Methamphetamine Psychosis Model: Simulation of Behaviors Induced by Methamphetamine Treatment in Rodents

Review Article

Methamphetamine Psychosis Model: Simulation of Behaviors Induced by Methamphetamine Treatment in Rodents

Corresponding author: Dr. Takayoshi Mamiya, Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan.


Methamphetamine (METH), an amphetamine related compound, is one of highly addictive psychostimulants. In these past 20 years, METH abuse has significantly risen worldwide, and is becoming increasingly problematic. METH abusers often suffer long-lasting cognitive deficits, psychosis, mood disorders, suicidal ideations, anxiety, hostility, psychomotor dysfunction, and in extreme cases paranoia, hallucinations, and delusions. Various animal models treated with METH have been produced and utilized, in order to investigate the neural influences of METH. Similar treatment regimens are used for behavioral observation carried out after METH treatment for 5-20 days with/without 1 day-10 weeks withdrawal in mice or rats.

In particular, behavioral sensitization, which is characterized by enhanced locomotor activity in response to a low challenge dose of METH even after the long-term withdrawal, is most useful and established phenomenon in rodents. Under such treatments, the rodents also show the memory deficits, depression, psychological dependence, and social withdrawal. Single METH treatment induces psychiatric symptoms, such as self-injurious behavior, anxiety observed in elevated plus-maze, and sensorimotor deficits in prepulse inhibition test. We can usually simulate a few aspects of complex psychotic behaviors observed in humans using animals, while repeated use of METH in human is multifaceted problems. We believe that those METH psychosis models of rodents will be helpful for clarifying the neuronal mechanism in METH abusers and the development of new therapeutic targets.


Methamphetamine (METH) is one of highly addictive psychostimulants [1-3] with reinforcing properties that are comparable to those of cocaine [4,5]. Till 1990s, most investigators who were interested in psychostimulants, focused on cocaine and amphetamine. During the past 20 years, METH abuse has been becoming an increasing problem. The United Nations Office on Drugs and Crime (UNODC) reports that the majority of METH and amphetamine users reside in Southeast Asia and North America, and the largest METH sources are in these areas [6,7]. METH abusers often suffer from long-lasting psychiatric and cognitive symptoms.

METH is a cationic lipophilic molecule that has dramatic effects on not only peripheral, but also central nervous system [8]. Generally, METH is metabolized by monoamine oxidase (MAO) in the liver to amphetamine, which is dependent on pH (Figure 1). Both METH and amphetamine are metabolized to 4-hydroxylation by P450 (CYP2D6) in human [9]. Early studies reported that amphetamine, 4-hydroxyamphetamine, and 4-hydroxyMETH are excreted in the urine as the dominant metabolites, which are almost 50 % of all metabolites excreted [10]. METH is more potent in the central nervous system than its metabolite, amphetamine, because a higher lipophilicity of METH allows a greater penetration through blood brain barrier [11]. Additionally, similar to amphetamine, METH stimulates the release of newly synthesized catecholamines and blocks the presynaptic reuptake of these neurotransmitters mediated through the dopamine transporter, which regulates dopaminergic transmission by facilitating dopamine reuptake [12]. Immediately after METH injection, users experience a number of highly desirable sensations, including a sense of euphoria caused by elevated levels of dopamine. Other desirable sensations associated with METH include increased productivity, heightened attentiveness and curiosity, hypersexuality, decreased anxiety, and increased energy [11,13]. Administration mode of METH varies the euphoric feelings in intensity and duration. Smoking or intravenous injecting of METH lead to intense, but brief euphoria. Oral ingestion or snorting of METH lead to a slightly less intense, but more long-lasting, “high” [14]. The excessive stimulation of the sympathetic nervous system also leads to a number of undesirable pharmacological effects, including tachycardia, hypertension, papillary dilation, diaphoresis, tachypnea, peripheral hyperthermia, and hyperpyrexia [11]. Repeated use of METH results in a depletion of catecholamines and has been shown to produce withdrawal symptoms marked by psychiatric complaints [11]. Withdrawal from METH, also known as “crashing”, can produce a constellation of symptoms including anhedonia, irritability, fatigue, depression, social deficits, aggression, and an intense craving for the drugs [11,15,16]. A number of psychological and behavioral studies have been identified as being related to repeated use of METH, including euphoric disinhibition, impaired judgment, grandiosity, and psychomotor agitation [7,11,17,18]. Additionally, results from neuroimaging, psychological and psychiatric studies have shown that heavy use of METH contributes to many psychiatric pathologies including cognitive deficits, psychosis, mood disorders, suicidal ideations, anxiety, hostility, psychomotor dysfunction [17,19,20-23], and in extreme cases paranoia, hallucinations, and delusions [24]. There is also compelling evidence that the negative consequences of METH abuse are due, at least in a part, to the brain caused by the neurotoxicity of METH.

Figure 1.

