The spatial learning and memory performance in methamphetamine–sensitized and withdrawn rats

Document Type: Original Article


1 Faculty of Psychology and Educational Sciences, University of Semnan, Semnan, Iran

2 Laboratory of Animal Addiction Models, Research Center and Department of Physiology, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran


Objective(s): There is controversial evidence about the effect of methamphetamine (METH) on spatial memory. We tested the time- dependent effects of METH on spatial short-term (working) and long-term (reference) memory in METH –sensitized and withdrawn rats in the Morris water maze.
Materials and Methods: Rats were sensitized to METH (2 mg/kg, daily/5 days, SC). Rats were trained in water maze (4 trials/day/ for 5 days). Probe test was performed 24 hr after training. Two days after probe test, working memory training (2 trials/day/ for 5 days) was conducted. Acquisition–retention interval was 75 min. The treatment was continued per day 30 and 120 min before the test. Two groups of METH –sensitized rats were trained in reference memory after a longer period of withdrawal (30 days).
Results: Sensitized rats exhibited significantly longer escape latencies on the training, spent significantly less time in the target zone (all, P<0.05), and their working memory impaired 30 min after injection. While, METH has no effect on the spatial learning process 120 min after injection, and rats spent significantly less time in the target zone (P<0.05), as well it has no effect on working memory. Also, impairment of reference memory persisted after prolonged abstinence.
Conclusion:Our findings indicated that METH impaired spatial learning and memory 30 min after injection, but spared spatial learning, either acquisition or retention of spatial working, but partially impaired retention of spatial reference memory following 120 min after injection in sensitized rats, which persisted even after prolonged abstinence.


1.   Cherner M, Suarez P, Casey C, Deiss R, Letendre S, Marcotte T, et al. Methamphetamine use parameters do not predict neuropsychological impairment in currently abstinent dependent adults. Drug Alcohol Depend 2010; 106:154-163.

2.   Swant J, Chirwa S, Stanwood G, Khoshbouei H. Methamphetamine reduces LTP and increases baseline synaptic transmission in the CA1 region of mouse hippocampus. PloS One 2010; 5:e11382.

3.   Johnson BA, Roache JD, Ait-Daoud N, Wells LT, Wallace CL, Dawes MA, et al. Effects of topiramate on methamphetamine-induced changes in attentional and perceptual-motor skills of cognition in recently abstinent methamphetamine-dependent individuals. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31:123-130.

4.   Kitanaka N, Kitanaka J, Tatsuta T, Tanaka K, Watabe K, Nishiyama N, et al. Withdrawal from fixed-dose injection of methamphetamine decreases cerebral levels of 3-methoxy-4-hydroxyphenylglycol and induces the expression of anxiety-related behavior in mice. Neurochem Res 2010; 35:749-760.

5.   Stumm G, Schlegel J, Schäfer T, Würz C, Mennel H, Krieg JC, et al. Amphetamines induce apoptosis and regulation of bcl-x splice variants in neocortical neurons. FASEB J 1999; 13:1065-1072.

6.   Scott JC, Woods SP, Matt GE, Meyer RA, Heaton RK, Atkinson JH, et al. Neurocognitive effects of methamphetamine: a critical review and meta-analysis. Neuropsychol Rev 2007; 17:275-297.

7.   Simon SL, Dean AC, Cordova X, Monterosso JR, London ED. Methamphetamine dependence and neuropsychological functioning: evaluating change during early abstinence. J Stud Alcohol Drugs 2010; 71:335-344.

8.   Woods SP, Rippeth JD, Conover E, Gongvatana A, Gonzalez R, Carey CL, et al. Deficient strategic control of verbal encoding and retrieval in individuals with methamphetamine dependence. Neuropsychology 2005;19:35-43.

9.   Kalechstein AD, De La Garza R 2nd, Newton TF. Modafinil administration improves working memory in methamphetamine‐dependent individuals who demonstrate baseline impairment. Am J Addict 2010; 19:340-344.

10. Mahoney JJ 3rd, Jackson BJ, Kalechstein AD, De La Garza R 2nd, Newton TF. Acute, low-dose methamphetamine administration improves attention/information processing speed and working memory in methamphetamine-dependent individuals displaying poorer cognitive performance at baseline. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35:459-465.

11. Simon SL, Dacey J, Glynn S, Rawson R, Ling W. The effect of relapse on cognition in abstinent methamphetamine abusers. J Subst Abuse Treat 2004; 27:59-66.

12. Kennedy CD, Houmes SW, Wyrick KL, Kammerzell SM, Lukowiak K, Sorg BA. Methamphetamine enhances memory of operantly conditioned respiratory behavior in the snail Lymnaea stagnalis. J Exp Biol 2010; 213:2055-2065.

