Research With Animals Has Examined Which Of These Different Properties Of Working Memory?

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Neurotoxicol Teratol. Writer manuscript; available in PMC 2009 Sep 1.

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PMCID: PMC2572720

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Methylphenidate improves performance on the radial arm maze in periadolescent rats

Abstract

Methylphenidate (Ritalin; MPD) is one of the most ordinarily prescribed drugs in childhood and adolescence and many clinical studies accept documented its efficacy. Due to the limitations of conducting invasive research in humans, animal models can be beneficial for studying drug effects. However, few animal studies have demonstrated the effects of methylphenidate on cognitive processes. The objective of this study was to discover a dose of methylphenidate that was effective in improving performance on a spatial working retentiveness cognitive task when administered orally to periadolescent rats. Therefore, we dosed subjects with methylphenidate at 1 or 3 mg/kg/twenty-four hours via gastric intubation from postnatal day 22 to 59 and assessed the furnishings of the drug on performance on the radial arm maze each day. To enhance performance overall, a 2nd experiment was conducted where the subjects were moderately food restricted (to xc% of the gratis-feeding weight). Results of Experiment 1 show that during the first week of testing simply the 3mg/kg MPD-treated males showed improved functioning (entries prior to repeated entry) when advertisement-lib fed and housed in pairs while the same dose significantly improved performance in both males and females nether weather condition of food-brake and individual housing in Experiment 2. MPD also produced a design of increased errors and arms entered during the first week, especially in Experiment 2. MPD increased locomotor activeness when tested at postnatal solar day 60 in both experiments. The information suggest that 3mg/kg oral methylphenidate improves operation on a spatial cognitive job only early on in treatment in the rat. While males testify improvement under conditions of both high and low motivation, females only show MPD effects when highly motivated. Hypothetically, methylphenidate may improve radial arm maze functioning through increased attention and improved spatial working memory and/or alterations in locomotion, reactivity to novelty or anxiety. Regardless, the study supports the utility of the rat equally a suitable model to examine the effects of depression dose oral MPD.

Keywords: Spatial working memory, sex differences, psychostimulants, periadolescence, food brake

one. Introduction

Attention deficit hyperactivity disorder (ADHD), a constellation of symptoms including inattentiveness, impulsivity and hyperactivity, affects up to 18 percent of children ages 3-17 in the US [xviii]. Methylphenidate (MPD, Ritalin^®), a psychostimulant pharmacologically related to cocaine and amphetamine, is the most widely prescribed medication for children and adolescents with ADHD [23;34], since between 5 and 15% of school anile children in the United States currently take MPD [16;17]. While the astute and chronic effects of MPD on cognitive function have been established in the human (see Solanto for review) [21], animate being models should be developed to obtain a thorough understanding of the neurochemistry and neuroanatomy of MPD effects. Unfortunately, about animal studies examine relatively high doses (5mg/kg and more than) of MPD and administer the drug intraperitoneally (ip). These factors limit the relevance of the piece of work to the human state of affairs. Behavioral manifestations of psychostimulants like MPD depend not only on the encephalon concentrations of the drug only besides on the rate of increase and clearance of drug from the encephalon. Intraperitoneal administration results in relatively rapid increases in encephalon MPD concentrations (compared to oral). Therefore, the best creature model to report the behavioral and neurochemical effects of MPD would be to use the oral route of assistants and depression clinically-relevant doses of the drug. Kuczenski and Segal [11] demonstrated that MPD doses of 3mg/kg and beneath administered orally during the dark-active phase in the boyish rat actually reduced locomotor activeness, an important attribute of modeling MPD effects in humans. They also establish that these doses of MPD increased extracellular norepinephrine in the hippocampus and had footling effect on dopamine levels in the nucleus accumbens, further suggesting that low MPD doses produce neurochemical changes which are singled-out from college doses which accept relatively greater furnishings on the DA organization. Recently there have been reports of the effects of depression doses of oral MPD on beliefs including Arnsten & Dudley [1] and Berridge et al [3]. Central components of cerebral role, sustained attending and working retentiveness, were found to exist improved by low doses of MPD. While clearly important findings, these studies utilized immature adult male rats and tested them during the lite phase of the low-cal-dark wheel. Young animals also often differ in drug sensitivity compared to adults[26] and behavior equally well every bit responses to MPD are largely impacted past the light-dark wheel [8]. Too Kuczenski and Segal [11] plant that the effects of MPD decreased in locomotion occurred in the nighttime-agile stage of the circadian cycles suggesting that calorie-free-cycle may be an of import gene in the model. Farther, since males and females ofttimes respond differently to psychostimulants, we wanted to include both sexes in the study. For these reasons, we conducted a study in juvenile rats of both sexes under weather of the normal active (dark) phase to decide whether MPD improved spatial working memory.