In order to develop new drugs for the treatment of METH psychosis patients, suitable animal models are needed. Generally, in the animal experiments, it seems that the regimen of repeated METH administration is used rather than single treatment. Animals exposed to repeated METH are necessary which should promise to induce significant changes in the behavioral parameters relevant to symptoms by METH in human. Animals usually simulate one or a few aspects of complex psychotic behaviors observed in humans, while repeated use of METH in human is multifaceted problems. Thus, various animal models have been reported to target distinct diagnostic characters of human symptoms. It is summarized that METH-induced major symptom in human and the tests to detect similar behaviors in rodents (Table 1). In this review, I picked up 6 symptoms; sensitization, cognitive impairments, anxiety, withdrawal, depression, and suicidal ideation. For those symptoms, in rodents it is thought to be similar, locomotor activity, learning/memory in the maze, the response to the height in the plus maze, social interaction, the response to the water, and self-injurious behavior, respectively. Investigators have established METH-induced abnormal behaviors in the animals to clarify the relationship between the long-lasting neurobiological effects of METH and the impaired performances of treated animals in several tasks.

Table 1.

Methamphetamine in rodents


Repeated administration of psychostimulants could induce behavioral sensitization characterized by enhanced locomotor activity to a low challenge dose of each stimulant even after the long-term withdrawal of psychostimulants in rodents. Behavioral sensitization by repeated treatment with METH could be observed without special technique and well established. Although methodological details differ among laboratories, any protocol for studying locomotor sensitization should use a route of administration with a fast onset of the drug’s effect. A number of reports use the similar regimens that behavioral tests were carried out 0-60 day-withdrawal after METH treatment (0.5-5 mg/kg) for 5-20 days in adult rats and mice (see, Table 2). Most groups administer once daily for several days. Our group fixes the subcutaneous treatment with METH

Table 2. Procedures for behavioral sensitization of locomotion in rodents.

Table 3. Water maze test.

(1 mg/kg) once daily for 7 days in mice [25-30] and METH (2 mg/kg) once daily for 5 days in rats [25,31,32] and those animals demonstrate behavioral (locomotor) sensitization without a challenge of METH. As shown in table 3, when the researchers analyze the behavioral sensitization, a same or less dose of METH is challenged after a few-10 day-drug free periods. The hyperlocomotion by a METH challenge could be observed in rodents after even lower frequency of drug treatment, once in two or more days.

Inhibition of dopamine transporter by METH leads to increase in synaptic dopamine, and then enhances dopaminergic system. This dopaminergic system especially in the mesocorticolimbic pathway plays a critical role in the initiation of behavioral sensitization [33], whereas different neurotransmitter systems such as glutamate, and serotonin transmission may be implicated [34]. The increase in striatal and accumbens extracellular dopamine is augmented following repeated treatment with METH as well as amphetamine [35]. Repeated METH exposure results in neuroplastic changes that could also lead to addictive behaviors through processes independent of those engaged in sensitization [36]. It is possible that METH-induced behavioral sensitization may reflect one of nonaddictive human symptoms. Amphetamine abuse can lead to increased anxiety and paranoia that closely resembles that found in paranoid schizophrenia [37,38]. Because of these shared characteristics, it has suggested that sensitization to METH may be a useful animal model of schizophrenia [34].

Cognitive impairments

Cognitive functions are evaluated by various behavioral tasks, including Morris water maze, object recognition, T-maze, sensorimotor gating by prepulse inhibition tests.

Spatial learning in Morris water maze: Morris water maze (MWM) task is generally considered to assess the ability of spatial learning and memory which is dependent on the hippocampus. This test can examine the ability of an animal to locate a platform that has been submerged beneath the surface of the water in order to escape from an aversive environment [39]. Most reports use the similar regimens that behavioral tests were carried out 1-10 weeks withdrawal after METH treatment (4-30 mg/kg) for 5-10 days in rats (see table 3). Friedman et al. [40] have been reported that METH (12.5 mg/kg x 4) with 65-days withdrawal induced the impairment of acquisition in spatial learning task. It has shown that repeated METH (10 mg/kg) for 7 days impaired spatial learning [41,42]. The animals were trained again in the MWM with the platform positioned in the opposite direction compared with the first training session. Acquisition of the “reversal of spatial learning” was evaluated as indexed by time spent in the area with the newly fixed platform. Under this experimental design, Chapman et al. [43] showed that impaired reversal learning 7 days after treatment was apparent in METH-treated rats.

There are reports examined the neurotoxicological influences of METH during prenatal or postnatal development of rodents. Acuff-Smith et al. [44] have shown that the METH exposures to rats during early stages of brain development (E7-12 and E13-18) failed to affect the spatial learning at adult. In later stages of brain development, higher frequency of exposure to METH (5-30 mg/kg) during P11-P20 exhibited spatial learning deficits, without affecting cued acquisition in rats [45-47] and in mice [48]. In addition, treatment of offspring on fewer days (P11-P15) caused similar MWM deficits [46].

