Brain Research 887 (2000) 276–284www.elsevier.com/ locate /bres

Research report

Valproate prevents the induction of sensitization to methylphenidate(ritalin) in rats

a,b a a,b a b ,*Pamela Yang , Anitra Beasley , Kary Eckermann , Alan Swann , Nachum DafnyaDepartment of Psychiatry and Behavioral Sciences, The University of Texas Medical School at Houston, PO Box 20708, Houston, TX 77225, USA

bDepartment of Neurobiology and Anatomy, The University of Texas Medical School at Houston, PO Box 20708, Houston, TX 77225, USA

Accepted 19 September 2000

Abstract

Repetitive exposure to methylphenidate (MPD) elicits sensitization to its locomotor effects. Drugs that affect the GABA system maymodify adaptations to drug exposure. Therefore, we have examined the effect of sodium valproate, which enhances GABA function, onthe development of sensitization to MPD using an automated, computerized animal activity monitoring system to record each rat’s motoractivities for 15 consecutive days. Rats were recorded before and after saline injection (Days 1–2) to provide baseline activity. Animalswere then randomly assigned to the following three groups that received: (1) 2.5 mg/kg MPD (s.c.) for six consecutive days (Days 3–8),(2) a single dose of valproate (50 mg/kg; i.p.) 1 h prior to the first (Day 3) of six daily doses of MPD (2.5 mg/kg; s.c.), or (3) five dailydoses of valproate (50 mg/kg, i.p.) 1 h prior to MPD (2.5 mg/kg, s.c.) on Days 4–8. There was no drug treatment during the next 5 days(Days 9–13). All rats were then re-challenged with MPD (2.5 mg/kg, s.c.) on Day 14. Group 2 rats were also re-challenged with 50mg/kg valproate followed by 2.5 mg/kg MPD 1 h later on Day 15. Administration of MPD alone produced a sensitized response.Multiple valproate injections prevented the induction of MPD-elicited sensitization in all four motor indices, while a single valproateinjection prevented the induction of MPD-elicited sensitization in two of four motor indices studied. In conclusion, a single injection 50mg/kg valproate given prior to any MPD treatment partially blocked the induction of MPD sensitization while repeated injections ofvalproate co-administered with MPD treatment completely prevented this effect. 2000 Elsevier Science B.V. All rights reserved.

Theme: Neurotransmitters, modulators, transporters, and receptors

Topic: Behavioral pharmacology

Keywords: Sensitization; Locomotor activity; Psychostimulants; GABA; Dopamine

1. Introduction Increased locomotor activities and stereotypic movementsincited by dopaminergic stimulation can be blocked byGABA agonists at doses where these agonists have noRepeated administrations of psychomotor stimulantsdirect effects [7,28]. Clonazepam, a potent GABA-benzo-such as amphetamine, cocaine [20,21], and methylpheni-diazepine agonist, was reported to prevent the developmentdate [11] have been shown to cause behavioral sensitiza-of stimulant-induced sensitization [16]. Sodium valproate,tion. Behavioral sensitization is characterized by an in-an anticonvulsant drug used in treating schizophrenia andcreased locomotor and/or stereotypic behavior resultedmania [24], can enhance GABA activity and has effectsfrom repetitive treatment over time to a given dose of asimilar to that of benzodiazepine derivatives in conditionalstimulant [27]. Systemic administration of GABA agonistsavoidance response studies [26]. The present study wasreduces dopamine turnover in the mesolimbic system [2].carried out to determine whether enhancement of GABAactivity from a single pretreatment of valproate prior toany MPD administration or multiple doses of valproate*Corresponding author. Tel.: 11-713-500-5616; fax: 11-713-500-given 1 h before MPD administration would prevent the0621.

E-mail address: Nachum.Dafny@uth.tmc.edu (N. Dafny). induction of locomotor sensitization to MPD.