We selected spatial working memory to test since MPD had been shown to improve spatial working memory in normal adults [7]. Finding a depression oral dose of MPD that would improve spatial working retentivity in young rodents would strengthen the utility of the rodent as a model for MPD effects in humans. We selected the radial arm maze (RAM) as a measure out of spatial working retentiveness because information technology is a job that can be learned fairly quickly by weanling rats and that could be completed within the time of maximum claret levels of the orally administered drug. MPD was administered daily from postnatal 24-hour interval 22 to 59 which includes juvenile, adolescent and postadolescent developmental stages and operation on the radial arm maze was tested each twenty-four hour period using the win-shift paradigm (all artillery baited for each daily trial). Initially, overall performance was poor possibly due to the fact that we did non food-restrict the rats. Therefore, nosotros conducted a second experiment in which the subjects were mildly food restricted to increase motivation. Overall, nosotros plant that 3mg/kg MPD improved performance during the first week of the testing menstruation in males regardless of the nutrient condition and in females simply when nutrient restricted. After the first week, no further comeback was observed every bit dosing and testing proceeded in both experiments.

ii. Methods

2.1. Experiment 1

ii.1A. Animals

Sixty Sprague-Dawley male and female rats (five cohorts) served equally subjects. Rats were purchased from Charles River Laboratories, (Wilmington, MA). Pups arrived at postnatal day (P) ane with a dam and were non handled until P21 except for normal cage cleaning. The room was kept at 20-22° C, in a reverse 12:12 light cycle (lights off at eleven:00 A.M.). At P21 pups were weaned and ear-punched, and housed in standard plastic tubs (8" H, 8" Due west and 17" L). For experiment 1, subjects were dually housed with same-sexual activity pups and received free admission to nutrient (Purina Rat Chow). These subjects received Hershey's Minichips semi-sweet chocolate chips in the cage a few days prior to training to reduce neophobia of the food reward. We tested the animals during preadolescence (or the juvenile stage), adolescent and postadolescence. Hence, nosotros describe the test period every bit periadolescence.

2.1B. Apparatus

A radial viii-arm maze (RAM) synthetic of gray-painted wood was used. The middle platform measured 31.six cm in diameter while each of the eight arms was 61 cm L × seven.8 cm W with a small low for the bait located 1 inch from the distal end of each arm. The maze stood fifty cm off the floor in a room with red-dimmed lights to permit observation of the dark adapted rats. The room measured 2.72 m L × four.77 m W × 3.10 m H with 7 visual cues surrounding the maze (102-112 cm from the center of the maze) and an observer situated 168 cm from the center of the maze. These visual cues were non changed during the experiment

Three Digiscan Activity Monitors (Accuscan, Columbus OH, USA) containing open Plexiglas boxes (42×42×30 cm with no bedding) were used for testing locomotion. The monitor had 48 infrared sensors spaced two.v cm apart with 16 sensors along each side to mensurate horizontal activity. Additionally, 16 sensors were 10 cm from the floor of the box to measure vertical activity. Each monitor was within a white laminate sound-attenuating chamber measuring 60×sixty×37 cm within and containing two six-Due west red light bulbs and a fan (model 30 CFM, Dayton). The lids were equipped with 30×30 cm one-manner mirrors to allow for observation of the rat.

2.1C. Drugs

Methylphenidate HCl (generous gift of National Institute on Drug Corruption, through the Inquiry Triangle Institute, Research Triangle Park, NC) was dissolved in sterile water (Baxter) at a dose of 1 or 3mg/ml. Vehicle and drugs were administered via gastric intubation at 1ml/kg body weight each twenty-four hour period 40 min prior to testing on the RAM since this is the time of maximum Norepinepherine response in hippocampus [11].

2.1D. Procedures

Randomization

At P 21, pups were weaned and designated to handling groups. Five cohorts of 12 rats each were used in Experiment 1. Each cohort was comprised of 6 male and 6 female person rats, with the exception of one accomplice which contained 7 males and five females, totaling 31 males and 29 females in Experiment one. The rats were weighed each mean solar day to monitor growth and calculate dosage.

Dosing

Within cohort, ideally 4 rats (2 males and ii females) were treated with methylphenidate at one mg/kg (MPD 1), 4 rats with methylphenidate at 3 mg/kg (MPD 3), and four rats received the vehicle h2o (MPD 0). From P22-60, drugs were intragastrically administered with a gavage needle. (P22-35, 18g × 2 inch, soft plastic gavage needle; P36-45, 18g × ii.5 inch stainless steel gavage needle; P46-60 18g × 3 inch, stainless steel gavage needle).

Testing on the Radial arm maze

After drug administration, rats were returned to their home cages for 40 minutes to allow for absorption of the drug from the alimentary canal. Then the rats were transferred to the side by side behavior room for testing on the RAM. The RAM was baited with Hershey'due south Minichips semi-sweetness chocolate chips. Forty minutes after dosing, each rat was placed in the eye of the RAM and retained for 10 seconds to bespeak the beginning of a trial. An observer, blinded to the rat'southward drug treatment, recorded the following dependent variables: sequence of arm entry, time to enter the first viii arms, total time to call back the bait and errors and entries to echo. Errors are indicated by a repeated entry to a given arm, and the number of arm entries prior to repeating an arm entry was recorded as entries to repeat or EtoR, a measure of choice accuracy. Criterion was reached when the rat achieved 7 correct entries earlier repeating an arm in five minutes or less for 4 or 5 consecutive trials. Rats were removed from the RAM afterwards they retrieved all the allurement or after a maximum of v minutes and then returned to their domicile cages. After each run, the maze was wiped with a 30% ethanol solution; males were tested earlier females on a given mean solar day to minimize potential odor distracters.

Once the rats reached criterion (entering at least vii arms without repeating for four out of five consecutive test days), dosing and testing connected until P59 such that all subjects had an equal number of doses of MPD and equivalent maze experience.

Activity Exam

On P60 rats received their final drug dose and were returned to their home cages. Forty minutes after drug administration, rats were placed in the Digiscan Activity Monitor for one hour to monitor locomotor activity. Each box was cleaned with an booze: lather solution, (thirty% ethanol: 10% hand lather in water), before testing. The number of beam interruptions was recorded.