Object recognition: The novel object recognition task could evaluate the rodents’ recalling which of two objects in the tests arena they encountered previously, with recognition memory being inferred from time spent exploring each object. This task has both training and retention sessions. During training session, animals explore two identical objects, one of which is replaced by a novel object immediately or some minutes later (short-term memory) or 24-48 hours later (long-term memory). In the retention session, in contrast to vehicle-treated animals, which demonstrate memory for the familiar object by spending the majority of their time in the retention session exploring the novel object, animals given METH in our protocol (1 mg/kg) for 7 days [26,30] or single-day 4x4mg/kg [41] dosing regimen showed no significant preference for novel object. In the retention session, METH-induced recognition deficits were seen 1 or 3 weeks after the administration in rats [41,49,50] and mice [26,51-53]. These METH-induced impairments were observed for both short- and long-term memory tests.

Spatial memory by T-maze: T-maze task is being utilized as a spatial and working memory task; mice have to learn a complex route to find the reward. Memory retention is evaluated as the ability of mice to locate the hidden food with decrement of latency and increment of correct decisions [54]. In this test, METH (2 mg/kg once daily for 5 days) produced dose-dependently the errors of food rewards consumed in the T-maze [55]. It is also reported that repeated METH (10 mg/kg once daily for 7 days) increased error counts during task [42].

Sensorimotor gating: Prepulse inhibition (PPI) of the startle reflex is commonly viewed as an operational measure of a process called “sensorimotor gating”, by which excess or trivial stimuli are screened or “gated out” of awareness [56,57]. PPI is the reduction of the startle response, which occurs when a weak sensory stimulus (prepulse) is presented several hundred milliseconds before a sudden intense stimulus (pulse) [58,59], is also a cross-species phenomenon. This behavioral impairment is also considered to be one of schizophrenia models. Deficits of PPI by a single treatment of METH (1 mg/kg) in mice [60,61] and (3 mg/kg) in rats [62,63] can be observed.


Elevated plus-maze: Elevated plus-maze is one of assays that are generally used to evaluate the anxiety induced by acute behavioral stress in rodents. It is reliably detects anxiolytic and anxiogenic activity of therapeutic and experimental drugs of different classes [64]. In acute METH treatment, Hayase et al. [65,66] has been reported that it at 4 mg/kg decreases the number of entries to and the time spent on the open arms, whereas at 2-20 mg/kg did not affect them compared to the vehicle treated mice [67]. On the contrary, there is a report that very low dose of METH (0.1 mg/kg) induces increase in both values in rats [68].

Light-dark box test: In the light-dark box, which consists of two black and white compartments test, rodents tend to avoid the white compartment, thus, the measures of exploration in this area are used as indices of anxiety. Mice treated with repeated METH (10 mg/kg x 4 per day) for 7 days increase the time spent in the dark box, suggesting that mice feel anxiety [42].

Conditioned fear stress test: Conditioned fear test is regarded as psychological stress and a simple animal model of anxiety or fear [69]. Conditioned suppression (freezing) in response to the same chamber which animals were received electric foot-shock in rats is observed. This suppression is decreased by acute METH at 1 mg/kg [70], but increased by escalating doses (1.25-5 mg/kg) of it [71,72].


Social interaction: Rodents are a social species and display behavioral social interaction (SI) [73]. SI measures in rodents are directly analogous to SI in humans, and have been therefore used to model both anxiety and negative symptoms of schizophrenia and autisms in rodents [28]. The dependent measure is amount of time a test animal spends engaged in active social behavior (e.g. sniffing, approaching, following, communal grooming, climbing on or under, etc) with an unfamiliar “stimulus” mouse. An increase in anxiety results in a decrease in SI time [74,75]. Single-day 2.5-5 x 4 mg/kg dosing regimen with 4 weeks withdrawal decrease in SI duration is associated with both serotonin and dopamine reductions [76-78]. It has been reported that rats treated with a METH (8 mg/kg) injection for 16 weeks followed by a 7-week period of abstinence showed the SI duration in adult rats [79].


Forced swimming test: Forced swimming test is the most widely used model for assessing pharmacological antidepressant activity [80]. The test is based upon the observation that rodents eventually develop immobility when they are placed in cylinder of water after they stop active escape behaviors, such as climbing or swimming. In this test, it has been demonstrated that a single dose of METH (1 mg/kg) reduces the immobility time in rats [81]. There are recent reports that acute METH treatment (4 mg/kg) failed to affect the time in rats [77], on the contrary it prolonged the immobility time in mice [40,42,82] have been reported that 14-day METH (0.3 and 1 mg/kg) does not influence the immobility time in mice.

Psychostimulant dependence has been studied with animal models, such as conditioned place preference and drug self-administration [83,84].

Conditioned place preference: Conditioned place preference (CPP) is a useful task to evaluate the psychological dependence in rodents. Usually, drug-induced CPP is designed to examine the rewarding effects of addictive drugs. Drug-induced CPP refers to the development of preference for an environment (such as one compartment of a two-compartment apparatus) that has previously been associated with the subjective effects provided by administration of a drug. Although methodological details differ among laboratories, a typical CPP procedure includes the pairing of environmental (contextual) cues with the stimulus of interest (drug or food). For example, a distinctive environment (one side of the testing chamber) is repeatedly paired with the administration of METH, and a different environment (the other side of the chamber) is repeatedly associated with the administration of vehicle (saline). This conditioning period depends on the laboratories for 4-20 times (Table 4). Following conditioning, animals are subjected to a choice trial in which they receive unrestricted exposure to both sides of the testing chamber in the absence of the previously administered drug. An increase in time spent in the drug-paired side relative to the vehicle-paired side is taken as evidence that the previously administered drug is rewarding and psychological dependence.