13. Schutová B, Hrubá L, Pometlová M, Deykun K, Šlamberová R. Cognitive functions and drug sensitivity in adult male rats prenatally exposed to methamphetamine. Physiol Res 2009; 58:741-750.

14. Acuff-Smith KD, Schilling MA, Fisher JE, Vorhees CV. Stage-specific effects of prenatal d-methamphetamine exposure on behavioral and eye development in rats. Neurotoxicol Teratol 1996; 18:199-215.

15. Nagai T, Noda Y, Ishikawa K, Miyamoto Y, Yoshimura M, Ito M, et al. The role of tissue plasminogen activator in methamphetamine‐related reward and sensitization. J Neurochem 2005; 92:660-667.

16. Nagai T, Takuma K, Dohniwa M, Ibi D, Mizoguchi H, Kamei H, et al. Repeated methamphetamine treatment impairs spatial working memory in rats: reversal by clozapine but not haloperidol. Psychopharmacology 2007; 194:21-32.

17. Melega WP, Williams AE, Schmitz DA, DiStefano EW, Cho AK. Pharmacokinetic and pharmacodynamic analysis of the actions of D-amphetamine and D-methamphetamine on the dopamine terminal. J Pharmacol Exp Ther 1995; 274:90-96.

18. Herring NR, Schaefer TL, Gudelsky GA, Vorhees CV, Williams MT. Effect of (+)-methamphetamine on path integration learning, novel object recognition, and neurotoxicity in rats. Psychopharmacology 2008; 199:637-650.

19. Miladi-Gorji H, Rashidy-Pour A, Fathollahi Y, Akhavan MM, Semnanian S, Safari M. Voluntary exercise ameliorates cognitive deficits in morphine dependent rats: the role of hippocampal brain-derived neurotrophic factor. Neurobiol Learn Mem 2011; 96:479-491.

20. Miladi Gorji H, Rashidy-Pour A, Fathollahi Y. Effects of morphine dependence on the performance of rats in reference and working versions of the water maze. Physiol Behav 2008; 93:622-627.

21. Vorhees CV, Skelton MR, Williams MT. Age-dependent effects of neonatal methamphetamine exposure on spatial learning. Behav Pharmacol 2007; 18:549-562.

22. Šlamberová R, Mikulecká A, Pometlová M, Schutová B, Hrubá L, Deykun K. The effect of methamphetamine on social interaction of adult male rats. Behav Brain Res 2010; 214:423-427.

23. Sokolov BP, Schindler CW, Cadet JL. Chronic methamphetamine increases fighting in mice. Pharmacol Biochem Behav 2004; 77:319-326.

24. Wallace TL, Gudelsky GA, Vorhees CV. Methamphetamine-induced neurotoxicity alters locomotor activity, stereotypic behavior, and stimulated dopamine release in the rat. J Neurosci 1999; 19:9141-9148.

25. Herring NR, Schaefer TL, Tang PH, Skelton MR, Lucot JP, Gudelsky GA, et al. Comparison of time-dependent effects of (+)-methamphetamine or forced swim on monoamines, corticosterone, glucose, creatine, and creatinine in rats. BMC Neurosci 2008; 9:49.

26. Williams MT, Morford LL, Wood SL, Wallace TL, Fukumura M, Broening HW, et al. Developmental D‐methamphetamine treatment selectively induces spatial navigation impairments in reference memory in the Morris water maze while sparing working memory. Synapse 2003; 48:138-148.

27. White S, Laurenzana E, Hendrickson H, Gentry WB, Owens SM. Gestation time-dependent pharmacokinetics of intravenous (+)-methamphetamine in rats. Drug Metab Dispos 2011; 39:1718-1726.

28. North A, Swant J, Salvatore MF, Gamble‐george J, Prins P, Butler B, et al. Chronic methamphetamine exposure produces a delayed, long‐lasting memory deficit. Synapse 2013; 67:245-257.

29. Schröder N, O'Dell SJ, Marshall JF. Neurotoxic methamphetamine regimen severely impairs recognition memory in rats. Synapse 2003; 49:89-96.

30. Hopkins KJ, Wang G-J, Schmued LC. Temporal progression of kainic acid induced neuronal and myelin degeneration in the rat forebrain. Brain Res 2000; 864:69-80.

31. Thrash B, Karuppagounder SS, Uthayathas S, Suppiramaniam V, Dhanasekaran M. Neurotoxic effects of methamphetamine. Neurochem Res 2010; 35:171-179.