2.2. Experiment 2

2.2A. Animals

For this experiment, 5 new cohorts of 12 rats each were used. These subjects were identical to those in Experiment 1 except they were food-restricted to 90% of the trunk weight of the advertizing lib groups get-go on P22. Food restriction was utilized in gild to obtain acceptable motivation for learning the maze within the 38 days allotted for the experiment. Since the chocolate fries had a stiff odor and nosotros were concerned that the rats may be using aroma as a cue, we used sucrose pellets every bit the bait for Experiment 2. Food-restricted rats were familiarized with Noyes sucrose pellets 5 days prior to radial arm maze (RAM) training to minimize neophobia. Also, subjects in Experiment 2 were individually housed to permit food restriction.

ii.2B. Appliance

The apparatus used was identical to that used in Experiment 1

2.2C. Drugs

The doses of methylphenidate and routes of assistants were identical to Experiment 1.

two.2nd. Procedures

All procedures were identical to those of Experiment i with the post-obit exceptions: 1) Sucrose pellets were used as the reward for Experiment two. two) All rats were food restricted and housed individually. 3) Rats received their daily food allotment afterward they completed the RAM.

2.3. Statistical Analyses

The cohort was used every bit the unit of statistical analysis for all measures. Body weight was analyzed in a mixed linear model with 2 fixed factors (dose, sex) and ane random factor (cohort) across days separately for Experiment 1 and 2. Examination of the learning curves for both experiments indicated that the greatest effects of MPD occurred during the commencement week of dosing. Therefore, performance during the first week was the initial focus of the analysis. Dependent measures (such as entries to repeat or errors) were analyzed for each set of animals (Experiment 1 and Experiment two) using a mixed linear model [fixed factors for day (i-vii), treatment (0, i, three mg/kg MPD), sex and their interactions with cohort as a random factor]. Number of days the subjects were on the maze for the full v min allotted during the outset 7 days of testing was analyzed using a generalized estimating equations analysis. Days to reach criterion (7/8 arms earlier repeating for 4 out of five test days) for Experiments i and two was analyzed using a positive stable fraility model due to the right censoring of the dependent variable (a substantial number of rats never reached benchmark). The positive stable frailty model is an extension to the well-known Cox regression modeling technique, that allows random effects as well as fixed effects to be introduced in survival analyses.[31]. Locomotor activity at P60 recorded in the Accuscan was analyzed using a mixed linear model as for EtoR or errors except that activeness in either the showtime v min or across all time blocks was examined instead of performance on days. Satterthwaite adjustments to denominator degrees of freedom were practical in mixed linear model analyses. SAS Release 9.1 (SAS Constitute, Cary NC) software was used for all analyses. Advisable post-hoc analyses were conducted and a p value of 0.05 or less was required for statistical significance.

3. Results

3.1. Experiment 1

three.1A. Trunk Weight

There were no furnishings of MPD treatment on body weight in this report. The but meaning difference in trunk weights occurred betwixt the male and female person rats with males naturally weighing more than females (p<.05) (data not shown).

3.1B. Performance on the Radial Arm Maze

The initial analysis of performance was the number of days needed to reach benchmark (run into section 3.3) and this did non reveal a handling effect. Visual exam of the learning curves indicated that in that location were differences in performance and that these occurred within the first week of testing. Therefore, this start calendar week was selected for further analysis. Assay of "entries-to-echo" (number of arms entered before repeating an entry) during the beginning week of testing showed that at that place was a chief outcome of day (trial) [F(6,140)=11.78, p<0.001] and a treatment by sex activity interaction [F(2,53.5)=3.45, p=0.039]. Simple effect analysis showed that there were no differences among females just for males, there were differences (p=0.010). Pair wise comparisons within males showed that those rats in the MPD 3 grouping (mean = 2.13) performed significantly better than the controls across all 7 days (mean = 0.83) [Tukey-adapted p=0.031]. At that place was no significant cohort consequence (Z=ane.xviii; p=0.119).

Figure one illustrates the learning curves generated for each group of rats (Experiment one and ii for each treatment, dose, and sexual practice). Since rats reached benchmark at widely different ages (P30 to not at all), and thereafter, were then tested in a different environment, the best fashion to illustrate functioning beyond all groups was to assign a score of 8 (the maximal score possible) for all trials once criterion was achieved. Daily operation (entries to repeat) averages for each sex activity/treatment group were calculated and displayed in Figure 1. In this way, the groups could exist compared across the entire treatment catamenia.

Learning curves generated for each group of rats (in Experiment 1 and Experiment 2) where once the rat has achieved criterion, a score of eight (the maximal score possible) was applied for the rest of that rats' trials. Analysis of the kickoff week of "entries-to-echo" for each prepare of animals showed that for Experiment 1, at that place was a master issue of twenty-four hours (trial) and a dose past sex interaction. Uncomplicated effect analysis showed that there were no differences among females but for males, there were differences (p=0.01). Pair wise comparisons inside males showed that those rats that received 3mg/kg performed significantly better than the controls during the first week. For Experiment two, there was a main effect of treatment and mail-hoc assay showed that the group receiving 3mg/kg performed better than the others. * indicates meaning departure between MPD 3 and MPD 0 on individual days (ANOVA; p<0.05). (Northward ≈ 10 for each sex/treatment group)

The total number of errors made during the first week of testing was analyzed using a mixed linear model with fixed factors of sex activity, treatment dose, and a random cistron of cohort. There were no significant effects of sex, treatment or their interactions for number of errors (Figure 2). The utilization of strategies such as adjacent arm entries was also examined and found not to differ across treatment groups. While the number of arms entered during the first week of testing appeared to be greater in the MPD iii groups compared to the MPD 1 and control groups, this difference was not statistically significant (Chi square for handling = two.98, p=0.226).

