- Email: [email protected]
Behavioural sensitisation to MK-801 is dose-dependent and independent of environmental context
Behavioural Brain Research 298 (2016) 241–245
Contents lists available at ScienceDirect
Behavioural Brain Research journal homepage: www.elsevier.com/locate/bbr
Behavioural sensitisation to MK-801 is dose-dependent and independent of environmental context Emilia M. Lefevre a , Darryl W. Eyles a,b , Thomas H.J. Burne a,b,∗ a b
Queensland Brain Institute, The University of Queensland, St Lucia, QLD 4072, Australia Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Richlands, QLD 4076, Australia
h i g h l i g h t s • Repeated exposure to the NMDA receptor antagonist MK-801 induced locomotor sensitisation in male Sprague Dawley rats. • Sensitisation to MK-801 was dose-dependent. • MK-801 induced sensitisation was not affected by the environmental context in which drug exposure occurred.
a r t i c l e
i n f o
Article history: Received 18 September 2015 Received in revised form 6 November 2015 Accepted 10 November 2015 Available online 28 November 2015 Keywords: Sensitisation MK-801 NMDA receptor Environmental context Animal model Schizophrenia
a b s t r a c t The pathophysiology of schizophrenia is associated with disturbed glutamate signalling, particularly via a dysfunction of the N-methyl-d-aspartate (NMDA) receptor. In rodents, behavioural sensitisation to the NMDA receptor antagonist MK-801 is proposed to recapitulate aspects of the NMDA receptor hypofunction hypothesis of schizophrenia. The aim of this study was to determine the modulatory role of MK-801 dose and environmental context on the development and expression of MK-801-induced behavioural sensitisation. Sprague Dawley rats were administered saline or varying doses of MK-801 (i.p.) once daily for 7 days and locomotor activity was recorded. After 5 days of withdrawal, rats were challenged with their respective dose to test for sensitisation. From this experiment a sensitising dose was obtained. In the second experiment the magnitude of sensitisation was compared between rats that were treated in either a home or test environmental context. Rats treated with 0.25 mg/kg MK-801 developed robust sensitisation when challenged after withdrawal. Rats treated with lower (0.1 mg/kg) or higher (0.5 mg/kg) doses of MK-801 did not develop locomotor sensitisation. Sensitisation to 0.25 mg/kg MK-801 developed equally between rats treated in the home or test context. The study shows that male Sprague Dawley rats develop behavioural sensitisation to repeated injections of MK-801. The development of sensitisation is selective to MK-801 dose in an inverted-U dose response fashion. In this paradigm MK801 induced sensitisation was expressed similarly between groups treated in two distinct environmental contexts. © 2015 Elsevier B.V. All rights reserved.
1. Introduction When rodents are exposed to a drug in a repetitive and intermittent paradigm, the response to the drug can be augmented after its withdrawal. This phenomenon, termed behavioural sensitisation, occurs with many drugs of abuse, including cocaine, amphetamine, morphine, ethanol, nicotine and MK-801 [27]. Drug sensitisation is divided into two key phases, induction and expression, which are mediated by distinct anatomical and neurochemical substrates [24]. The induction of sensitisation refers to the neuro-
∗ Corresponding author at: Queensland Brain Institute, The University of Queensland, St Lucia, Qld 4072, Australia. Fax: +61 7 3346 6301 E-mail address: [email protected] (T.H.J. Burne). http://dx.doi.org/10.1016/j.bbr.2015.11.014 0166-4328/© 2015 Elsevier B.V. All rights reserved.
logical changes that develop with repeated drug exposure, whereas the expression of sensitisation is characterized as the enhanced response to a drug challenge following a period of drug abstinence [17]. Behavioural sensitisation in laboratory rodents has been used to model disorders, such as schizophrenia and drug addiction [29]. Animal models of behavioural sensitisation have predominately focused on the psychostimulants amphetamine and cocaine, and have led to a substantial understanding of the neural mechanisms involved in this phenomenon. Furthermore, the impact of factors such as pattern of administration, drug dosage and environmental context on modulating the onset of tolerance or sensitisation to these commonly abused stimulants have been extensively characterised. For example, continuous intravenous
242
E.M. Lefevre et al. / Behavioural Brain Research 298 (2016) 241–245
cocaine administration in rodents has been shown to induce tolerance to the behavioural effects of cocaine, whereas intermittent intraperitoneal administration led to behavioural sensitisation [8,26,18]. Furthermore, higher levels of drug intake appear to induce tolerance and lower levels induce sensitisation [8]. Sensitisation to a number of drugs, such as amphetamine, cocaine, morphine and nicotine, is facilitated by environmental context [5]. It is consistently reported that sensitisation to drugs of abuse is modulated by environmental context. Rodents display a greater sensitisation when repeated drug administration occurs in a context-paired environment (novel test cage) compared to drug administration occurring in a context-unpaired environment (home cage) [2–4]. Studies also report context-paired drug administration produces a conditioned response when a saline injection is given in the drug-associated context [23,2,21]. Therefore, contextual conditioning is proposed to have an enhancing effect on locomotor sensitisation to drugs of abuse. Few studies have investigated MK-801 (non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist)-induced behavioural sensitisation. However, MK-801-induced behavioural sensitisation in rodents is proposed to recapitulate aspects of the NMDA receptor hypofunction hypothesis of schizophrenia, warranting further investigation using this agent. In order to investigate the neural mechanisms of MK-801 sensitisation, and its potential relevance to schizophrenia, it is first critical to characterize external factors that may modulate sensitisation. Studies examining the effect of MK-801 on methamphetamine [19] or morphine-induced [16] behavioural sensitisation give an indication to the role of drug dose on the development or expression of MK-801 sensitisation. In a paradigm used to induce methamphetamine sensitisation, mice repeatedly injected with MK-801 every few days were shown to develop a progressive tolerance to a high dose of MK-801 (1 mg/kg), locomotor sensitisation with an intermediate dose (0.3 mg/kg) and no behavioural change with a low dose of MK-801 (0.1 mg/kg) [19]. Although this study did not demonstrate whether this dose response holds true subsequent to drug withdrawal, Jeziorski et al. [16] reported the expression of behavioural sensitisation was evident in rats after 5 days withdrawal from repeated daily (7–10) administrations of 0.25 mg/kg but not 0.1 mg/kg MK-801. No studies to date have examined the role of environmental context on the development and expression of MK-801 induced sensitisation. The modulatory effect of environmental context is thought to involve associative learning via activation of the NMDA receptors [12]. It is therefore hypothesised that the use of a drug that antagonizes NMDA-receptors may not be affected by environmental context. The purpose of this report was to determine the modulatory role of drug dose and environmental context on the development and expression of MK-801 induced sensitisation. The first experiment manipulated the doses of MK-801 in the sensitisation paradigm. We identified an inverted-U dose response in the development of behavioural sensitisation, whereby only one dose was sufficient to induce sensitisation. The dose that induced sensitisation was selected to assess whether MK-801-induced sensitisation was dependent on environmental context. This was achieved by treating separate groups of rats in one of two environments during the induction phase.