Drug self-administration: The animal model of drug self administration have been developed originally to assess the ability of a drug to serve as a reinforcer when delivered intravenously through chronic indwelling catheters in rats [85]. This model subsequently came to be seen as a valid approach to studying variables related to human drug-taking behavior. Furthermore, this model and its extensions have been widely used in basic/preclinical drug abuse research. Once an animal has learned to intravenously self-administer a drug, the influences of drug priming, stressors, or presentation of drug-associated stimuli on drug self-administration behavior or relapse to extinguished drug-seeking behavior provide useful measures for studying several distinct behavioral aspects of drug dependence [86]. These behavioral aspects provide good face validity for human addiction and relapse, as well as adequate predictive validity and potential construct validity [87]. Recent reports have also emphasized the so-called incubation of rats that increase their responding on a previously drug-paired lever when they are repeatedly exposed to drug-associated stimuli but not the drug itself [88]. Our group has been established and clarified the molecular mechanism of METH-taking behavior in mice [84,89-92].

Table 4. Procedures for conditioned place preference in rodents.

Other measures

Self-injury behavior: Self-injury behavior (SIB) is one of the unique behaviors by METH treatment and consists of skin-picking, self-biting around the chest. These abnormal behaviors are observed in rodents with both acute and repeated METH. There are reported that acute METH (10, 15 and 20, but not 5 mg/kg) produces SIB and the phenomenon were implicated with not only dopaminergic, but also glutamatergic and serotonergic system in mice [93-95]. It is reported that 4 injections of 4 mg/kg in one day also induces self-biting that causes a break in the skin [96].

Sexual behavior: METH abusers use this drug for feeling the ecstasy of sexual behaviors in humans. In male rats, acute METH (4 or 5 mg/kg) inhibits the intromitting and ejaculating behavior was reported [97,98], but it has shown the enhanced effects of METH at 4, 16 and 64 mg/kg [99].


METH reproduces many neuropsychological symptoms in rodents as well as human. A number of neuropsychological, psychiatric and neuroimaging studies have been identified as being related to use of METH including cognitive deficits, mood disorders, suicidal ideations, anxiety, hostility, psychomotor dysfunction, and in extreme cases paranoia, hallucinations, and delusions. We can usually simulate one or a few aspects of complex psychotic behaviors observed in humans using animals, while repeated use of METH in human is multifaceted problems. Additionally, since METH induces many of the deficits associated with schizophrenia, especially those most closely associated with positive symptoms, it is often considered and utilized as a schizophrenia model. We hope and believe that the METH psychosis rodent models will be helpful for clarifying the neuronal mechanism in METH abusers and the development of new therapeutic drugs.


This work was supported by JSPS KAKENHI (Grant Numbers 24590304 and 22790233); the Research Project Supported by the Takeda Science Foundation; the Nakatomi Foundation; the Smoking Research Foundation Grant for Biomedical Research; the Sasakawa Scientific Research Grant from the Japan Science Society; and Basic Research Grants from the Japan Health and Research Institute and the Aichi Health Promotion Foundation.


1.Woolverton WL, Cervo L, Johanson CE. Effects of repeated methamphetamine administration on methamphetamine self-administration in rhesus monkeys. Pharmacol Biochem Behav. 1984, 21(5): 737-741.

2.Cho AK. Ice: A New Dosage Form of an Old Drug. Science. 1990, 249(4969): 631-634.

3.Hart CL, Ward AS, Haney M, Foltin RW, Fischman MW. Methamphetamine self-administration by humans. Psychopharmacology (Berl). 2001, 157(1): 75-81.

4.Peltier RL, Li DH, Lytle D, Taylor CM, Emmett-Oglesby MW. Chronic d-amphetamine or methamphetamine produces cross-tolerance to the discriminative and reinforcing stimulus effects of cocaine. J Pharmacol Exp Ther. 1996, 277(1): 212-218.

5.Shimosato K, Ohkuma S. Simultaneous monitoring of conditioned place preference and locomotor sensitization following repeated administration of cocaine and methamphetamine. PharmacolBiochemBehav. 2000, 66(2):285-292.

6.The United Nations Office on Drugs and Crime (UNODC). World Drug Report, 2008. Vienna, Austria: UNODC Research and Analysis Section, 2008.

7.Winslow BT, Voorhees KI, Pehl KA. Methamphetamine abuse. Am Fam Physician. 2007, 76(8): 1169-1174.

8.Davidson C, Gow AJ, Lee TH, Ellinwood EH. Methamphetamine neurotoxicity: necrotic and apoptotic mechanisms and relevance to human abuse and treatment. Brain Res Brain Res Rev. 2001, 36(1): 1-22.

9.Lin LY, Di Stefano EW, Schmitz DA, Hsu L, Ellis SW et al. Oxidation of methamphetamine and methylenedioxymethamphetamine by CYP2D6. Drug MetabDispos. 1997, 25(9): 1059-1064.