Comparison of errors and arms entered during the offset week of testing on the radial arm maze. Information are complanate into intervals: days 1-ii, days three-5 and days vi-vii. The average number of errors and arms entered for the unabridged 7 days catamenia is also shown. At that place was no significant effect of dose or sex for errors in Experiment 1 (top panels). Even so, for Experiment 2 (lesser panels), there was a main outcome of handling for errors with the MPD three groups showing more errors than the other groups. * indicates a significant increase in errors overall compared to the controls. Analysis of errors/arms entered for Experiment 2 likewise indicated that the MPD iii group made more errors/arm entered on testing mean solar day 1-2 merely. * indicates that the MPD 3 group made significantly more errors/arm entered than the controls.

Number of days the subjects were on the maze for the full 5 min allotted during the first 7 days of testing was used as an indicator of functioning since if the field of study was on the maze for v minutes, performance was generally poor. These data were analyzed using a generalized estimating equations analysis. There was no significant departure in the number of days that the various handling groups or sexes utilized the maximal v minutes allotted during the beginning week of testing. [Chi-square analysis for each group independently; p>0.05] (data non shown).

Therefore, the MPD males showed more entries to retreat than the MPD1 or control males over the first week of testing while no other indices of operation were altered.

3.1.C. Locomotor Activity at P60

Locomotor activeness was collected 40 min following dosing on P60 in Accuscan activeness chambers for simply three cohorts of rats. Activeness for the starting time 5 min was analyzed using a mixed linear model and gender [F(1,28)=17.viii, p<0.001] and the interaction between gender and handling [F(2,28)=4.43, p=0.021] were significant (see Figure 3A). Elementary effects analysis showed that in that location was a pregnant treatment consequence among females with the MPD 3 females showing greater activity than the control females while in that location were no differences amid males. In improver, at that place were significant gender differences within the MPD 1 groups and the MPD three groups but not the controls. Data for 12 5 min time blocks were averaged and compared. Treatment produced a main effect [F(2,28) =v.22, p=0.012] with the MPD 3 group showing significantly greater activity than the controls [Tukey p=0.013]. Sex besides produced a meaning principal event [F(1,28) = 6.27, p=0.018] with females showing greater action than males (Effigy 3B).

Locomotor activity at postnatal twenty-four hour period 60 in both male and female rats 40 min afterward being dosed with 0, 1 or 3 mg/kg methylphenidate(mean +sem). A) Beams interrupted during the showtime 5 min of the recording in rats in Exp 1. * indicates that MPD three females showed greater activity than the MPD 0 females during the get-go time cake. B) Average action across the whole 60 min session in Exp ane. # indicates that the MPD 3 group was more active than the MPD 0 group when collapsed across sex. There was likewise a master effect of sex with females showing more than action than males. C) Beams interrupted during the first 5 min of the recording in rats in Exp 2. # as for panel B D) Average activity across the whole threescore min session in Exp 2. # as for panel B. Again females were more active than males.

iii.2. Experiment ii

iii.2.A. Body Weight

The body weights in this experiment were controlled by food brake to be equivalent to those of the aforementioned sex and age subjects. Therefore, in this experiment the simply significant difference in body weights occurred betwixt the male and female rats (p<.05)(data non shown).

3.2.B. Performance on the Radial Arm Maze

Equally in Experiment 1, the initial analysis of performance was the number of days the subjects needed to accomplish criterion (see section three.3) and this was not significant for handling. Therefore, we analyzed performance during the first calendar week of testing based on the apparent treatment effects seen in Figure 1. For Experiment 2, entries to echo during the first week of testing showed a main effect of day [F(half dozen,126) =12.55, p<0.001] and a main effect of treatment [F(2,52)=6.iv, p=0.003]. Post-hoc pair-wise comparisons showed that the MPD 3 grouping performed significantly better than the controls [adjusted mean of MPD three group = ii.96 while that of controls =1.46; Tukey p=0.003]. There was no departure between the sexes. There was no meaning accomplice effect (Z=0.8; p=0.213).

For errors during the first week of testing in Experiment two, there was a primary effect of treatment dose [F(ii,fifty)=5.54, p=0.007] but no significant effect of sex activity or sex by treatment interaction (Effigy two). The MPD 3 group (adjusted mean .93, SE 0.09) showed a significantly greater number of errors per day than either the MPD 0 grouping (mean .54, SE 0.09) (p=0.005) or the MPD ane group (hateful 3.55, SE 0.09) (p=0.006). Since this increase in errors may simply reflect a greater number of arms entered on each twenty-four hour period of testing, we analyzed the number of errors/arm entered using a generalized estimating equation with an unstructured intra-subject covariance matrix. This analysis indicated that the MPD three group had greater errors per arm entered (24%) than the MPD one group (8%) or the control group (13%). Every bit shown in Effigy two, the MPD 3 group entered approximately twice as many arms during the first week as the controls did (average six arms/rat/day compared to 3.4 artillery for the controls). Nonetheless, the enhanced number of arms entered in the MPD 3 group was coincident with an increase in errors/arm. Initially then, MPD at 3mg/kg increased the number of arms entered before making an fault but also increased the number of errors the subjects fabricated following the kickoff error. Such that the total errors/arm entered was college in the MPD 3 groups.