cycle (light phase 0600-1800) with food and water ad libitum. All testing was conducted during the light phase between 0800 and 1700 h (room temperature 24 ◦ C, 50% humidity). All procedures were performed with the approval from The University of Queensland Animal Ethics Committee, under the guidelines of the National Health and Medical Research Council of Australia. 2.2. Apparatus Locomotor activity was assessed with Ethovision automated video tracking software (Noldus Information Technology, Wageningen, Netherlands). The experimental context consisted of black Perspex chambers (45 × 45 × 60 cm) illuminated by a central LED strip (17 lux). Data was collected via a centrally placed video camera (Vivotek) situated above the chamber. The apparatus were located in a behavioural testing room, separate to the housing room. All chambers were cleaned with 70% ethanol after each test. 2.3. General procedure and drugs Except when otherwise stated in the following sections, the same experimental protocol was used to induce and test the behavioural sensitisation to MK-801 in male Sprague Dawley rats. The general sensitisation paradigm was similar to protocols utilised by Yang et al. [35] and Jeziorski et al. [16]. The behavioural sensitisation paradigm consists of three key phases; induction, withdrawal and expression. The induction phase involved once-daily injections for 7 consecutive days in the test cage. Over the 5-day withdrawal phase, rats were left untreated in their home cages. On Day 13 of the behavioural paradigm, the expression of locomotor sensitisation was observed by challenging rats with MK-801 in the test cage. Each experimental day, rats were weighed in their homeroom. They were then moved to the experimental room and allowed a 30 min acclimation period. Rats were placed individually into a test cage. After a 30 min period of habituation to the test cage, rats were injected with either saline or MK-801. MK-801 has an elimination half life in plasma and brain of 1.9 and 2.05 h, respectively [30]. MK-801 induced locomotor activity lasts approximately 2–3 h [1]; therefore MK-801 induced locomotor activity was recorded for 3 h post-injection. MK-801 (Sigma) was dissolved in 0.9% saline solution. Injections were administered at 1 ml/kg via the intraperitoneal (i.p.) route in all experiments. 2.4. Experiment 1: dose-dependent effects on MK-801 induced sensitisation The first experiment was designed to determine at which dose MK-801 induces behavioural sensitisation in male Sprague Dawley rats. The rats were divided into four dose treatment groups (n = 7–8/group). The four treatment groups were saline, low dose MK-801 (0.1 mg/kg), intermediated dose MK-801 (0.25 mg/kg) and high dose MK-801 (0.5 mg/kg). The dose used within each group remained constant between the induction and expression phases. Behavioural sensitisation paradigms to other stimulant drugs may often use a lower dose for challenge. Due to the hyperlocomotor inducing effects of MK-801 occurring within a tight range window [1], a lower dose challenge was not ideal in this paradigm. This design has previously been implemented in other research inducing MK-801 locomotor sensitisation [32,35,31].
2. Methods and materials 2.1. Animals
2.5. Experiment 2: effect of environmental context on MK-801 induced sensitisation
Adult (70 days of age) male Sprague Dawley rats (ARC, WA, Australia) were pair housed and allowed at least 1-week habituation to the homeroom. Rats were kept on a constant 12 h light/dark
Experiment 2 aimed to test whether the behavioural sensitisation to MK-801 (0.25 mg/kg) in Sprague Dawley male rats was altered by environmental context. Saline and MK-801-treated rats
E.M. Lefevre et al. / Behavioural Brain Research 298 (2016) 241–245
A
B
60
*
* *
*
Saline MK-801 (0.1mg/kg) MK-801 (0.25mg/kg) MK-801 (0.5mg/kg) *
*
40
* * *
20
30
60
90
120
150
180
Time Post Injection (min)
500 Distance Travelled (m/3hr)
Distance travelled (m)
80
0
243
#
Induction (Day 1) Expression (Day 13) 400 300
*
200 100 0
0
0.1
0.25
0.5
MK-801 Dose (mg/kg)
Fig. 1. The effect of dose on MK-801 induced behavioural sensitisation. (A) Acute response (±SEM) to increasing doses of MK-801 (0, 0.1, 0.25 and 0.5 mg/kg) on day 1 of induction. Rats were injected with saline or MK-801 after a 30 min habituation period to the novel environment. A steep dose–response curve to the locomotor stimulating effects of MK-801. p < 0.01 significantly different to saline controls. (B) Comparison of total distance travelled over the 180 min post-injection testing period (mean response ± SEM post-injection) on Day 1 of induction (white bars) and Day 13 at expression (dark grey bars). *p < 0.05 significantly different between test days. #p < 0.05 significantly different from the saline control group.
were subdivided into two context groups (n = 20/group); home and test. During the induction phase the test group received the 7 daily injections in the test chamber as described above. The home group however, received the same 7 daily injections in the homeroom and were placed immediately back into their home cage after injection. On Day 13, both context groups were placed in the test cage and challenged with MK-801 (0.25 mg/kg). Experiment 2 also examined whether repeated administration of MK-801 (0.25 mg/kg) in the test cage produces a conditioned response upon re-exposure subsequent to withdrawal. This phenomenon has previously been observed in sensitisation to other stimulant drugs. A simultaneous separate cohort was also treated with saline or MK-801 under home or test conditions (n = 8/group). On Day 13, all rats were challenged with a saline injection in the test cage to assess for a conditioned response. 2.6. Statistical analysis Statistical comparisons on the total distance travelled were made using mixed subjects ANOVA. MK-801 treatment and environmental context pre-treatment served as between-subjects factors. Day served as a within-subjects factor. The presence of sensitisation from Day 1 to Day 13 was computed using repeated measures ANOVA. A Bonferroni correction was used to control for multiple comparisons where appropriate. A Pearson correlation analysis was performed for locomotor activity on Day 1 and Day 13. Statistical significance was set at p < 0.05. All data are reported as mean ± SEM. Statistical analyses were made using the SPSS statistics (version 20) program. 3. Results 3.1. Experiment 1: dose-dependent effects on MK-801 induced sensitisation Male Sprague Dawley rats were administered either saline or one of three doses of MK-801 (0.1, 0.25 and 0.5 mg/kg) once daily for 7 days. Subsequent to a 5-day period of abstinence, rats were re-exposed to the same dose of saline or MK-801. On Day 1, a significant effect of MK-801 dose on locomotor activity was observed (F(3,28) = 8.8, p < 0.01). The highest dose, 0.5 mg/kg, elicited hyperlocomotion compared to saline (Fig. 1a,b). Neither of the lower doses (0.1 and 0.25 mg/kg) significantly increased locomotor activ-
ity on the first day of induction. To determine the presence of sensitisation, repeated measures ANOVA was performed on the total distance travelled between Days 1 and 13 (Fig. 1b) of testing revealing a main effect of dose (F(3,27) = 5.16, p = 0.006). Sensitisation defined as a significant increase in locomotor activity on Day 13 compared to Day 1, was only evident in rats treated with the intermediate dose (0.25 mg/kg) of MK-801 (t6 = 2.5, p < 0.05). There was a significant positive correlation (R2 = 0.84, p = 0.001) between the acute response to 0.25 mg/kg MK-801 on Day 1 and the sensitised response on Day 13. There was no significant increase (or decrease) in locomotor activity from Day 1 to Day 13 in rats treated with 0.1 mg/kg and 0.5 mg/kg MK-801 (Fig. 1b). This indicates that neither locomotor sensitisation nor tolerance developed to these doses of MK-801. Overall, the development of MK-801-induced sensitisation displayed an inverted-U dose response. Therefore, the subsequent experiment utilised only the 0.25 mg/kg dose of MK801 to investigate the role of environmental context. 3.2. Experiment 2: effect of environmental context on MK-801 induced sensitisation The main aim of this experiment was to characterize the effect environmental context had on the development of MK-801 induced sensitisation. Rats received saline or MK-801 (0.25 mg/kg) injections in either the home or test environment during the induction phase. At expression, all rats were challenged with MK-801 in the test environment and locomotor activity assessed (Fig. 2a). Twoway ANOVA revealed a significant effect of drug treatment (saline vs. MK-801; F(1,76) = 5.23, p = 0.023). In contrast, there was no significant main effect of environmental context and no significant interaction between drug treatment and environmental context. The expression of locomotor sensitisation to MK-801 was not significantly different between MK-801 groups treated in either the home or test environmental context (Fig. 2a). It has been shown that repeated administration of drugs of abuse potentiates the response to saline challenge given in the same environment [21]. Thus, the secondary aim of this experiment was to determine whether repeated MK-801 injections in the test cage would enhance response to saline challenge and a second cohort of rats was treated with saline or MK-801 in the home or test environmental context during induction. At expression, this cohort was instead challenged with saline in the text environment and locomotor activity assessed (Fig. 2b). The two-way ANOVA revealed no significant main effects of drug treatment or environmental
244
E.M. Lefevre et al. / Behavioural Brain Research 298 (2016) 241–245
Distance Travelled (m/3hr)
Sensitisation Test (MK-801 0.25mg/kg) 500 400
Home Test *
Conditioning test (Saline 1ml/kg) 500 400
300
300
200
200
100
100
0
Saline MK-801 Induction Treatment
0
Home Test
Saline MK-801 Induction Treatment
Fig. 2. Effect of environmental context on the expression of MK-801 sensitisation. (A) At the expression phase rats that were previously treated in the home (white bars) or test (light grey bars) context were challenged with 0.25 mg/kg MK-801 to test for sensitisation or (B) challenged with Saline to test for contextual conditioning. *p < 0.05 compared to saline treated controls.