0006-8993/00/$ – see front matter 2000 Elsevier Science B.V. All rights reserved.PI I : S0006-8993( 00 )02996-6

P. Yang et al. / Brain Research 887 (2000) 276 –284 277

2. Materials and methods which grouped them into several different locomotorindices. Animal activity was recorded continuously for 15

2.1. Subjects days.The following four locomotor indices were analyzed: (1)

Male Sprague–Dawley rats (N528; Harlan, Houston, horizontal activity (HA), which measured the overallTX), weighing from 180 to 230 g, were housed in groups motor activity in the lowest tier of the testing cages andof four in Plexiglas cages inside the experimental room on assessed the overall amount of motor activity, (2) totala 12-h light /dark schedule (light on at 07:00 h). The distance (TD), which recorded the specific motor behaviorexperimental room was maintained at an ambient tempera- of forward movement, (3) vertical activity (VA) whichture of 21628C and at a relative humidity of 37–42%. counted the specific instances of rearing, and (4) numberAfter a minimum of 48 h of habituation, each rat was of stereotypes (NOS) which determined the stereotypicrandomly placed inside a test (home) cage where its behaviors, measured by repeated interruption of the samelocomotor activity recording began in all groups after 24 h beam [10].of acclimation to the home cages and continued for 15days. Rats were supplied with food pellets and water ad 2.4. Control and treatment groupslibitum.

There were three experimental groups: Group 1 (N512)2.2. Drugs — after baseline and saline, animals treated with 6 days of

MPD followed by five washout days and MPD re-chal-Both sodium valproate (VAL; Research Biochemicals lenge on Day 14 (Table 1); Group 2 (N58) — similar to

International, Natick, MA) and methylphenidate hydro- Group 1 but, in addition, animals were given a singlechloride (MPD; Sigma Chemicals, St Louis, MO) were administration of valproate (50 mg/kg) on Day 3 and Daydissolved in 0.9% saline. Valproate was injected intraperi- 15 1 h prior to MPD; and Group 3 (N58) — multipletoneally (i.p.), while MPD was injected subcutaneously administrations of valproate (50 mg/kg) was given on(s.c.). All injections were of equal volume (0.8 ml) and Days 4–8 1 h prior to each dose of MPD (Table 1). Thegiven between 12:00 h and 14:00 h. The selected valproate following is the general protocol for these groups: Day 1dose was 50 mg/kg and MPD dose was 2.5 mg/kg. These — baseline activity; Day 2 — saline injection (0.9%, i.p.);dosages were selected based on previous dose–response Day 3 — Groups 1 and 3 were treated with MPD, Group 2studies [8,10,11]. It was shown in preliminary studies that was given valproate 1 h prior to MPD; Days 4–8 —the dose of valproate chosen had no motor effect of its Groups 1 and 2 were treated with daily MPD, Group 3 wasown [8]. given valproate 1 h prior to daily MPD on Days 4–8; Days

9–13 — washout for all three groups; Day 14 — MPD2.3. Apparatus was given to all three groups; and Day 15 — valproate 1 h

prior to MPD was given to Group 2.A computerized animal activity monitoring (CAAM,

AccuScan Instruments, Inc., Columbus, OH) system was 2.5. Data analysisused to record locomotor activities continuously through-out the 15 experimental days [10]. The activity chambers Variability in baseline activity among animals wasconsisted of clear acrylic open field boxes (40.5340.53 observed; therefore, the best comparison for the drug31.5 cm) with two levels tiers, each consists of 16 infrared effects is to have each animal served as its own control.beams. The first and second levels of the tiers were placed The drug effect for each motor index was determined by6 and 12.5 cm from the cage floor, respectively. The subtracting the activity score of the 2-h after salineCAAM recorded any interruption of each of the beams at a injection (Day 2) from that of the 2 h after MPD injectionfrequency of 100 Hz. The interruption of any beam was to eliminate any handling and injection effects [10–12].counted. Total counts were compiled and downloaded Thus, the activity of saline injection served as baseline andevery 10 min into the OASIS data collection program, the absolute change in activity from saline represented

Table 1Treatment schedule

Day 0 1 2 3 4–8 9–13 14 15

Group 1 (N512) H B S MPD @ 14.00 MPD @ 14:00 WO MPD @ 14:00 WOGroup 2 (N58) H B S VAL @ 13:00, S @ 13:00, WO S @ 13:00, VAL @ 13:00,

MPD @ 14:00 MPD @ 14:00 MPD @ 14:00 MPD @ 14:00Group 3 (N58) H B S S @ 13:00, VAL @ 13:00; WO S @ 13:00, WO

MPD @ 14:00 MPD @ 14:00 MPD @ 14:00

H5habituation; B5baseline; S50.9% saline (i.p.); MPD52.5 mg/kg methylphenidate (s.c.); WO5washout; VAL550 mg/kg sodium valproate (i.p.).