In order to determine whether the pattern of entrances could be explained by the use of a strategy such equally entering side by side arms, nosotros analyzed the percent side by side arm entries of the total arm entries in the session using a generalized linear model of the binomially-distributed dependent variable. Gender and treatment were entered every bit fixed factors and a correction for overdispersion was applied. There were no differences in proportions of adjacent arms entered F(3,34)=0.59) (p=0.624). Adjacent entry rates for the command males were 16%, for command females 23%, for MPD iii males 22% and MPD iii females 22%. Analyses of other strategies such as inbound alternate arms more than once or fifty-fifty entering every third arm more than than once revealed that these strategies were rarely used.

Number of days the subjects were on the maze for the full five min allotted during the get-go 7 days of testing showed that in that location was no meaning divergence between the diverse treatment groups or sexes. [Chi-square analysis for each group independently; p>0.05] [information not shown].

3.2.C. Locomotor Activity at P60

Locomotor activeness was collected 40 min following dosing on P60 in Accuscan activity chambers. Data for the first 5 min were analyzed using a mixed linear model and handling produced a meaning effect [F(1,48)=8.07, p<0.001] while sexual activity and the interaction did not (see Figure 3C). Post hoc pair-wise comparisons amid treatment groups showed that the MPD iii group was more active than the controls [p<0.001, Tukey-adapted]. Additionally, data for 12 5 min time blocks were averaged and the averages were compared (Figure 3D). Handling produced a principal effect [F(2,48) =iv.25, p=0.020] with the MPD iii group showing significantly greater activity than the controls [Tukey p=0.015] (Figure 3). Sex also produced a significant main effect [F(1,48) = 15.7, p<0.001] with females showing greater activity than males.

iii.3. Days to accomplish criterion in both Experiment 1 and 2

Days to reach benchmark (entering vii/8 artillery before repeating an arm entry for 4 out of 5 sequential test days) for nutrient restricted and ad-lib fed subjects was analyzed using a positive stable fraility model due to the correct censoring of the dependent variable (a substantial number of rats never reached criterion). While there were no significant treatment or sex differences when all subjects were analyzed together, there was a clear trend for a more rapid attainment of criterion in the males receiving MPD three (Effigy 4). A likelihood ratio test of accomplice result was statistically pregnant (χ²=vii.74, df=1, p=0.005). This suggests that while days to criterion was not significantly afflicted by the treatment or sexual activity, it was significantly dependent upon the cohort existence examined and presumably the food restriction. For instance, the fed males receiving MPD 0 in Experiment 1 required 32 days to achieve criterion while the food-restricted males in Experiment two required an average of only 22 days. Similarly, the MPD iii males in Experiment 2 achieved criterion an boilerplate of 10 days earlier than those in Experiment i.

Days to reach criterion (vii/8 arms entered before repeating for iv out of 5 test days) for nutrient restricted and ad-lib fed subjects. While at that place were no significant handling or sex differences, there was a clear trend for a more than rapid attainment of criterion in the males receiving 3 mg/kg methylphenidate. (hateful + sem).

4. Discussion

MPD enhanced performance on the RAM during the commencement week of testing in P22-29 rats, especially in males (Figure ane). This enhancement was somewhat greater in food-restricted, individually housed subjects compared to the extemporaneous fed subjects and was only seen in the subjects receiving the MPD 3 dose, an oral dose which is considered low [21]. I mg/kg had no effect on learning under whatever conditions. By the end of the first week of testing, performance of the controls had "caught upwardly" to that of the MPD 3 group and was identical from that point onward including "days to reach criterion."

Improved attention to the RAM task certainly could contribute to the improved performance seen in the MPD three groups. Attention is a major component of any cerebral measure in that if a discipline is easily distracted, the performance on the chore will subtract. Clearly, MPD improves attention in humans with ADHD [28;29] and our results are consistent with the notion that, at least early on in the training, MPD may ameliorate performance past improving attention. Since the subjects in Experiment 1 were less motivated due to the fed status compared to Experiment 2, (food restriction = higher motivation/arousal), enhanced attention to the maze may accept played a bigger role in Experiment ane compared to Experiment two. Berridge et al [three], take demonstrated that depression oral doses of MPD increase norepinephrine and dopamine release in prefrontal cortex, a finding which is consistent with an effect on attention and working retention, two functions which rely on an intact prefrontal cortex. The RAM is designed as a exam of spatial working memory. Deficits in working memory are considered endophenotypic of ADHD [v] and MPD has been shown to improve functioning on tests of spatial working retention in humans [30]. These improvements in working memory tasks occur with specific alterations in prefrontal cortex and posterior parietal blood menstruation in humans [12]. Noradrenergic efferents from the locus coeruleus to prefrontal cortex are thought to mediate the furnishings of psychomotor stimulants on working memory [see review [22]]. Therefore, our data suggest that low oral doses of MPD may activate the noradrenergic afferents to the prefrontal cortex and enhance spatial working memory in pre-adolescent rats. Evidence from studies in the adult also support this concept [i;3].

In Experiment 2 the MPD iii subjects made significantly more errors during the first week of testing. An analysis of the errors in relation to the number of arms entered revealed the MPD 3 group made more errors even when the number of arms entered was taken into consideration (Figure 2). Since the MPD 3 group entered a greater number of artillery before repeating an arm but so connected to enter arms in mistake during these early sessions, subjects seemed to search for rewards inspite of multiple non-successful attempts. This is suggestive of preservative beliefs [1;24]. However, the procedures we used were non designed to test for perseverative behavior per se. Another potential factor which may contribute to an improved operation on the RAM is that of utilization of sequencing to solve the maze. That is, rats may have selected adjacent arms, or selected every other arm or every tertiary arm and solved the maze without utilizing spatial working memory. In improver, a high level of nutrient-impecuniousness shifts rats toward utilizing sequential entries [ten]. A detailed analysis of adjacent arms entered revealed that there were no significant differences in the percent adjacent arms entered in the male person and female control groups compared to those in the 3 mg/kg group. Use of consecutive entries of every other arm or every third arm was exceedingly rare across all groups. Since sequential arm entries may exist considered stereotyped beliefs, our results would not back up an increase in stereotyped beliefs post-obit low-dose oral MPD administration. However, overall MPD stimulated a greater number of attempts at bait retrieval than did the vehicle.