context and no significant interaction between the two. SpragueDawley rats treated with MK-801 in the test cage did not produce a conditioned response to saline challenge compared to either their MK-801 treated home cage counterparts (Fig. 2b). Furthermore, there was no difference in response to saline challenge between rats treated with MK-801 or saline in the test environment. 4. Discussion Our results show that adult male Sprague Dawley rats develop behavioural sensitisation after repeated MK-801 exposure. Sensitisation occurred when an intermediate dose of 0.25 mg/kg MK-801 was repeatedly injected. We found that using a lower or higher MK-801 dose did not induce locomotor sensitisation, at least in the current paradigm. The results of the second experiment demonstrate that the expression of sensitisation to MK-801 was unaltered between rats treated in two different environmental contexts. The magnitude of locomotor sensitisation was similar between Sprague Dawley rats receiving MK-801 treatment in the home or test cage during the induction phase. To the best of our knowledge this is the first study to assess whether MK-801 induced sensitisation is modulated by environmental context. In Experiment 1, we report a steep dose-response curve to the acute locomotor stimulatory effects of MK-801 and this finding was consistent with a multitude of acute MK-801 studies [13,14,20,11,28]. This experiment also found the development of sensitisation to MK-801 in Sprague Dawley rats showed an inverted-U shape dose response curve, similar to what has been reported in mice [19]. Kuribara et al. [19] demonstrated that in the ddY mouse strain, an intermittent sensitisation paradigm only resulted in locomotor sensitisation with an intermediate dose of MK-801 (0.3 mg/kg), compared to low (0.1 mg/kg) or high (1 mg/kg) doses. Furthermore, [16] reported that locomotor sensitisation was observed in Sprague Dawley rats 5 days after repeated daily (7–10 days) administrations of 0.25 mg/kg but not 0.1 mg/kg MK801. In the current study, repeated administration of 0.1 mg/kg or 0.5 mg/kg did not produce sensitisation, nor was there a significant decrease in response to indicate the development of tolerance. This would suggest tolerance was not a competing mechanism. In the present study, we found no evidence that behavioural sensitisation to MK-801 was dependent on or modulated by environmental context. Firstly, rats treated with the sensitising dose (0.25 mg/kg) of MK-801 in the home cage developed locomotor sensitisation to the same extent as the rats treated in the test context. Secondly, MK-801 sensitised rats did not display a conditioned
hyperlocomotor response to a saline challenge when re-exposed to the drug-paired context. This study is the first to report a lack of environmental dependency for MK-801 sensitisation and is consistent with that described for sensitisation to another NMDA receptor antagonist, PCP [9,34]. Taken together, these results suggest that sensitisation to MK-801 is not influenced by the environmental context in which the drug is administered, contrary to the literature on behavioural sensitisation to other drugs of abuse. A number of studies have demonstrated that environmental context modulates the susceptibility to sensitisation induced by psychostimulant drugs including amphetamine, cocaine and morphine [5]. Pairing the repeated drug exposure with a novel context was found to further augment the sensitised response in rodents compared to the drug treatment occurring in the home cage. Although not completely understood, the modulatory role of environmental context is thought to involve a number of factors including associative learning, as well as gene expression and synaptic plasticity in brain regions associated with reward. Furthermore, NMDA receptor activation is known to play a critical role in context-dependent sensitisation [6,7] and contextual conditioning [25,33]. For example, co-administration of MK-801 with amphetamine during the induction phase was shown to specifically attenuate the development of amphetamine sensitisation in a context-dependent paradigm, without affecting sensitisation in a context-independent paradigm [6]. Thus it would appear that antagonism of the NMDA receptor abolishes contextual conditioning. In mice, the development of behavioural sensitisation to ethanol, an indirect NMDA receptor antagonist, was recently reported to also be independent of environmental context [10] as has been observed with the direct NMDA receptor antagonists MK-801 (present study) and PCP [9,34]. Overall, the absence of environmental contextual modulation on MK-801 sensitisation reported in this study is congruent with the literature. In conclusion, the present report demonstrates that sensitisation to repeated administrations of MK-801 in male Sprague Dawley rats develops at selective doses. Sensitisation was only observed with an intermediate MK-801 dose of 0.25 mg/kg, whereas repeated injections of a lower dose (0.1 mg/kg) or higher (0.5 mg/kg) produced neither sensitisation nor tolerance. In this paradigm, behavioural sensitisation is not modulated by the environmental context in which drug administration occurs. [15] first suggested that long-term exposure to NMDA receptor antagonists more qualitatively represented symptoms of schizophrenia compared to acute exposure. In animals, withdrawal from repeated NMDA receptor antagonist treatment has been proposed to present with neurochemical, neuroanatomical and behavioural alterations closely correlated to clinical observations of schizophrenia [22]. In this study we have established a model of MK-801 induced sensitisation incorporating both features of long-term exposure and withdrawal. This model will be useful in future studies of putative NMDA-mediated pathological mechanisms in schizophrenia and can also be used to evaluate novel therapeutics. Conflict of interest The authors report no conflict of interest. Acknowledgement This work was supported by NHMRC project grant 1024239. References [1] P. Andine, N. Widermark, R. Axelsson, G. Nyberg, U. Olofsson, E. Martensson, M. Sandberg, Characterization of MK-801-induced behavior as a putative rat model of psychosis, J. Pharmacol. Exp. Ther. 290 (1999) 1393–1408.