10.Caldwell J, Dring LG, Williams RT. Metabolism of (14C) methamphetamine in man, the guinea pig and the rat. Biochem J. 1972, 129(1): 11-22.

11.Meredith CW, Jaffe C, Ang-Lee K, Saxon AJ. Implications of chronic methamphetamine use: a literature review. Harv Rev Psychiatry. 2005, 13(3): 141-154.

12.Cho AK, Melega WP. Patterns of methamphetamine abuse and their consequences. J Addict Dis. 2002, 21(1): 21-34.

13.Cretzmeyer M, Sarrazin MV, Huber DL, Block RI, Hall JA. Treatment of methamphetamine abuse: research findings and clinical directions. J Subst Abuse Treat. 2003, 24(3): 267-277.

14.Homer BD, Solomon TM, Moeller RW, Mascia A, DeRaleau L et al. Methamphetamine abuse and impairment of social functioning: a review of the underlying neurophysiological causes and behavioral implications. Psychol Bull. 2008, 134(2): 301-310.

15.Cantwell B, McBride AJ. Self detoxication by amphetamine dependent patients: a pilot study. Drug Alcohol Depend. 2008, 49(2): 157-163.

16.Newton TF, Kalechstein AD, Duran S, Vansluis N, Ling W. Methamphetamine abstinence syndrome: preliminary findings. Am J Addict. 2004, 13(3): 248-255.

17.Batki SL, Harris DS. Quantitative drug levels in stimulant psychosis: relationship to symptom severity, catecholamines and hyperkinesias. Am J Addict. 2004, 13(5): 461-470.

18.Richards JR, Bretz SW, Johnson EB, Turnipseed SD, Brofeldt BT et al. Methamphetamine abuse and emergency department utilization. West J Med. 1999, 170(4): 198-202.

19.Goldstein RZ, Volkow ND. Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex. Am J Psychiatry. 2002, 159(10): 1642-1652.

20.Caligiuri MP, Buitenhuys C. Do preclinical findings of methamphetamine-induced motor abnormalities translate to an observable clinical phenotype? Neuropsychopharmacology. 2005, 30(1): 2125-2134.

21.Gonzalez R, Rippeth JD, Carey CL, Heaton RK, Moore DJ et al. Neurocognitive performance of methamphetamine users discordant for history of marijuana exposure. Drug Alcohol Depend. 2004, 76(2): 181-190.

22.London ED, Simon SL, Berman SM, Mandelkern MA, Lichtman AM et al. Mood disturbances and regional cerebral metabolic abnormalities in recently abstinent methamphetamine abusers. Arch Gen Psychiatry. 2004, 61(1): 73-84.

23.Zweben JE, Cohen JB, Christian D, Galloway GP, Salinardi M et al. Methamphetamine treatment project: Psychiatric symptoms in methamphetamine users. Am J Addict. 2004, 13(2): 181-190.

24.Logan BK. Methamphetamine and driving impairment. J Forensic Sci. 1996, 41(13): 457-464.

25.Nagai T, Noda Y, Ishikawa K, Miyamoto Y, Yoshimura M et al. The role of tissue plasminogen activator in methamphetamine-related reward and sensitization. J Neurochem. 2005, 92(3): 660-667.

26.Kamei H, Nagai T, Nakano H, Togan Y, Takayanagi M et al. Repeated methamphetamine treatment impairs recognition memory through a failure of novelty-induced ERK1/2 activation in the prefrontal cortex of mice. Biol Psychiatry. 2006, 59(1): 75-84.

27.Niwa M, Nitta A, Yamada Y, Nakajima A, Saito K et al. Tumor necrosis factor-alpha and its inducer inhibit morphine-induced rewarding effects and sensitization. Biol Psychiatry. 2007, 69(6): 658-668.

28.Crawley JN. Mouse behavioral assays relevant to the symptoms of autism. Brain Pathol. 2007, 17(4): 448-459.

29.Cen X, Nitta A, Ibi D, Zhao Y, Niwa M et al. Identification of Piccolo as a regulator of behavioral plasticity and dopamine transporter internalization. Mol Psychiatry. 2008, 13(4): 349,451-463.

30.Fukakusa A, Nagai T, Mizoguchi H, Otsuka N, Kimura H et al. Role of tissue plasminogen activator in the sensitization of methamphetamine-induced dopamine release in the nucleus accumbens. J Neurochem. 2008, 105(2): 436-444.

31.Ishikawa K, Nitta A, Mizoguchi H, Mohri A, Murai R et al. Effects of single and repeated administration of methamphetamine or morphine on neuroglycan C gene expression in the rat brain. Int J Neuropsychopharmacol. 2006, 9(4): 407-415.

32.Mizoguchi H, Yamada K, Mouri A, Niwa M, Mizuno T et al. Role of matrix metalloproteinase and tissue inhibitor of MMP in methamphetamine-induced behavioral sensitization and reward: implications for dopamine receptor down-regulation and dopamine release. J Neurochem. 2007a, 102(5): 1548-1560.

33.Kalivas PW, Stewart J. Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity. 1991, 16(3): 223-244.