278 P. Yang et al. / Brain Research 887 (2000) 276 –284

effects of the drugs. For Groups 1 and 3, the presence of In the line graph (Fig. 1), each 10-min sample on Day 3sensitization in each treatment group was determined by was compared to the same sample on Day 14 for the initialcomparing results of Days 4 to 8 and 14 with that of MPD 120 min following MPD administration. With respect tochallenge on Day 3 (first day of MPD administration in HA and VA, the first seven samples (i.e., 70 min after

¨naıve animals) within that group. For Group 2, the MPD injection) significantly differed in Days 3 and 14presence of sensitization was determined by comparing (P,0.01). For TD, five of the initial samples of Day 14results of Days 5 to 8 and 14 to 15 with that of Day 4 after MPD treatment differed significantly from Day 3.(second day of MPD administration, without valproate). The differences in Day 3 and 14 were strongest in NOSResults were subjected to a within-group repeated measure with the first seven samples (70 min after injection; P,

analysis of variance (ANOVA, two levels: treatment day 0.001). Thus, MPD induced activities were greatest withinand 10 min sample). The significant differences in in- the first 70 min after drug injection.dividual 10-min samples were determined with post-hocFischer’s (LSD) method. Significance for all of the above 3.2. Single administration of valproatecomparisons was set at *P,0.05, **P,0.01, or ***P,

0.001. Values are presented as the mean6S.E.M. for each The effect of a single dose of valproate given 1 h prior10 min after injection or for the sum of 2-h sample. In to MPD injection on Day 3 is summarized in Fig. 2. Aaddition, the difference in the magnitude of motor re- single injection of valproate given prior to any MPDsponses was also determined by calculating the ratio of the treatment prevented the induction of MPD sensitization forabsolute change in activity between MPD challenge (Day TD and NOS as expressed in the first 2 h after MPD3 for Groups 1 and 3; Day 4 for Group 2) and MPD injection. However, there were significant differences onre-challenge (Day 14). Results were analyzed using re- Day 7 (Fig. 2 bar graph) and 14 from Day 3 with respect topeated measure analysis of variance (one-way ANOVA: HA (P,0.05) and VA (P,0.05 for Day 7; P,0.01 fortreatment day), and any significant difference between the Day 14); thus, a single valproate injection did not preventgroups was determined with the Dunnett test. Significance the induction of MPD-sensitization for these indices. Thefor this comparison was set at *P,0.05. effects of the second injection of valproate 1 h prior to

MPD (Day 15) also differed significantly from the effectsof the first valproate injection 1 h prior to MPD (Day 3;

3. Results P,0.05) for VA, while there were no significant differ-ences for the other three indices. Therefore, a single

3.1. Control injection of valproate prior to any MPD injection pre-vented the induction of sensitization to TD and NOS but

Time control (15 days) and saline injection (Days 2 to not to HA and VA.8) on identical experimental protocols showed that themotor indices studied had remained similar over time as 3.3. Multiple administration of valproatewell as following multiple saline injections, and anydeviation from the time control or saline treatment was the The effect of multiple injections of valproate 1 h prior toresult of the drug effect(s) [6,10,12]. The effects of MPD injections on Days 4 to 8 on the induction of MPDrepeated MPD (2.5 mg/kg) treatment for HA, TD, VA, and sensitization is summarized in Fig. 3. The total count of 2NOS are summarized in Fig. 1. The bar graph shows the h after MPD injection of Days 4 to 8 compared to Day 3total activity score for the 2 h after MPD injection exhibited no significant differences in locomotor activitythroughout the experimental protocol. The line graph between any of the days with respect to HA, TD, VA, andrepresents the 10-min temporal response over the 2 h after NOS. Thus, concurrent administration of MPD and val-MPD injection on Days 3 and 14. In general, MPD’s proate prevented the development of MPD sensitization.effects on motor activity differed significantly betweenDay 3 (the initial challenge day) and Days 4 to 8 (the 3.4. Magnitude of sensitization between groupsinduction days) and Day 14 (the re-challenge day). ForHA, Days 6, 8, and 14 showed the greatest difference The motor activity response ratio of MPD re-challenge(P,0.001), but Days 4, 5, and 7 were also significantly and challenge for Groups 1–3 and the statistical com-different from Day 3 (P,0.01 for Day 7; P,0.05 for Days parison between these groups is summarized in Fig. 4. Fig.4 and 5). For VA, only Days 6, 8, and 14 significantly 4a shows that multiple administration of valproate (Groupdiffered from Day 3 (P,0.01, P,0.001, and P,0.001, 3) significantly (P,0.05) decreased the HA response ratiorespectively). For TD, sensitization was exhibited by the of MPD re-challenge and challenge compared to that offourth MPD injection on Day 6 (P,0.001), while Group 1, which was treated with only MPD. However,stereotypic sensitization (NOS) had developed by the there is no difference in the HA response ratio when Groupsecond MPD injection, i.e., Day 4 (P,0.05). In summary, 2, which received a single administration of valproate, wasby Day 6 (the fourth MPD injection) sensitization had compared to Group 1. Fig. 4b shows the observation of thedeveloped in all four motor indices studied. TD response which was similar to the HA response (Fig.