E.M. Lefevre et al. / Behavioural Brain Research 298 (2016) 241–245 [2] A. Badiani, K.E. Browman, T.E. Robinson, Influence of novel versus home environments on sensitization to the psychomotor stimulant effects of cocaine and amphetamine, Brain Res. 674 (1995) 291–298. [3] A. Badiani, D.M. Camp, T.E. Robinson, Enduring enhancement of amphetamine sensitization by drug-associated environmental stimuli, J. Pharmacol. Exp. Ther. 282 (1997) 787–794. [4] A. Badiani, M.M. Oates, T.E. Robinson, Modulation of morphine sensitization in the rat by contextual stimuli, Psychopharmacology (Berl.) 151 (2000) 273–282. [5] A. Badiani, T.E. Robinson, Drug-induced neurobehavioral plasticity: the role of environmental context, Behav. Pharmacol. 15 (2004) 327–339. [6] J.J. Battisti, N.J. Uretsky, L.J. Wallace, NMDA glutamate receptor role in the development of context-dependent and independent sensitization of the induction of stereotypy by amphetamine or apomorphine, Behav. Brain Res. 114 (2000) 167–174. [7] J.J. Battisti, L.J. Wallace, N.J. Uretsky, NMDA receptor activation mediates the conditioned component of behavioral sensitization to amphetamine, FASEB J. 13 (1999) A1107. [8] E.S. Calipari, M.J. Ferris, B.A. Zimmer, D.C.S. Roberts, S.R. Jones, Temporal pattern of cocaine intake determines tolerance vs sensitization of cocaine effects at the dopamine transporter, Neuropsychopharmacology 38 (2013) 2385–2392. [9] M. Clark, B.G. Johnson, R.A. Wright, J.A. Monn, D.D. Schoepp, Effects of the mGlu2/3 receptor agonist LY379268 on motor activity in phencyclidine-sensitized rats, Pharmacol. Biochem. Behav. 73 (2002) 339–346. [10] V. Didone, C. Quoilin, E. Tirelli, E. Quertemont, Parametric analysis of the development and expression of ethanol-induced behavioral sensitization in female Swiss mice: effects of dose, injection schedule, and test context, Psychopharmacology (Berl.) 201 (2008) 249–260. [11] J.P. Druhan, H. Rajabi, J. Stewart, MK-801 increases locomotor activity without elevating extracellular dopamine levels in the nucleus accumbens, Synapse 24 (1996) 135–146. [12] M. Gronig, A. Atalla, K. Kuschinsky, The role of of glutamate NMDA receptors in the expression of associative and non-associative sensitization to the increase in extracellular dopamine in the nucleus accumbens and to locomotor activity induced by d-amphetamine, Naunyn-Schmiedebergs Arch. Pharmacol. 369 (2004) R85. [13] M. Hiramatsu, A.K. Cho, T. Nabeshima, Comparison of the behavioral and biochemical effects of the nmda receptor antagonists, Mk-801 and phencyclidine, Eur. J. Pharmacol. 166 (1989) 359–366. [14] M. Irifune, T. Shimizu, M. Nomoto, T. Fukuda, Involvement of N-methyl-d-aspartate (Nmda) receptors in noncompetitive Nmda Receptor antagonist-induced hyperlocomotion in mice, Pharmacol. Biochem. Behav. 51 (1995) 291–296. [15] J.D. Jentsch, R.H. Roth, The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia, Neuropsychopharmacology 20 (1999) 201–225. [16] M. Jeziorski, F.J. White, M.E. Wolf, Mk-801 prevents the development of behavioral sensitization during repeated morphine administration, Synapse 16 (1994) 137–147. [17] P.W. Kalivas, B.A. Sorg, M.S. Hooks, The pharmacology and neural circuitry of sensitization to psychostimulants, Behav. Pharmacol. 4 (1993) 315–334. [18] G.R. King, Z. Xiong, E.H. Ellinwood, Blockade of the expression of sensitization and tolerance by ondansetron, a 5-HT3 receptor antagonist, administered
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27] [28]
[29] [30]
[31]
[32]
[33]
[34] [35]
245
during withdrawal front intermittent and continuous cocaine, Psychopharmacology (Berl.) 135 (1998) 263–269. H. Kuribara, T. Asami, I. Ida, Y. Iijima, T.S. Adokoro, Effects of repeated Mk-801 on ambulation in mice and in sensitization following methamphetamine, Psychopharmacology (Berl.) 108 (1992) 271–275. H. Kuribara, T. Asami, I. Ida, S. Tadokoro, Characteristics of the ambulation-increasing effect of the noncompetitive nmda antagonist Mk-801 in mice—assessment by the coadministration with central-acting drugs, Jpn. J. Pharmacol. 58 (1992) 11–18. C.S. Mcpherson, A.J. Lawrence, Exposure to amphetamine in rats during periadolescence establishes behavioural and extrastriatal neural sensitization in adulthood, Int. J. Neuropsychopharmacol. 9 (2006) 377–392. A. Mouri, Y. Noda, T. Enomoto, T. Nabeshima, Phencyclidine animal models of schizophrenia: approaches from abnormality of glutamatergic neurotransmission and neurodevelopment, Neurochem. Int. 51 (2007) 173–184. T. Ohmori, T. Abekawa, K. Ito, T. Koyama, Context determines the type of sensitized behaviour: a brief review and a hypothesis on the role of environment in behavioural sensitization, Behav. Pharmacol. 11 (2000) 211–221. R.C. Pierce, P.W. Kalivas, A circuitry model of the expression of behavioral sensitization to amphetamine-like psychostimulants, Brain Res. Rev. 25 (1997) 192–216. J.J. Quinn, F. Loya, Q.D. Ma, M.S. Fanselow, Dorsal hippocampus NMDA receptors differentially mediate trace and contextual fear conditioning, Hippocampus 15 (2005) 665–674. M.E.A. Reith, M. Benuck, A. Lajtha, Cocaine disposition in the brain after continuous or intermittent treatment and locomotor stimulation in mice, J. Pharmacol. Exp. Ther. 243 (1987) 281–287. T.E. Robinson, K.C. Berridge, The neural basis of drug craving—an incentive-sensitization theory of addiction, Brain Res. Rev. 18 (1993) 247–291. J.P. Rung, A. Carlsson, K.R. Markinhuhta, M.L. Carlsson, (+)-MK-801 induced social withdrawal in rats; a model for negative symptoms of schizophrenia, Prog. Neuropsychopharmacol. Biol. Psychiatry 29 (2005) 827–832. H. Ujike, Stimulant-induced psychosis and schizophrenia: the role of sensitization, Curr. Psychiatry Rep. 4 (2002) 177–184. A. Vezzani, R. Serafini, M.A. Stasi, S. Caccia, I. Conti, R.V. Tridico, R. Samanin, Kinetics of Mk-801 and its effect on quinolinic acid-induced seizures and neurotoxicity in rats, J. Pharmacol. Exp. Ther. 249 (1989) 278–283. K. Wedzony, K. Golembiowska, V. Klimek, MK-801-induced symptoms of sensitization. The lack of correlation with the extracellular concentration of dopamine in the rat prefrontal cortex, Brain Res. 625 (1993) 333–336. M.E. Wolf, M.R. Khansa, Repeated administration of MK-801 produces sensitization to its own locomotor stimulant effects but blocks sensitization to amphetamine, Brain Res. 562 (1991) 164–168. X.H. Xie, A.A. Arguello, A.M. Wells, A.M. Reittinger, R.A. Fuchs, Role of a hippocampal Src-family kinase-mediated glutamatergic mechanism in drug context-induced cocaine seeking, Neuropsychopharmacology 38 (2013) 2657–2665. X.J. Xu, E.F. Domino, Phencyclidine-induced behavioral sensitization, Pharmacol. Biochem. Behav. 47 (1994) 603–608. P.B. Yang, A.C. Swann, N. Dafny, Valproate prevents the induction and the expression of MK-801 sensitization, Brain Res. 954 (2002) 151–159.