By the end of the beginning week of handling, performance of the controls and low-dose groups was just as good as the MPD iii groups. Tolerance may take developed. However, we do non believe rats adult tolerance to the effects of MPD since functioning does not decrease with repeated exposure, a hallmark of tolerance. The use of a more complex task after the start calendar week of testing would be helpful to determine whether tolerance to the effects of the drug does develop or whether the lack of continued superior performance is due to a ceiling event (the 8 arm maze is relatively like shooting fish in a barrel to master).

There are several non-cognitive furnishings of MPD which may contribute to the improved operation on the spatial working memory task including: increased motivation, increased speed of performing the chore or reduced fright of traveling to the terminate of the RAM. The cistron of motivation was quite dissimilar in Experiment i and Experiment 2. In Experiment 1 (no food restriction) MPD was effective at the 3mg/kg dose in the males alone. This suggests that fifty-fifty under less-motivated conditions when all groups perform more poorly compared to the food-restricted groups, MPD however improves functioning. If MPD produced anorexia, one would hypothesize that operation would be inferior in an appetitive task. Notwithstanding, MPD did not alter body weight of the ad-lib fed males and females (come across likewise Bolanos) [4] and has been shown to not affect food consumption in this dose range [25]. Therefore, presumably MPD would not reduce motivation for a food reward. Too, we used chocolate chips equally the reward in the fed status to improve motivation merely clearly the fed subjects did not perform equally well every bit the food-restricted ones. The fed rats eventually did reach criterion but the average number of days required was most 30% more than in the food-restricted condition (meet Effigy 4). The housing status could also contribute to the enhanced effect of MPD in Experiment two, that is, while the ad-lib fed rats were housed in pairs, the food-restricted rats were individually housed. Since private housing is considered a mild stress and stress enhances psychostimulant effects, individual housing likely contributed to enhanced effects of MPD in Experiment 2 particularly in the females.

Another possible reason why MPD may accept improved performance on the RAM is that it may have increased the speed at which the rats ran the maze. While we quantified locomotor action on 24-hour interval 60 subsequently the concluding dose of the drug and found that there were significant increases in activeness, specially in the MPD 3 groups, this finding may or may not exist relevant to the possible enhancement of locomotor activity in P22-29 rats, the ages which showed enhanced functioning on the RAM. By P60 following 38 doses of MPD, locomotor sensitization may have occurred. However, the 3mg/kg dose has been shown to subtract locomotor activity [11] when quantified in the home cage in adult male rats. Too a recent study by Zeise et al [32] found improvements on the Morris water maze following oral dosing of MPD to preadolescent rats which were not due to increased swim speed. In add-on, examination of the arms entered during the first week of testing revealed that there were no meaning differences between the MPD 3 group and the controls suggesting that the drug did not produce non-specific increases in activeness on the maze. Also, in a related report, MPD at 3mg/kg did not alter activity later xviii days of dosing at P40 [33]. The simply way to make up one's mind the contribution of locomotion to our results is to quantify this beliefs post-obit MPD dosing direct in subjects during the P22-29 age period.

Another factor which may have contributed to the improved performance in the MPD groups is that the drug may accept reduced anxiety and facilitated the movement of the rats out onto the open artillery. Psychostimulants at low doses have been shown to exist anxiolytic [19;27] and the MPD 3 dose may take functioned in this manner, hypothetically reducing the subjects' fear of going out onto the open arms. This may explain the early improvement in performance of the MPD treated rats. The control subjects may "catch up" to the treated subjects once their presumed fright of being on the open artillery is overcome. MPD at low oral doses has been institute to reduce thigmotaxis, a measure out of anxiety in the Morris water maze [32]. In that report, later on the first few sessions of testing, there were no differences between MPD-treatment and controls, a finding which parallels our overall results quite well. Another factor which may have contributed to the results of the present study is that MPD may have altered the response to novelty in the postweaning rats. If the treated rats explored more in the novel environment, and so they may have learned the maze more quickly than the controls did.

Other factors which could contribute to the findings of the electric current written report include a possible shift to the utilization of proximal cues to solve the job. Traditionally, the RAM is believed to tap distal spatial (allothetic) cues [13] but the drug may alter this strategy and thus improve functioning. While possible, the pattern of errors made would suggest that enhanced motivation to obtain a reward, enhanced attention and/or enhanced spatial working memory were greater factors. Low dose MPD has also been shown to enhance goal-directed behavior without improving learning per se [32].