P. Yang et al. / Brain Research 887 (2000) 276 –284 279

Fig. 1. The effects of multiple MPD (2.5 mg/kg, s.c.) treatment on locomotor activity. Temporal response in 10-min samples for 120 min after MPDinjection (line graph) and 2-h total activity (bar graph) for the four motor indices studied: horizontal activity, vertical activity, total distance, and number ofstereotypic movements following administration of MPD. Sensitization to locomotor activities resulted from daily injection of MPD was well establishedby the third MPD injection (Day 6) and was still expressed several days later (Day 14). Presence of sensitization to MPD was determined by comparingresults obtained after the second to the sixth injection with that obtained at Day 3.Values are presented as the mean6S.E.M. for each 10-min or 2-h sample.*P,0.05; **P,0.01 and ***P,0.001 compared to Day 3.

280 P. Yang et al. / Brain Research 887 (2000) 276 –284

Fig. 2. The effects of single valproate (50 mg/kg, i.p.) administration (‘ — ’ indicates day of valproate injection in bar graph) 1 h prior to the initial MPDinjection on experimental Day 3 and Day 15. Temporal response (line graph) and 2-h total (bar graph) for horizontal activity, vertical activity, totaldistance, and number of stereotypic movements following administration of 2.5 mg/kg MPD (s.c.). All days are compared to the MPD challenge day (Day4) in both line and bar graphs. A single dose of valproate given 1 h prior to the initial MPD treatment prevented significant increases in total distance andnumber of stereotypic movements but not in horizontal (P,0.05) and vertical activities (P,0.01). Values are presented as the mean6S.E.M. for each10-min or 2-h sample. *P,0.05; **P,0.01 and ***P,0.001 as compared to Day 4.

P. Yang et al. / Brain Research 887 (2000) 276 –284 281

Fig. 3. The effects of multiple valproate (50 mg/kg, i.p.) administration (‘ — ’ indicates days of valproate injection in bar graph) 1 h prior to MPD onDays 4 to 8. The total count over the 2-h (bar graph) and the temporal response (line graph) after MPD injection are shown for horizontal activity, verticalactivity, total distance, and number of stereotypic movements. Multiple valproate administration prevented significant increases in MPD induced locomotoractivities throughout the experimental phase in all four behavioral indices. Values are presented as the mean1S.E.M. for each 10-min or 2-h sample.*P,0.05 and **P,0.01 as compared to Day 3.

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Fig. 4. This figure shows the motor activity response ratio of MPD re-challenge and challenge for Groups 1–3 and the statistical comparison between thesegroups. (a) shows that multiple administration of valproate (Group 3) significantly (P,0.05) decreased the horizontal activity (HA) response ratio of MPDre-challenge and challenge compared to that of Group 1; while there is no difference in the HA response ratio for Group 2, which received a singleadministration of valproate, when compared to Group 1. Similar results are shown in (b) involving total distance (TD) response.

4a). These observations indicate that multiple administra- tration prevented the induction of MPD-sensitization in alltion of valproate prevented MPD-elicited sensitization. four motor indices throughout the 6 days of repeated MPD

treatment and in the MPD re-challenge on Day 14.Interestingly, in a comparison of between groups involving

4. Discussion the motor activity response ratio of MPD re-challenge andchallenge, it was found that multiple administration of

Methylphenidate has the potential of abuse because it valproate (Group 3) prevented MPD-elicited sensitizationhas pharmacological stimulant properties similar to am- compared to the administration of MPD alone (Group 1) asphetamine and cocaine [9,31]. Its use in the treatment of demonstrated in the HA and TD responses (Fig. 4a).attention deficit /hyperactivity disorder (ADHD) has drasti- However, single administration of valproate (Group 2) didcally increased over the years [15]. The chronic use of not prevent MPD-elicited sensitization compared to thepsychostimulants, such as amphetamines, has been re- administration of MPD alone (Fig. 4b). These observationsported to produce a progressive enhancement in paranoid further support the efficacy of multiple treatments ofbehaviors that can result in psychosis [18,27] and in a valproate in blocking behavioral sensitization.reciprocal cross-sensitization between itself and other Behavioral sensitization consists of two phases: initia-stimulants [4], which may be analogous to sensitization in tion / induction and expression. There is evidence sug-rodents [27]. gesting that the induction and the expression of sensitiza-