Contents lists available at ScienceDirect
Behavioural Brain Research journal homepage: www.elsevier.com/locate/bbr
Behavioural sensitisation to MK-801 is dose-dependent and independent of environmental context Emilia M. Lefevre a , Darryl W. Eyles a,b , Thomas H.J. Burne a,b,∗ a b
Queensland Brain Institute, The University of Queensland, St Lucia, QLD 4072, Australia Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Richlands, QLD 4076, Australia
h i g h l i g h t s • Repeated exposure to the NMDA receptor antagonist MK-801 induced locomotor sensitisation in male Sprague Dawley rats. • Sensitisation to MK-801 was dose-dependent. • MK-801 induced sensitisation was not affected by the environmental context in which drug exposure occurred.
a r t i c l e
i n f o
Article history: Received 18 September 2015 Received in revised form 6 November 2015 Accepted 10 November 2015 Available online 28 November 2015 Keywords: Sensitisation MK-801 NMDA receptor Environmental context Animal model Schizophrenia
a b s t r a c t The pathophysiology of schizophrenia is associated with disturbed glutamate signalling, particularly via a dysfunction of the N-methyl-d-aspartate (NMDA) receptor. In rodents, behavioural sensitisation to the NMDA receptor antagonist MK-801 is proposed to recapitulate aspects of the NMDA receptor hypofunction hypothesis of schizophrenia. The aim of this study was to determine the modulatory role of MK-801 dose and environmental context on the development and expression of MK-801-induced behavioural sensitisation. Sprague Dawley rats were administered saline or varying doses of MK-801 (i.p.) once daily for 7 days and locomotor activity was recorded. After 5 days of withdrawal, rats were challenged with their respective dose to test for sensitisation. From this experiment a sensitising dose was obtained. In the second experiment the magnitude of sensitisation was compared between rats that were treated in either a home or test environmental context. Rats treated with 0.25 mg/kg MK-801 developed robust sensitisation when challenged after withdrawal. Rats treated with lower (0.1 mg/kg) or higher (0.5 mg/kg) doses of MK-801 did not develop locomotor sensitisation. Sensitisation to 0.25 mg/kg MK-801 developed equally between rats treated in the home or test context. The study shows that male Sprague Dawley rats develop behavioural sensitisation to repeated injections of MK-801. The development of sensitisation is selective to MK-801 dose in an inverted-U dose response fashion. In this paradigm MK801 induced sensitisation was expressed similarly between groups treated in two distinct environmental contexts. © 2015 Elsevier B.V. All rights reserved.
1. Introduction When rodents are exposed to a drug in a repetitive and intermittent paradigm, the response to the drug can be augmented after its withdrawal. This phenomenon, termed behavioural sensitisation, occurs with many drugs of abuse, including cocaine, amphetamine, morphine, ethanol, nicotine and MK-801 [27]. Drug sensitisation is divided into two key phases, induction and expression, which are mediated by distinct anatomical and neurochemical substrates [24]. The induction of sensitisation refers to the neuro-
∗ Corresponding author at: Queensland Brain Institute, The University of Queensland, St Lucia, Qld 4072, Australia. Fax: +61 7 3346 6301 E-mail address: [email protected] (T.H.J. Burne). http://dx.doi.org/10.1016/j.bbr.2015.11.014 0166-4328/© 2015 Elsevier B.V. All rights reserved.
logical changes that develop with repeated drug exposure, whereas the expression of sensitisation is characterized as the enhanced response to a drug challenge following a period of drug abstinence [17]. Behavioural sensitisation in laboratory rodents has been used to model disorders, such as schizophrenia and drug addiction [29]. Animal models of behavioural sensitisation have predominately focused on the psychostimulants amphetamine and cocaine, and have led to a substantial understanding of the neural mechanisms involved in this phenomenon. Furthermore, the impact of factors such as pattern of administration, drug dosage and environmental context on modulating the onset of tolerance or sensitisation to these commonly abused stimulants have been extensively characterised. For example, continuous intravenous
242
E.M. Lefevre et al. / Behavioural Brain Research 298 (2016) 241–245
cocaine administration in rodents has been shown to induce tolerance to the behavioural effects of cocaine, whereas intermittent intraperitoneal administration led to behavioural sensitisation [8,26,18]. Furthermore, higher levels of drug intake appear to induce tolerance and lower levels induce sensitisation [8]. Sensitisation to a number of drugs, such as amphetamine, cocaine, morphine and nicotine, is facilitated by environmental context [5]. It is consistently reported that sensitisation to drugs of abuse is modulated by environmental context. Rodents display a greater sensitisation when repeated drug administration occurs in a context-paired environment (novel test cage) compared to drug administration occurring in a context-unpaired environment (home cage) [2–4]. Studies also report context-paired drug administration produces a conditioned response when a saline injection is given in the drug-associated context [23,2,21]. Therefore, contextual conditioning is proposed to have an enhancing effect on locomotor sensitisation to drugs of abuse. Few studies have investigated MK-801 (non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist)-induced behavioural sensitisation. However, MK-801-induced behavioural sensitisation in rodents is proposed to recapitulate aspects of the NMDA receptor hypofunction hypothesis of schizophrenia, warranting further investigation using this agent. In order to investigate the neural mechanisms of MK-801 sensitisation, and its potential relevance to schizophrenia, it is first critical to characterize external factors that may modulate sensitisation. Studies examining the effect of MK-801 on methamphetamine [19] or morphine-induced [16] behavioural sensitisation give an indication to the role of drug dose on the development or expression of MK-801 sensitisation. In a paradigm used to induce methamphetamine sensitisation, mice repeatedly injected with MK-801 every few days were shown to develop a progressive tolerance to a high dose of MK-801 (1 mg/kg), locomotor sensitisation with an intermediate dose (0.3 mg/kg) and no behavioural change with a low dose of MK-801 (0.1 mg/kg) [19]. Although this study did not demonstrate whether this dose response holds true subsequent to drug withdrawal, Jeziorski et al. [16] reported the expression of behavioural sensitisation was evident in rats after 5 days withdrawal from repeated daily (7–10) administrations of 0.25 mg/kg but not 0.1 mg/kg MK-801. No studies to date have examined the role of environmental context on the development and expression of MK-801 induced sensitisation. The modulatory effect of environmental context is thought to involve associative learning via activation of the NMDA receptors [12]. It is therefore hypothesised that the use of a drug that antagonizes NMDA-receptors may not be affected by environmental context. The purpose of this report was to determine the modulatory role of drug dose and environmental context on the development and expression of MK-801 induced sensitisation. The first experiment manipulated the doses of MK-801 in the sensitisation paradigm. We identified an inverted-U dose response in the development of behavioural sensitisation, whereby only one dose was sufficient to induce sensitisation. The dose that induced sensitisation was selected to assess whether MK-801-induced sensitisation was dependent on environmental context. This was achieved by treating separate groups of rats in one of two environments during the induction phase.