34.D’amico E J, Ellickson P L, Wagner E F, Turiusi R, Fromme K et al. Developmental considerations for substance use interventions from middle school through college. Alcoholism: Clinical and Experimental Research. 2005, 29: 474-483.

35.Sharp T, Zetterstrom T, Ljungberg T. A direct comparison of amphetamine-induced be haviours and regional brain dopamine release in the rat using intracerebral dialysis. Brain Res. 1987, 401(12): 322-330, 401: 322-330.

36.Kalivas, PW. How we do determine which drug-induce neuroplastic changes are important? Nat Neurosci. 2005, 8: 1440-1441.

37.Ellinwood EH Jr, Sudilovsky A, Nelson LM. Evolving behavior in the clinical and experimental amphetamine (model) psychosis. Am J Psychiatry. 1973, 130(10) :1088-1093.

38.Angrist B, Gershon S. Clinical response to several dopamine agonists in schizophrenic and nonschizophrenic subjects. AdvBiochemPsychopharmacol. 1977, 16: 677-680.

39.Morris RG, Garrud P, Rawlins JN, O’Keefe J. Place navigation impaired in rats with hippocampal lesions. Nature. 1982, 297(5868): 681-683.

40.Friedman SD, Castañeda E, Hodge GK. Long-term monoamine depletion, differential recovery, and subtle behavioral impairment following methamphetamine-induced neurotoxicity. PharmacolBiochemBehav. 1988, 61(1): 35-44.

41.Schröder N, O’Dell SJ, Marshall JF. Neurotoxic methamphetamine regimen severely impairs recognition memory in rats. Synapse. 49(2): 89-96.

42.Wu CF, Liu YL, Song M, Liu W, Wang JH et al. Protective effects of pseudoginsenoside-F11 on methamphetamine-induced neurotoxicity in mice. PharmacolBiochem Behav. 2003, 76(1): 103-109.

43.Chapman DE, Hanson GR, Kesner RP, Keefe KA. Long-term changes in basal ganglia function after a neurotoxic regimen of methamphetamine. J PharmacolExpTher. 2001, 296(2): 520-527.

44.Acuff-Smith KD, Schilling MA, Fisher JE, Vorhees CV. Stage-specific effects of prenatal d-methamphetamine exposure on behavioral and eye development in rats. NeurotoxicolTeratol. 1996, 18(2): 199-215.

45.Vorhees CV, Ahrens KG, Acuff-Smith KD, Schilling MA, Fisher JE. Methamphetamine exposure during early postnatal development in rats: I. Acoustic startle augmentation and spatial learning deficits. Psychopharmacology (Berl). 1994, 114(3): 392-401.

46.Williams MT, Brown RW, Vorhees CV. Neonatal methamphetamine administration induces region-specific long-term neuronal morphological changes in the rat hippocampus, nucleus accumbens and parietal cortex. Eur J Neurosci. 2004, 19(12): 3165-3170.

47.Skelton MR, Williams MT, Schaefer TL, Vorhees CV. Neonatal (+)-methamphetamine increases brain derived neurotrophic factor, but not nerve growth factor, during treatment and results in long-term spatial learning deficits. Psychoneuroendocrinology. 2007, 32(6): 734-745.

48.Acevedo SF, de Esch IJ, Raber J. Sex- and histamine-dependent long-term cognitive effects of methamphetamine exposure. Neuropsychopharmacology. 2007, 32(3): 665-672.

49.Belcher AM, Feinstein EM, O’Dell SJ, Marshall JF. Methamphetamine influences on recognition memory: comparison of escalating and single-day dosing regimens. Neuropsychopharmacology. 2008, 33(6): 1453-1463.

50.Marshall JF, Belcher AM, Feinstein EM, O’Dell SJ. Methamphetamine-induced neural and cognitive changes in rodents. Addiction. 2007, 102(S1): 61-69.

51.Ito Y, Takuma K, Mizoguchi H, Nagai T, Yamada K. A novel azaindolizinone derivative ZSET1446 (spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one) improves methamphetamine-induced impairment of recognition memory in mice by activating extracellular signal-regulated kinase 1/2. J PharmacolExpTher. 2007, 320(2): 819-827.

52.Nagai T, Takuma K, Dohniwa M, Ibi D, Mizoguchi H et al. Repeated methamphetamine treatment impairs spatial working memory in rats: reversal by clozapine but not haloperidol. Psychopharmacology (Berl). 2007, 194(1): 21-32.

53.Mizoguchi H, Takuma K, Fukakusa A, Ito Y, Nakatani A et al. Improvement by minocycline of methamphetamine-induced impairment of recognition memory in mice. Psychopharmacology (Berl) 196(2): 233-241.

54.Gerlai R. Behavioral tests of hippocampal function: simple paradigms complex problems. Behav Brain Res. 2001, 125(1-2): 269-277.

55.Shoblock JR, Maisonneuve IM, Glick SD. Differences between d-methamphetamine and d-amphetamine in rats: working memory, tolerance, and extinction. Psychopharmacology (Berl). 2003, 170(2): 150-156.

