: further studies of the CS–US interval. Am J Psychol 77:15–28
Bilotta J, Barnett J, Hancock L, Saszik S (2004) Ethanol exposure alters zebrafish development: a novel model of fetal alcohol syndrome. Neurotoxicol Teratol 26:737–743
Buccafusco JJ, Jackson WJ (1991) Beneficial effects of nicotine administered prior to a delayed matching-to-sample task in young and aged monkeys. Neurobiol Aging 12:233–238
Buccafusco JJ, Terry AV Jr (2001) Nicotine and cognition in young and aged non-human primates. In: Levin ED (ed) Nicotine and the nervous system (methods in neuroscience). CRC, New York
Buccafusco JJ, Jackson WJ, Terry AV, Marsh KC, Decker MW, Arneric SP (1995) Improvement in performance of a delayed matching-to-sample task by monkeys following ABT-418: a novel cholinergic channel activator for memory enhancement. Psychopharmacology 120:256–266
Clarke PB, Schwartz RD, Paul SM, Pert CB, Pert A (1985) Nicotinic binding in rat brain: autoradiographic comparison of [3H]acetylcholine, [3H]nicotine, and [125I]-alpha-bungarotoxin. J Neurosci 5:1307–1315
Dunnett SB, Martel FL (1990) Proactive interference effects on short-term memory in rats: 1. Basic parameters and drug effects. Behav Neurosci 104:655–665
Eskin RM, Bitterman ME (1960) Fixed-interval and fixed-ratio performance in the fish as a function of prefeeding. Am J Psychol 73:417–423
Gentry C, Lukas R (2002) Regulation of nicotinic acetylcholine receptor numbers and function by chronic nicotine exposure. Curr Drug Target CNS Neurol Disord 1:359–385
Kaethner RJ, Stuermer CA (1997) Dynamics of process formation during differentiation of tectal neurons in embryonic zebrafish. J Neurobiol 32:627–639
Levin ED, Chen E (2004) Nicotinic involvement in memory function in zebrafish. Neurotoxicol Teratol 26:731–735
Levin ED, Christopher NC (2002) Persistence of nicotinic agonist RJR 2403 induced working memory improvement in rats. Drug Dev Res 55:97–103
Levin ED, Rezvani AH (2001) Nicotinic involvement in cognitive function in rats. In: Levin ED (ed) Nicotine and the nervous system (methods in neuroscience). CRC Press, New York, pp 167–178
Levin E, Rezvani A (2002) Nicotinic treatment for cognitive dysfunction. Curr Drug Target CNS Neurol Disord 1:423–431
Levin ED, Simon BB (1998) Nicotinic acetylcholine involvement in cognitive function in animals. Psychopharmacology 138:217–230
Levin ED, Torry D, Christopher NC, Yu X, Einstein G, Schwartz-Bloom R (1997) Is binding to nicotinic acetylcholine and dopamine receptors related to working memory in rats? Brain Res Bull 43:295–304
Levin ED, Crysthansis E, Yacisin K, Linney E (2003) Chlorpyrifos exposure of developing zebrafish: effects on survival and long-term effects on response latency and spatial discrimination. Neurotoxicol Teratol 25:51–57
Levin ED, Tizabi Y, Rezvani AH, Caldwell DP, Petro A, Getachew B (2005) Chronic nicotine and dizocilpine effects on regionally specific nicotinic and NMDA glutamate receptor binding. Brain Res 1041:132–142
Loucks E, Carvan M III (2004) Strain-dependent effects of developmental ethanol exposure in zebrafish. Neurotoxicol Teratol 26:745–755
Mundy WR, Iwamoto ET (1988) Nicotine impairs acquisition of radial-arm maze performance in rats. Psychopharmacology 94:267–274
Newhouse PA, Kelton M (2000) Nicotinic systems in central nervous systems disease: degenerative disorders and beyond. Pharm Acta Helv 74:91–101
Newhouse PA, Potter A, Levin ED (1997) Nicotinic system involvement in Alzheimer's and Parkinson's diseases: implications for therapeutics. Drugs Aging 11:206–228
Ochoa ELM, Chattopadhyay A, McNamee MG (1989) Desensitization of the nicotinic acetylcholine receptor: molecular mechanisms and effect of modulators. Cell Mol Neurobiol 9:141–178
Quick M, Lester R (2002) Desensitization of neuronal nicotinic receptors. J Neurobiol 53:457–478
Reimers M, Flockton A, Tanguay R (2004) Ethanol- and acetaldehyde-mediated developmental toxicity in zebrafish. Neurotoxicol Teratol 26:769–781
Rozin P (1965) Temperature independence of an arbitrary temporal discrimination in the goldfish. Science 149:561–563
Welzl H, Alessandri B, Oettinger R, Bättig K (1988) The effects of long-term nicotine treatment on locomotion, exploration and memory in young and old rats. Psychopharmacology 96:317–323
Wullimann MF, Rupp B, Reichert H (1996) Neuroanatomy of the zebrafish brain: a topological atlas. Burkhauser, Basel
Yin RY, French ED (2000) A comparison of the effects of nicotine on dopamine and non-dopamine neurons in the rat ventral tegmental area: an in vitro electrophysiological study. Brain Res Bull 51:507–514
Zirger JM, Beattie CE, McKay DB, Boyd RT (2003) Cloning and expression of zebrafish neuronal nicotinic acetylcholine receptors. Gene Expr Patterns 3:747–754
Acknowledgements
Research described in this article was supported by the Philip Morris USA Inc., and Philip Morris International.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Levin, E.D., Limpuangthip, J., Rachakonda, T. et al. Timing of nicotine effects on learning in zebrafish. Psychopharmacology 184, 547–552 (2006). https://doi.org/10.1007/s00213-005-0162-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-005-0162-9