cycle (light phase 0600-1800) with food and water ad libitum. All testing was conducted during the light phase between 0800 and 1700 h (room temperature 24 ◦ C, 50% humidity). All procedures were performed with the approval from The University of Queensland Animal Ethics Committee, under the guidelines of the National Health and Medical Research Council of Australia. 2.2. Apparatus Locomotor activity was assessed with Ethovision automated video tracking software (Noldus Information Technology, Wageningen, Netherlands). The experimental context consisted of black Perspex chambers (45 × 45 × 60 cm) illuminated by a central LED strip (17 lux). Data was collected via a centrally placed video camera (Vivotek) situated above the chamber. The apparatus were located in a behavioural testing room, separate to the housing room. All chambers were cleaned with 70% ethanol after each test. 2.3. General procedure and drugs Except when otherwise stated in the following sections, the same experimental protocol was used to induce and test the behavioural sensitisation to MK-801 in male Sprague Dawley rats. The general sensitisation paradigm was similar to protocols utilised by Yang et al. [35] and Jeziorski et al. [16]. The behavioural sensitisation paradigm consists of three key phases; induction, withdrawal and expression. The induction phase involved once-daily injections for 7 consecutive days in the test cage. Over the 5-day withdrawal phase, rats were left untreated in their home cages. On Day 13 of the behavioural paradigm, the expression of locomotor sensitisation was observed by challenging rats with MK-801 in the test cage. Each experimental day, rats were weighed in their homeroom. They were then moved to the experimental room and allowed a 30 min acclimation period. Rats were placed individually into a test cage. After a 30 min period of habituation to the test cage, rats were injected with either saline or MK-801. MK-801 has an elimination half life in plasma and brain of 1.9 and 2.05 h, respectively [30]. MK-801 induced locomotor activity lasts approximately 2–3 h [1]; therefore MK-801 induced locomotor activity was recorded for 3 h post-injection. MK-801 (Sigma) was dissolved in 0.9% saline solution. Injections were administered at 1 ml/kg via the intraperitoneal (i.p.) route in all experiments. 2.4. Experiment 1: dose-dependent effects on MK-801 induced sensitisation The first experiment was designed to determine at which dose MK-801 induces behavioural sensitisation in male Sprague Dawley rats. The rats were divided into four dose treatment groups (n = 7–8/group). The four treatment groups were saline, low dose MK-801 (0.1 mg/kg), intermediated dose MK-801 (0.25 mg/kg) and high dose MK-801 (0.5 mg/kg). The dose used within each group remained constant between the induction and expression phases. Behavioural sensitisation paradigms to other stimulant drugs may often use a lower dose for challenge. Due to the hyperlocomotor inducing effects of MK-801 occurring within a tight range window [1], a lower dose challenge was not ideal in this paradigm. This design has previously been implemented in other research inducing MK-801 locomotor sensitisation [32,35,31].
2. Methods and materials 2.1. Animals
2.5. Experiment 2: effect of environmental context on MK-801 induced sensitisation
Adult (70 days of age) male Sprague Dawley rats (ARC, WA, Australia) were pair housed and allowed at least 1-week habituation to the homeroom. Rats were kept on a constant 12 h light/dark
Experiment 2 aimed to test whether the behavioural sensitisation to MK-801 (0.25 mg/kg) in Sprague Dawley male rats was altered by environmental context. Saline and MK-801-treated rats
E.M. Lefevre et al. / Behavioural Brain Research 298 (2016) 241–245
A
B
60
*
* *
*
Saline MK-801 (0.1mg/kg) MK-801 (0.25mg/kg) MK-801 (0.5mg/kg) *
*
40
* * *
20
30
60
90
120
150
180
Time Post Injection (min)
500 Distance Travelled (m/3hr)
Distance travelled (m)
80
0
243
#
Induction (Day 1) Expression (Day 13) 400 300
*
200 100 0
0
0.1
0.25
0.5
MK-801 Dose (mg/kg)
Fig. 1. The effect of dose on MK-801 induced behavioural sensitisation. (A) Acute response (±SEM) to increasing doses of MK-801 (0, 0.1, 0.25 and 0.5 mg/kg) on day 1 of induction. Rats were injected with saline or MK-801 after a 30 min habituation period to the novel environment. A steep dose–response curve to the locomotor stimulating effects of MK-801. p < 0.01 significantly different to saline controls. (B) Comparison of total distance travelled over the 180 min post-injection testing period (mean response ± SEM post-injection) on Day 1 of induction (white bars) and Day 13 at expression (dark grey bars). *p < 0.05 significantly different between test days. #p < 0.05 significantly different from the saline control group.
were subdivided into two context groups (n = 20/group); home and test. During the induction phase the test group received the 7 daily injections in the test chamber as described above. The home group however, received the same 7 daily injections in the homeroom and were placed immediately back into their home cage after injection. On Day 13, both context groups were placed in the test cage and challenged with MK-801 (0.25 mg/kg). Experiment 2 also examined whether repeated administration of MK-801 (0.25 mg/kg) in the test cage produces a conditioned response upon re-exposure subsequent to withdrawal. This phenomenon has previously been observed in sensitisation to other stimulant drugs. A simultaneous separate cohort was also treated with saline or MK-801 under home or test conditions (n = 8/group). On Day 13, all rats were challenged with a saline injection in the test cage to assess for a conditioned response. 2.6. Statistical analysis Statistical comparisons on the total distance travelled were made using mixed subjects ANOVA. MK-801 treatment and environmental context pre-treatment served as between-subjects factors. Day served as a within-subjects factor. The presence of sensitisation from Day 1 to Day 13 was computed using repeated measures ANOVA. A Bonferroni correction was used to control for multiple comparisons where appropriate. A Pearson correlation analysis was performed for locomotor activity on Day 1 and Day 13. Statistical significance was set at p < 0.05. All data are reported as mean ± SEM. Statistical analyses were made using the SPSS statistics (version 20) program. 3. Results 3.1. Experiment 1: dose-dependent effects on MK-801 induced sensitisation Male Sprague Dawley rats were administered either saline or one of three doses of MK-801 (0.1, 0.25 and 0.5 mg/kg) once daily for 7 days. Subsequent to a 5-day period of abstinence, rats were re-exposed to the same dose of saline or MK-801. On Day 1, a significant effect of MK-801 dose on locomotor activity was observed (F(3,28) = 8.8, p < 0.01). The highest dose, 0.5 mg/kg, elicited hyperlocomotion compared to saline (Fig. 1a,b). Neither of the lower doses (0.1 and 0.25 mg/kg) significantly increased locomotor activ-
ity on the first day of induction. To determine the presence of sensitisation, repeated measures ANOVA was performed on the total distance travelled between Days 1 and 13 (Fig. 1b) of testing revealing a main effect of dose (F(3,27) = 5.16, p = 0.006). Sensitisation defined as a significant increase in locomotor activity on Day 13 compared to Day 1, was only evident in rats treated with the intermediate dose (0.25 mg/kg) of MK-801 (t6 = 2.5, p < 0.05). There was a significant positive correlation (R2 = 0.84, p = 0.001) between the acute response to 0.25 mg/kg MK-801 on Day 1 and the sensitised response on Day 13. There was no significant increase (or decrease) in locomotor activity from Day 1 to Day 13 in rats treated with 0.1 mg/kg and 0.5 mg/kg MK-801 (Fig. 1b). This indicates that neither locomotor sensitisation nor tolerance developed to these doses of MK-801. Overall, the development of MK-801-induced sensitisation displayed an inverted-U dose response. Therefore, the subsequent experiment utilised only the 0.25 mg/kg dose of MK801 to investigate the role of environmental context. 3.2. Experiment 2: effect of environmental context on MK-801 induced sensitisation The main aim of this experiment was to characterize the effect environmental context had on the development of MK-801 induced sensitisation. Rats received saline or MK-801 (0.25 mg/kg) injections in either the home or test environment during the induction phase. At expression, all rats were challenged with MK-801 in the test environment and locomotor activity assessed (Fig. 2a). Twoway ANOVA revealed a significant effect of drug treatment (saline vs. MK-801; F(1,76) = 5.23, p = 0.023). In contrast, there was no significant main effect of environmental context and no significant interaction between drug treatment and environmental context. The expression of locomotor sensitisation to MK-801 was not significantly different between MK-801 groups treated in either the home or test environmental context (Fig. 2a). It has been shown that repeated administration of drugs of abuse potentiates the response to saline challenge given in the same environment [21]. Thus, the secondary aim of this experiment was to determine whether repeated MK-801 injections in the test cage would enhance response to saline challenge and a second cohort of rats was treated with saline or MK-801 in the home or test environmental context during induction. At expression, this cohort was instead challenged with saline in the text environment and locomotor activity assessed (Fig. 2b). The two-way ANOVA revealed no significant main effects of drug treatment or environmental
244
E.M. Lefevre et al. / Behavioural Brain Research 298 (2016) 241–245
Distance Travelled (m/3hr)
Sensitisation Test (MK-801 0.25mg/kg) 500 400
Home Test *
Conditioning test (Saline 1ml/kg) 500 400
300
300
200
200
100
100
0
Saline MK-801 Induction Treatment
0
Home Test
Saline MK-801 Induction Treatment
Fig. 2. Effect of environmental context on the expression of MK-801 sensitisation. (A) At the expression phase rats that were previously treated in the home (white bars) or test (light grey bars) context were challenged with 0.25 mg/kg MK-801 to test for sensitisation or (B) challenged with Saline to test for contextual conditioning. *p < 0.05 compared to saline treated controls.