In general, the effects of MPD may exist specific to the postweaning period. That is, simply a few papers have reported on the furnishings of MPD in developed rats on various cognitive tests (due east.grand. [3]). Arnsten & Dudley [1] reported that MPD improved performance in young adult male rats on a task which was dependent upon the prefrontal cortex. Conspicuously somewhat older subjects should be examined using the RAM to make up one's mind whether MPD improves performance in older subjects as well. Too, somewhat surprisingly, MPD improved performance less in female person subjects than in males in our study. Typically, psychostimulants have greater furnishings on behavioral activation in female rats than males [9;20]. We examined higher doses of MPD (5mg/kg) in a pilot written report, and constitute that performance of the females was worse than at 3mg/kg dose (Zhu & Dow-Edwards, unpublished observations). While the subjects in the current study were pre-pubertal at the onset of the experiment, females practise take relatively high circulating levels of estrogen and estrogens have been plant to collaborate with multiple neurotransmitter systems [2;six;14;15]. Arousal mediated by noradrenergic signaling has been shown to be estrogen dependent [6]. It appears as though a combination of factors (individual housing and food-restriction) resulted in an improvement in performance in females receiving MPD. Since food-restriction has been shown to modulate estrogen receptors in noradrenergic neurons in the hypothalamus [15], a similar enhancement of noradrenergic activity may have occurred in prefrontal cortex to better spatial working memory in the food restricted females receiving MPD 3.

In summary, methylphenidate at 3 mg/kg improves functioning during the get-go calendar week of testing on the radial arm maze in males and females particularly if they take been mildly food restricted. There were no significant effects on number of days the subjects spent the full v min on the maze or on "days to benchmark" although the males receiving MPD 3 tended to practice better than all other groups. Therefore, methylphenidate at 3mg/kg improves functioning on the radial arm maze peculiarly in food restricted, individually housed males and females during the first week of testing. Prolonged dosing did not continue to improve performance, and females simply showed improvement nether conditions of increased motivation. MPD appears to amend attention and spatial working memory in juvenile rats as it does in humans. In addition, MPD appears to increase the number of errors/endeavour to obtain a reward and if this can exist extrapolated to the human being, MPD may amend the try exerted by the subject in spite of the increment in errors. Notably, errors had minimal negative consequences in this study. Therefore additional effort ultimately did produce additional reward.

Acknowledgments

The skilful technical assistance of Apr Jackson, Lucille Grullon and Stacy Stephenson is gratefully best-selling. The authors would like to thank Dr. Ning Zhao and Dothlyn Dunkley, MS for manuscript preparation and James Ranck, Md for thoughtful comments on this paper.

Inquiry Supported past NIH grant R21MH066852. Methylphenidate was a generous souvenir of NIDA through Inquiry Triangle Plant, Research Triangle Park, NC

Footnotes

Disclaimers: The authors have no financial interest in the results of this study

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Reference List

1. Arnsten AFT, Dudley AG. Methylphenidate improves prefrontal cortical cerebral function through á2 adrenoceptor and dopamine D1 receptor actions: Relevance to therapeutic furnishings in Attention Deficit Hyperactivity Disorder. Behav Brain Func. 2005;1:one–14. [PMC gratuitous article] [PubMed] [Google Scholar]

2. Becker JB. Gender differences in dopaminergic function in striatum and nucleus accumbens. Pharmacol Biochem Behav. 1999;64:803–812. [PubMed] [Google Scholar]

3. Berridge CW, Devilbliss DM, Andrzejewski ME, Arnsten AFT, Kelley AE, Schmeichel B, Hamilton C, Spencer RC. Methylphenidate Preferentially Increases Catecholamine Neurotransmission within the prefrontal cortex at Low Doses that Enhance Cognitive Function. Biol Psychiatry. 2006;threescore:1111–1120. [PubMed] [Google Scholar]

iv. Bolanos CA, Barrot M, Berton O, Wallace-Black D, Nestler EJ. Methylphenidate treatment during pre- and periadolescence alters behavioral responses to emotional stimuli at adulthood. Biol Psychiatry. 2003;54:1317–1329. [PubMed] [Google Scholar]

5. Castellanos FX, Tannock R. Neuroscience of attention-arrears/hyperactivity disorder: the search for endophenotypes. Nat Rev Neurosci. 2002;3:617–628. [PubMed] [Google Scholar]

six. Devidze N, Lee AW, Zhou J, Pfaff WW. CNS arousal mechanisms bearing on sex and other biologically regulated behaviors. Physiol Behav. 2006;88:283–293. [PubMed] [Google Scholar]

vii. Elliott R, Sahakian BJ, Matthews M, Bannerjea A, Rimmer J, Robbins TW. Effects of methylphenidate on spatial working retentiveness and planning in healthy young adults. Psychopharmacology. 1997;131:196–206. [PubMed] [Google Scholar]

eight. Gaytan O, Yang P, Swann A, Dafny N. Diurnal differences in sensitization to methylphenidate. Brain Res. 2000;864:24–39. [PubMed] [Google Scholar]

nine. Haney M, Castanon N, Cador Thou, Le Moal Thousand, Mormede P. Cocaine sensitivity in Roman High and Low Avoidance rats is modulated by sexual practice and gonadal hormone condition. Brain Res. 1994;645:179–185. [PubMed] [Google Scholar]

x. Hoges H. Maze procedures: the radial-arm and water maze compared. Cognitive Encephalon Res. 1996;3:167–181. [PubMed] [Google Scholar]

11. Kuczenski R, Segal DS. Exposure of adolescent rats to oral methylphenidate: preferential effects on extracellular norepinephrine and absence of sensitization and cross-sensitization to methamphetamine. J Neurosci. 2002;22:7264–7271. [PMC free article] [PubMed] [Google Scholar]

12. Mehta MA, Owen AM, Sahakian BJ, Mavaddat N, Pickard JD, Robbins TW. Methylphenidate enhances working memory by modulating discrete frontal and parietal lobe regions in the man brain. J Neurosci. 2000;20:1–6. [PMC free article] [PubMed] [Google Scholar]

xiii. Olton DS, Collison C, Werz MA. Spatial Memory and Radial Arm Maze Performance of Rats. Learning Motivation. 1977;eight:289–314. [Google Scholar]

xiv. Pandaranandaka J, Poonyachoti S, Kalandakanond-Thongsong South. Anxiolytic property of estrogen related to the changes of the monoamine levels in various brain regions of ovariectomized rats. Physiol Behav. 2006;87:828–835. [PubMed] [Google Scholar]