The results show that daily repeated administration of tion to psychostimulants involve different anatomical andMPD (2.5 mg/kg) for six consecutive days produced physiological mechanisms. The initiation of sensitizationsensitization to its effects on locomotor and stereotypic consists of the immediate molecular and/or cellular effectsbehavior from the second or fourth injection, which that induce behavioral sensitization and are altered by drugpersisted when rats were re-challenged with MPD on Day actions in the somatodendritic regions of the A10/A914. Similar behavioral sensitization has been reported dopamine neurons [18]. In contrast, changes in dopaminefollowing multiple treatment with MPD [11] and other transmission within the nucleus accumbens seem to bepsychostimulants such as amphetamine and cocaine responsible for the expression of sensitization, which refers[19,27]. The objective of the present study was to de- to the long-term consequences of molecular and/or cellulartermine whether a single or multiple administration of effects that induce behavioral sensitization [18].valproate would prevent the development, or induction, of It has been hypothesized that dopamine plays a crucialbehavioral sensitization to the locomotor effect of repeti- part in the locomotor sensitization elicited by psycho-tive treatment with MPD. The data suggests that single stimulants because these stimulants elevate extracellularadministration of valproate given 1 h prior to the initial dopamine in brain regions that mediate enhanced locomo-MPD administration did not prevent the induction of MPD tion and stereotypic behaviors [5,14,17,22,23,30]. Thesensitization following repetitive MPD administration as significant role of dopamine in locomotor sensitization hasexpressed by horizontal and vertical activities, although also been supported by the observation that hyperactivesingle valproate injection prevented the induction of MPD behavior is a result of high concentrations of extracellularsensitization in total distance and number of stereotypic dopamine in the stratium of dopamine transporter knockoutmovements. In contrast, repeated daily valproate adminis- mice [14]. g-Aminobutyric acid (GABA) participates in

P. Yang et al. / Brain Research 887 (2000) 276 –284 283

the regulation of the activity of dopamine neurons by sensitization [34]. Moreover, there is evidence that excitat-reducing dopamine release and inhibiting dopaminergic ory amino acids, particularly N-methyl-D-aspartateactivity [1]. GABAergic neurons in the A10/A9 region (NMDA), may be essential for the development of aplay an important role in the modulation of the D sensitized response [32]. Pretreatment with dizocilpine1

receptors that are involved in the initiation of behavioral (MK-801), a non-competitive N-methyl-D-aspartatesensitization [18]. (NMDA) receptor antagonist, prior to amphetamine [20] or

g-Aminobutyric acid agonists have been shown to block methylphenidate injection [13,29] prevented the inductionthe augmented locomotor activity and stereotyped behavior of behavioral sensitization produced by these drugs but notresulting from dopaminergic stimulation [1,7,28]. Bac- the expression of behavioral sensitization [32]. Therefore,lophen, a specific GABA agonist agent, was found to it was suggested that the disruption of glutamatergicb

block the effect of amphetamine on discriminative learning projections to dopamine terminal fields may affect thein rats [3]. Locomotor stimulation in rodents induced by induction of sensitization [18] and that the induction andamphetamine or apomorphine was also inhibited by the expression of behavioral sensitization involve separateGABAergic drugs [2]. In the present study, multiple mechanisms [20]. Our results suggest that stimulation ofadministration of valproate prevented the induction of GABA activity, like inhibition of NMDA receptors, pre-MPD sensitization in all four motor indices studied. vented induction of behavioral sensitization.However, a single administration of valproate given 1 hbefore the initial MPD treatment prevented the inductionof sensitization to MPD in total distance and number of Acknowledgementsstereotypic movements but not in horizontal and verticalactivities. Valproate treatment enhanced GABA activity The authors wish to thank Dr. Miguel Bedolla for hiswithin the brain [25] by inhibiting its degradation, help with the statistics. This study was supported in part bystimulating its synthesis and release, and directly enhanc- the Pat Rutherford Chair in Psychiatry.ing its postsynaptic effect [24]. Therefore, valproate mayhave prevented sensitization to MPD by increasingGABAergic function. In addition to enhancing GABA Referencesactivity, valproate has also been reported to enhance

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