56.Hoffman HS, Ison JR. Reflex modification in the domain of startle: I. Some empirical findings and their implications for how the nervous system processes sensory input. Psychol Rev. 1980, 87(2): 175-189.

57.Braff DL, Geyer MA. Sensorimotor gating and schizophrenia. Human and animal model studies. Arch Gen Psychiatry. 1990, 47(2):181-188.

58.Swerdlow NR, Braff DL, Geyer MA. Cross-species studies of sensorimotor gating of the startle reflex. Ann N Y AcadSci. 1999, 877: 202-216.

59.Swerdlow NR, Geyer MA, Braff DL. Neural circuit regulation of prepulse inhibition of startle in the rat: current knowledge and future challenges. Psychopharmacology (Berl). 2001, 156(2-3): 194-215.

60.Dai H, Okuda T, Sakurai E, Kuramasu A, Kato M, Jia F et al. Blockage of histamine H1 receptor attenuates social isolation-induced disruption of prepulse inhibition: a study in H1 receptor gene knockout mice. Psychopharmacology (Berl). 2005, 183(3): 285-293.

61.Arai S, Takuma K, Mizoguchi H, Ibi D, Nagai T et al. Involvement of pallidotegmental neurons in methamphetamine- and MK-801-induced impairment of prepulse inhibition of the acoustic startle reflex in mice: reversal by GABAB receptor agonist baclofen. Neuropsychopharmacology. 2008, 33(13): 3164-3175.

62.Maehara S, Hikichi H, Satow A, Okuda S, Ohta H. Antipsychotic property of a muscarinic receptor agonist in animal models for schizophrenia. PharmacolBiochemBehav. 2008, 91(1): 140-149.

63.Satow A, Maehara S, Ise S, Hikichi H, Fukushima M et al. Pharmacological effects of the metabotropic glutamate receptor 1 antagonist compared with those of the metabotropic glutamate receptor 5 antagonist and metabotropic glutamate receptor 2/3 agonist in rodents: detailed investigations with a selective allosteric metabotropic glutamate receptor 1 antagonist, FTIDC [4-[1-(2-fluoropyridine-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide].J PharmacolExpTher. 2008, 326(2): 577-586.

64.Pellow S, Chopin P, File SE, Briley M. Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods. 1985, 14(3): 149-167.

65.Hayase T, Yamamoto Y, Yamamoto K. Persistent anxiogenic effects of a single or repeated doses of cocaine and methamphetamine: interactions with endogenous cannabinoid receptor ligands. BehavPharmacol. 2005, 16(5-6): 395-404.

66.Hayase T, Yamamoto Y, Yamamoto K. Behavioral effects of ketamine and toxic interactions with psychostimulants. BMC Neurosci. 2006, 7: 25.

67.Kitanaka J, Kitanaka N, Tatsuta T, Morita Y, Takemura M. Blockade of brain histamine metabolism alters methamphetamine-induced expression pattern of stereotypy in mice via histamine H1 receptors. Neuroscience. 2007, 147(3): 765-777.

68.Szumlinski KK, Haskew RE, Balogun MY, Maisonneuve IM, Glick SD. Iboga compounds reverse the behavioural disinhibiting and corticosterone effects of acute methamphetamine: Implications for their antiaddictive properties. PharmacolBiochemBehav. 2000, 69(3-4): 485-491.

69.Fanselow MS, Helmstetter FJ. Conditional analgesia, defensive freezing, and benzodiazepines. BehavNeurosci. 1988, 102(2): 233-243.

70.Kameyama T, Nagasaka M. Effects of apomorphine and methamphetamine on a quickly-learned conditioned-suppression response in rats. Neuropharmacology. 1983, 22(7): 813-817.

71.Tsuchiya K, Inoue T, Izumi T, Hashimoto S, Koyama T. Effects of footshock stress on regional brain monoamine metabolism and the acquisition of conditioned freezing in rats previously exposed to repeated methamphetamine. ProgNeuropsychopharmacolBiol Psychiatry. 1996, 20(7): 1239-1250.

72.Tsuchiya K, Inoue T, Koyama T. Effect of repeated methamphetamine pretreatment on freezing behavior induced by conditioned fear stress. PharmacolBiochemBehav. 1996, 54(4): 687-691.

73.File SE, Seth P. A review of 25 years of the social interaction test. Eur J Pharmacol. 2003, 463(1-3): 35-53.

74.File SE, Hyde JR. Can social interaction be used to measure anxiety? Br J Pharmacol. 1978, 62(1): 19-24.

75.File SE. The use of social interaction as a method for detecting anxiolytic activity of chlordiazepoxide-like drugs. J Neurosci Methods. 1980, 2(3): 219-238.

76.Brown PL, Wise RA, Kiyatkin EA. Brain hyperthermia is induced by methamphetamine and exacerbated by social interaction. J Neurosci. 2003, 123(9): 3924-3929.

77.Clemens KJ, Cornish JL, Li KM, Hunt GE, McGregor IS. MDMA (‘Ecstasy’) and methamphetamine combined: order of administration influences hyperthermic and long-term adverse effects in female rats. Neuropharmacology. 2005, 49(2): 195-207.