context and no significant interaction between the two. SpragueDawley rats treated with MK-801 in the test cage did not produce a conditioned response to saline challenge compared to either their MK-801 treated home cage counterparts (Fig. 2b). Furthermore, there was no difference in response to saline challenge between rats treated with MK-801 or saline in the test environment. 4. Discussion Our results show that adult male Sprague Dawley rats develop behavioural sensitisation after repeated MK-801 exposure. Sensitisation occurred when an intermediate dose of 0.25 mg/kg MK-801 was repeatedly injected. We found that using a lower or higher MK-801 dose did not induce locomotor sensitisation, at least in the current paradigm. The results of the second experiment demonstrate that the expression of sensitisation to MK-801 was unaltered between rats treated in two different environmental contexts. The magnitude of locomotor sensitisation was similar between Sprague Dawley rats receiving MK-801 treatment in the home or test cage during the induction phase. To the best of our knowledge this is the first study to assess whether MK-801 induced sensitisation is modulated by environmental context. In Experiment 1, we report a steep dose-response curve to the acute locomotor stimulatory effects of MK-801 and this finding was consistent with a multitude of acute MK-801 studies [13,14,20,11,28]. This experiment also found the development of sensitisation to MK-801 in Sprague Dawley rats showed an inverted-U shape dose response curve, similar to what has been reported in mice [19]. Kuribara et al. [19] demonstrated that in the ddY mouse strain, an intermittent sensitisation paradigm only resulted in locomotor sensitisation with an intermediate dose of MK-801 (0.3 mg/kg), compared to low (0.1 mg/kg) or high (1 mg/kg) doses. Furthermore, [16] reported that locomotor sensitisation was observed in Sprague Dawley rats 5 days after repeated daily (7–10 days) administrations of 0.25 mg/kg but not 0.1 mg/kg MK801. In the current study, repeated administration of 0.1 mg/kg or 0.5 mg/kg did not produce sensitisation, nor was there a significant decrease in response to indicate the development of tolerance. This would suggest tolerance was not a competing mechanism. In the present study, we found no evidence that behavioural sensitisation to MK-801 was dependent on or modulated by environmental context. Firstly, rats treated with the sensitising dose (0.25 mg/kg) of MK-801 in the home cage developed locomotor sensitisation to the same extent as the rats treated in the test context. Secondly, MK-801 sensitised rats did not display a conditioned
hyperlocomotor response to a saline challenge when re-exposed to the drug-paired context. This study is the first to report a lack of environmental dependency for MK-801 sensitisation and is consistent with that described for sensitisation to another NMDA receptor antagonist, PCP [9,34]. Taken together, these results suggest that sensitisation to MK-801 is not influenced by the environmental context in which the drug is administered, contrary to the literature on behavioural sensitisation to other drugs of abuse. A number of studies have demonstrated that environmental context modulates the susceptibility to sensitisation induced by psychostimulant drugs including amphetamine, cocaine and morphine [5]. Pairing the repeated drug exposure with a novel context was found to further augment the sensitised response in rodents compared to the drug treatment occurring in the home cage. Although not completely understood, the modulatory role of environmental context is thought to involve a number of factors including associative learning, as well as gene expression and synaptic plasticity in brain regions associated with reward. Furthermore, NMDA receptor activation is known to play a critical role in context-dependent sensitisation [6,7] and contextual conditioning [25,33]. For example, co-administration of MK-801 with amphetamine during the induction phase was shown to specifically attenuate the development of amphetamine sensitisation in a context-dependent paradigm, without affecting sensitisation in a context-independent paradigm [6]. Thus it would appear that antagonism of the NMDA receptor abolishes contextual conditioning. In mice, the development of behavioural sensitisation to ethanol, an indirect NMDA receptor antagonist, was recently reported to also be independent of environmental context [10] as has been observed with the direct NMDA receptor antagonists MK-801 (present study) and PCP [9,34]. Overall, the absence of environmental contextual modulation on MK-801 sensitisation reported in this study is congruent with the literature. In conclusion, the present report demonstrates that sensitisation to repeated administrations of MK-801 in male Sprague Dawley rats develops at selective doses. Sensitisation was only observed with an intermediate MK-801 dose of 0.25 mg/kg, whereas repeated injections of a lower dose (0.1 mg/kg) or higher (0.5 mg/kg) produced neither sensitisation nor tolerance. In this paradigm, behavioural sensitisation is not modulated by the environmental context in which drug administration occurs. [15] first suggested that long-term exposure to NMDA receptor antagonists more qualitatively represented symptoms of schizophrenia compared to acute exposure. In animals, withdrawal from repeated NMDA receptor antagonist treatment has been proposed to present with neurochemical, neuroanatomical and behavioural alterations closely correlated to clinical observations of schizophrenia [22]. In this study we have established a model of MK-801 induced sensitisation incorporating both features of long-term exposure and withdrawal. This model will be useful in future studies of putative NMDA-mediated pathological mechanisms in schizophrenia and can also be used to evaluate novel therapeutics. Conflict of interest The authors report no conflict of interest. Acknowledgement This work was supported by NHMRC project grant 1024239. References [1] P. Andine, N. Widermark, R. Axelsson, G. Nyberg, U. Olofsson, E. Martensson, M. Sandberg, Characterization of MK-801-induced behavior as a putative rat model of psychosis, J. Pharmacol. Exp. Ther. 290 (1999) 1393–1408.