15. Reyes BA, Tsukamura H, L'Anson H, Estacio MA, Hirunagi 1000, Maeda KI. Temporal expression of estrogen receptor á in the hypothalamus and medulla oblongata during fasting: a role of noradrenergic neurons. J Endocrinol. 2006;190:593–600. [PubMed] [Google Scholar]

16. Robison LM, Sclar DA, Skaer TL, Galin RS. National trends in the prevalence of attention-deficit/hyperactivity disorder and the prescribing of methylphenidate among school-age children: 1990-1995. Clin Pediatr. 1999;38:209–217. [PubMed] [Google Scholar]

17. Safer DJ, Zito JM, Fine EM. Increased methylphenidate usage for attending deficit disorder in the 1990s. Pediatrics. 1996;98:1084–1088. [PubMed] [Google Scholar]

eighteen. Sagvolden T, Sergeant JA. Attention deficit/hyperactivity disorder--from brain dysfunctions to behaviour. Behav Brain Res. 1998;1:1–10. [PubMed] [Google Scholar]

19. Sanberg PR, Zoloty SA, Willis R, Ticarich CD, Rhoads 1000, Nagy RP, Mitchell SG, Laforest AR, Jenks JA, Harkabus LJ, Gurson DB, Finnefrock JA, Bednarik EJ. Digiscan Activity: Automated Measurement of Thigmotactic and Stereotypic Behavior in Rats. Pharmacol Biochem Behav. 1987;27:569–572. [PubMed] [Google Scholar]

twenty. Sircar R, Kim D. Female Gonadal Hormones Differentially Modulate Cocaine-Induced Behavioral Sensitization in Fischer, Lewis, and Sprague-Dawley Rats. J Pharmacol Exp Ther. 1999;289:54–65. [PubMed] [Google Scholar]

21. Solanto MV. Dopamine dysfunction in AD/Hard disk: integrating clinical and bones neuroscience research. Behav Brain Res. 2002;130:65–71. [PubMed] [Google Scholar]

22. Solanto MV. Neuropsychopharmacological mechanisms of stimulant drug activeness in attention-deficit hyperactivity disorder: a review and integration. Behav Brain Res. 1998;94:127. [PubMed] [Google Scholar]

23. Swanson JM, Sergeant JA, Taylor E, Sonuga-Barke EJS, Jensen PS, Cantwell DP. Attention-deficit hyperactivity disorder and hyperkinetic disorder. Lancet. 1998;351:429–433. [PubMed] [Google Scholar]

24. Tannock R, Schachar R. Methylphenidate and cognitive perseveration in hyperactive children. J Child Psych Psychol. 2008;33:1217–1228. [PubMed] [Google Scholar]

25. Teo S, Stirling D, Thomas South, Hoberman A, Kiorpes A, Khetani V. A xc-day oral gavage toxicity study of D-methylphenidate and D,50-methylphenidate in Sprague-Dawley rats. Toxicol. 2002;179:183–196. [PubMed] [Google Scholar]

26. Torres-Reveron A, Dow-Edwards DL. Repeated administration of methylphenidate in immature, adolescent and mature rats affects the response to cocaine later in adulthood. Psychopharmacology. 2005;181:38–47. [PubMed] [Google Scholar]

27. Treit D, Fundytus Thousand. Thigmotaxis as a Test for Anxiolytic Activeness in Rats. Pharmacol Biochem Behav. 1989;31:959–962. [PubMed] [Google Scholar]

28. Tucha O, Mecklinger L, Laufkotter R, Klein HE, Walitza S, Lange KW. Methylphenidate-induced improvements of various measures of attention in adults with Attention Arrears Hyperactivity Disorder. J Neural Transm. 2006;113:1575–1592. [PubMed] [Google Scholar]

29. Tucha O, Prell S, Mecklinger L, Bormann-Kischkel B, Kubber South, Linder M, Walitza S, Lange KW. Effects of methylphenidate on multiple components of attention in children with attention deficit hyperactivity disorder. Psychopharmacol. 2006;185:315–326. [PubMed] [Google Scholar]

30. Turner DC, Blackwell Advertizing, Dowson JH, Mclean A, Sahakian BJ. Neurocognitive effects of methylphenidate in adult attending-deficit/hyperactivity disorder. Psychopharmacol. 2005;178:286–295. [PubMed] [Google Scholar]

31. Wang ST, Klein JP, Moeschberger ML. Semi-parametric estimation of covariate effects using the positive stable frailty model. Applied Stochastic Models & Data Analysis. 1995;11:121–133. [Google Scholar]

32. Zeise ML, Espinoza S, González A, Cerda FS, Nacarate J, Yáñez CG, Morales B. Methylphenidate improves cue navigation in the Morris water maze in rats. Neuroreport. 2007;18:1059–1062. [PubMed] [Google Scholar]

33. Zhu N, Weedon J, Dow-Edwards DL. Oral methylphenidate improves spatial learning and memory in pre- and periadolescent. Behav Neurosci. 2007;121:1272–1279. [PubMed] [Google Scholar]

34. Zito JM, Safer DJ, dosReis S, Gardner JF, Boles Thousand, Lynch F. Trends in the prescribing of psychotropic medications to preschoolers. JAMA. 2000;283:1025–1030. [PubMed] [Google Scholar]

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2572720/

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