78.Clemens KJ, Van Nieuwenhuyzen PS, Li KM, Cornish JL, Hunt GE, McGregor IS. MDMA (“ecstasy”), methamphetamine and their combination: long-term changes in social interaction and neurochemistry in the rat. Psychopharmacology (Berl). 2004, 173(3-4): 318-325.

79.Clemens KJ, Cornish JL, Hunt GE, McGregor IS. Repeated weekly exposure to MDMA, methamphetamine or their combination: long-term behavioural and neurochemical effects in rats. Drug Alcohol Depend. 2007, 86(2-3): 183-190.

80.Porsolt RD, Le Pichon M, Jalfre M. Depression: a new animal model sensitive to antidepressant treatments. Nature. 1997, 266(5604): 730-732.

81.Kitada Y, Miyauchi T, Satoh A, Satoh S. Effects of antidepressants in the rat forced swimming test. Eur J Pharmacol. 1981, 72(2-3): 145-152.

82.Noda Y, Yamada K, Furukawa H, Nabeshima T. Enhancement of immobility in a forced swimming test by subacute or repeated treatment with phencyclidine: a new model of schizophrenia. Br J Pharmacol. 1995, 116(5): 2531-2537.

83.Niwa M, Yan Y, Nabeshima T. Genes and molecules that can potentiate or attenuate psychostimulant dependence: relevance of data from animal models to human addiction. Ann N Y AcadSci. 2008, 1141: 76-95.

84.Yan Y, Nabeshima T. Mouse model of relapse to the abuse of drugs: procedural considerations and characterizations. Behav Brain Res. 2009, 196(1): 1-10.

85.Weeks JR. Experimental morphine addiction: method for automatic intravenous injections in unrestrained rats. Science. 1962, 138(3537): 143-144.

86.Shalev U, Grimm J, Shaham Y. Neurobiology of relapse to heroin and cocaine seeking: a review. Pharmacol Rev. 2002, 54(1): 1-42.

87.Epstein DH, Preston KL, Stewart J, Shaham Y. Toward a model of drug relapse: an assessment of the validity of the reinstatement procedure. Psychopharmacology (Berl). 2006, 189(1): 1-16.

88.Grimm JW, Hope B, Wise R, Shaham Y. Incubation of cocaine craving after withdrawal. Nature. 2001, 412(6843): 141-142.

89.Yan Y, Nitta A, Mizoguchi H, Yamada K, Nabeshima T. Relapse of methamphetamine-seeking behavior in C57BL/6J mice demonstrated by a reinstatement procedure involving intravenous self-administration. Behav Brain Res. 2006, 168(1): 137-143.

90.Yan Y, Nitta A, Mizuno T, Nakajima A, Yamada K, Nabeshima T. Discriminative-stimulus effects of methamphetamine and morphine in rats are attenuated by cAMP-related compounds. Behav Brain Res. 2006, 173(1): 39-46.

91.Yan Y, Yamada K, Niwa M, Nagai T, Nitta A et al. Enduring vulnerability to reinstatement of methamphetamine-seeking behavior in glial-cell-line-derived neurotrophic factor mutant mice. FASEB J. 2007, 21(9): 1994-2004.

92.Yan Y, Yamada K, Nitta A, Nabeshima T. Transient drug-primed but persistent cue-induced reinstatement of extinguished methamphetamine-seeking behavior in mice. Behav Brain Res. 2007, 177(2): 261-268.

93.Shishido T, Watanabe Y, Kato K, Horikoshi R, Niwa SI. Effects of dopamine, NMDA, opiate, and serotonin-related agents on acute methamphetamine-induced self-injurious behavior in mice. PharmacolBiochemBehav. 2000, 66(3): 579-583.

94.Mori T, Ito S, Kita T, Sawaguchi T. Effects of dopamine- and serotonin-related compounds on methamphetamine-induced self-injurious behavior in mice. J PharmacolSci. 2004, 96(4): 459-464.

95.Mori T, Ito S, Kita T, Narita M, Suzuki T, Sawaguchi T. Effects of mu-, delta- and kappa-opioid receptor agonists on methamphetamine-induced self-injurious behavior in mice. Eur J Pharmacol. 2004, 532(1-2): 81-87.

96.Kita T, Matsunari Y, Saraya T, Shimada K, O’Hara K, Kubo K et al. Evaluation of the effects of alpha-phenyl-N-tert-butyl nitrone pretreatment on the neurobehavioral effects of methamphetamine. Life Sci. 2000, 67(13): 1559-1571

97.Saito TR, Aoki S, Saito M, Amao H, Niwa T et al. Effects of methamphetamine on copulatory behavior in male rats. JikkenDobutsu. 1991, 40(4): 447-452.

98.Slamberová R, Charousová P, Pometlová M. Maternal behavior is impaired by methamphetamine administered during pre-mating, gestation and lactation. ReprodToxicol. 2005, 20(1): 103-110.

99.Levy Andersen M, Bignotto M, Tufik S. Facilitation of ejaculation after methamphetamine administration in paradoxical sleep deprived rats. Brain Res. 2003, 978(1-2): 31-37.

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