E.M. Lefevre et al. / Behavioural Brain Research 298 (2016) 241–245 [2] A. Badiani, K.E. Browman, T.E. Robinson, Influence of novel versus home environments on sensitization to the psychomotor stimulant effects of cocaine and amphetamine, Brain Res. 674 (1995) 291–298. [3] A. Badiani, D.M. Camp, T.E. Robinson, Enduring enhancement of amphetamine sensitization by drug-associated environmental stimuli, J. Pharmacol. Exp. Ther. 282 (1997) 787–794. [4] A. Badiani, M.M. Oates, T.E. Robinson, Modulation of morphine sensitization in the rat by contextual stimuli, Psychopharmacology (Berl.) 151 (2000) 273–282. [5] A. Badiani, T.E. Robinson, Drug-induced neurobehavioral plasticity: the role of environmental context, Behav. Pharmacol. 15 (2004) 327–339. [6] J.J. Battisti, N.J. Uretsky, L.J. Wallace, NMDA glutamate receptor role in the development of context-dependent and independent sensitization of the induction of stereotypy by amphetamine or apomorphine, Behav. Brain Res. 114 (2000) 167–174. [7] J.J. Battisti, L.J. Wallace, N.J. Uretsky, NMDA receptor activation mediates the conditioned component of behavioral sensitization to amphetamine, FASEB J. 13 (1999) A1107. [8] E.S. Calipari, M.J. Ferris, B.A. Zimmer, D.C.S. Roberts, S.R. Jones, Temporal pattern of cocaine intake determines tolerance vs sensitization of cocaine effects at the dopamine transporter, Neuropsychopharmacology 38 (2013) 2385–2392. [9] M. Clark, B.G. Johnson, R.A. Wright, J.A. Monn, D.D. Schoepp, Effects of the mGlu2/3 receptor agonist LY379268 on motor activity in phencyclidine-sensitized rats, Pharmacol. Biochem. Behav. 73 (2002) 339–346. [10] V. Didone, C. Quoilin, E. Tirelli, E. Quertemont, Parametric analysis of the development and expression of ethanol-induced behavioral sensitization in female Swiss mice: effects of dose, injection schedule, and test context, Psychopharmacology (Berl.) 201 (2008) 249–260. [11] J.P. Druhan, H. Rajabi, J. Stewart, MK-801 increases locomotor activity without elevating extracellular dopamine levels in the nucleus accumbens, Synapse 24 (1996) 135–146. [12] M. Gronig, A. Atalla, K. Kuschinsky, The role of of glutamate NMDA receptors in the expression of associative and non-associative sensitization to the increase in extracellular dopamine in the nucleus accumbens and to locomotor activity induced by d-amphetamine, Naunyn-Schmiedebergs Arch. Pharmacol. 369 (2004) R85. [13] M. Hiramatsu, A.K. Cho, T. Nabeshima, Comparison of the behavioral and biochemical effects of the nmda receptor antagonists, Mk-801 and phencyclidine, Eur. J. Pharmacol. 166 (1989) 359–366. [14] M. Irifune, T. Shimizu, M. Nomoto, T. Fukuda, Involvement of N-methyl-d-aspartate (Nmda) receptors in noncompetitive Nmda Receptor antagonist-induced hyperlocomotion in mice, Pharmacol. Biochem. Behav. 51 (1995) 291–296. [15] J.D. Jentsch, R.H. Roth, The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia, Neuropsychopharmacology 20 (1999) 201–225. [16] M. Jeziorski, F.J. White, M.E. Wolf, Mk-801 prevents the development of behavioral sensitization during repeated morphine administration, Synapse 16 (1994) 137–147. [17] P.W. Kalivas, B.A. Sorg, M.S. Hooks, The pharmacology and neural circuitry of sensitization to psychostimulants, Behav. Pharmacol. 4 (1993) 315–334. [18] G.R. King, Z. Xiong, E.H. Ellinwood, Blockade of the expression of sensitization and tolerance by ondansetron, a 5-HT3 receptor antagonist, administered
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27] [28]
[29] [30]
[31]
[32]
[33]
[34] [35]
245
during withdrawal front intermittent and continuous cocaine, Psychopharmacology (Berl.) 135 (1998) 263–269. H. Kuribara, T. Asami, I. Ida, Y. Iijima, T.S. Adokoro, Effects of repeated Mk-801 on ambulation in mice and in sensitization following methamphetamine, Psychopharmacology (Berl.) 108 (1992) 271–275. H. Kuribara, T. Asami, I. Ida, S. Tadokoro, Characteristics of the ambulation-increasing effect of the noncompetitive nmda antagonist Mk-801 in mice—assessment by the coadministration with central-acting drugs, Jpn. J. Pharmacol. 58 (1992) 11–18. C.S. Mcpherson, A.J. Lawrence, Exposure to amphetamine in rats during periadolescence establishes behavioural and extrastriatal neural sensitization in adulthood, Int. J. Neuropsychopharmacol. 9 (2006) 377–392. A. Mouri, Y. Noda, T. Enomoto, T. Nabeshima, Phencyclidine animal models of schizophrenia: approaches from abnormality of glutamatergic neurotransmission and neurodevelopment, Neurochem. Int. 51 (2007) 173–184. T. Ohmori, T. Abekawa, K. Ito, T. Koyama, Context determines the type of sensitized behaviour: a brief review and a hypothesis on the role of environment in behavioural sensitization, Behav. Pharmacol. 11 (2000) 211–221. R.C. Pierce, P.W. Kalivas, A circuitry model of the expression of behavioral sensitization to amphetamine-like psychostimulants, Brain Res. Rev. 25 (1997) 192–216. J.J. Quinn, F. Loya, Q.D. Ma, M.S. Fanselow, Dorsal hippocampus NMDA receptors differentially mediate trace and contextual fear conditioning, Hippocampus 15 (2005) 665–674. M.E.A. Reith, M. Benuck, A. Lajtha, Cocaine disposition in the brain after continuous or intermittent treatment and locomotor stimulation in mice, J. Pharmacol. Exp. Ther. 243 (1987) 281–287. T.E. Robinson, K.C. Berridge, The neural basis of drug craving—an incentive-sensitization theory of addiction, Brain Res. Rev. 18 (1993) 247–291. J.P. Rung, A. Carlsson, K.R. Markinhuhta, M.L. Carlsson, (+)-MK-801 induced social withdrawal in rats; a model for negative symptoms of schizophrenia, Prog. Neuropsychopharmacol. Biol. Psychiatry 29 (2005) 827–832. H. Ujike, Stimulant-induced psychosis and schizophrenia: the role of sensitization, Curr. Psychiatry Rep. 4 (2002) 177–184. A. Vezzani, R. Serafini, M.A. Stasi, S. Caccia, I. Conti, R.V. Tridico, R. Samanin, Kinetics of Mk-801 and its effect on quinolinic acid-induced seizures and neurotoxicity in rats, J. Pharmacol. Exp. Ther. 249 (1989) 278–283. K. Wedzony, K. Golembiowska, V. Klimek, MK-801-induced symptoms of sensitization. The lack of correlation with the extracellular concentration of dopamine in the rat prefrontal cortex, Brain Res. 625 (1993) 333–336. M.E. Wolf, M.R. Khansa, Repeated administration of MK-801 produces sensitization to its own locomotor stimulant effects but blocks sensitization to amphetamine, Brain Res. 562 (1991) 164–168. X.H. Xie, A.A. Arguello, A.M. Wells, A.M. Reittinger, R.A. Fuchs, Role of a hippocampal Src-family kinase-mediated glutamatergic mechanism in drug context-induced cocaine seeking, Neuropsychopharmacology 38 (2013) 2657–2665. X.J. Xu, E.F. Domino, Phencyclidine-induced behavioral sensitization, Pharmacol. Biochem. Behav. 47 (1994) 603–608. P.B. Yang, A.C. Swann, N. Dafny, Valproate prevents the induction and the expression of MK-801 sensitization, Brain Res. 954 (2002) 151–159.