BEHAVIORAL AND NEUROLOGICAL DOSE EFFECTS OF METHYLPHENIDATE (MPH) IN THE MALE LONG-EVANS HOODED RAT - PowerPoint PPT Presentation

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BEHAVIORAL AND NEUROLOGICAL DOSE EFFECTS OF METHYLPHENIDATE (MPH) IN THE MALE LONG-EVANS HOODED RAT

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Title: BEHAVIORAL AND NEUROLOGICAL DOSE EFFECTS OF METHYLPHENIDATE (MPH) IN THE MALE LONG-EVANS HOODED RAT


1
BEHAVIORAL AND NEUROLOGICAL DOSE EFFECTS OF
METHYLPHENIDATE (MPH) IN THE MALE LONG-EVANS
HOODED RAT Tracey L. Wheeler, M.A., Adam
Winsler, PhD., Linda Chrosniak, PhD., Robert
Smith, PhD.
  • Abstract
  • The stimulant methylphenidate (MPH) is prescribed
    to children as young as two years of age, even
    though there is little research on the
    pharmacological consequences of such treatment on
    these very young children. Animal studies
    provide the opportunity to evaluate direct
    effects of MPH during development. Male
    Long-Evans hooded rats received commonly
    prescribed oral doses of MPH, administered in
    apple juice. In order to uncover potential
    differences between animals dosed with MPH
    solution and those dosed with solution alone,
    working memory was examined using the Morris
    Water Maze (MWM). It was hypothesized that MPH
    administration would alter the growth and
    neurodevelopment of these very young animals and
    that this disruption would be observed through
    weight and MWM behavioral performance. As
    hypothesized, we found that animals dosed with
    MPH gained weight slower than the control
    animals. MPH did not enhance working memory
    ability in the rat, but it did increase
    consistency in improvement. The drug group
    demonstrated potential detrimental effects during
    the early stage of testing. We propose that MPH
    may alter working memory ability in the rat under
    stressful conditions as demonstrated in early
    testing of the MWM.
  • Introduction
  • The present study was designed to uncover
    differences between animals dosed with MPH and
    genetically identical animals dosed with no drug.
    This study remains unique as dose levels were
    adjusted for weight and did not exceed commonly
    prescribed human doses. In addition, when
    possible, all experimental controls were
    manipulated in order to increase applicability to
    a human childs environment. Some examples
    include enriched environments, oral dosing,
    group housing, and drug dilution in apple juice.
    We believe that these controls contribute to more
    subtle results than seen in similar studies.
    However, these subtle differences contain greatly
    increased applicability to human children.
  • Methods
  • Twice daily dosing from postnatal day 10 through
    50.
  • Oral administration 1mg/kg dissolved in apple
    juice. Undosed animals received apple juice
    alone. Hence, animal weight was recorded 2Xs
    per day.
  • Upon weaning, both dose groups were reared in
    enriched housing environments
  • Ad libitum food and water were provided to both
    dose groups.
  • All animals were introduced to the MWM before
    testing began by placement on the hidden platform
    for 30 seconds.
  • Each day animals were tested on three trials, 90
    seconds maximum, with 30 seconds between trials
    in the home cage.
  • Results
  • MPH animals gained weight slower than control
    animals F(24, 12) 7.14, p lt .01 (Figures 12).
  • Control animals found the platform faster (M
    56.96, SD 29.55) than MPH animals (M 76.37,
    SD 23.12), on trial 1A t(42) 2.33, p .03
    (Figure 3).
  • There was no significant difference between MPH
    and control animals, regarding working memory
    ability (latency to platform), over time.
  • There was a significant interaction regarding
    latency between day, trial, and dose condition
    F(18, 23) 2.18, p lt.05.
  • MPH animals were more consistent in performance
    improvement from trial b to c F(1, 40) 4.26, p
    lt .05 (Figure 4).

Discussion / Conclusion We suggest that a
commonly prescribed oral dose of MPH (1.0 mg/kg)
retards growth and that the growth impairment is
in fact a product of MPH and not an artifact of
ADHD as all animals were genetically similar and
randomly assigned a dose condition, they were not
bred to display symptoms of ADHD (Figures 12).
This is in contrast to the suggestion of some
workers that the growth reduction observed in
human children on MPH might be a developmental
artifact associated with ADHD (Greenhill et al.,
2002). We uncovered a significant difference
between groups on trial 1A (Figure 3). Control
animals found the platform over 19 seconds faster
than MPH animals. However,it has been shown that
the MWM can induce stress in the rodent
(McLaughlin, Blustein, Hoffman, 2002). If the
initial introduction to the MWM is indeed a
stressful experience, differences between groups
may be more apparent. High levels of stress could
play a negative role in MPH animals working
memory ability. Another possibility for the
difference observed in latency is that trial time
was limited to 90 seconds. It is common that
most animals will not find the platform within 90
seconds on the first few days of testing.
Therefore, this artificial ceiling may have
contributed to the observed significance. We
found no overall increase in working memory
ability in rats dosed with MPH compared to
control rats. However, we did find a significant
day x dose x trial interaction. In order to
further understand this interaction we examined
latency as a proportion for performance
improvement (trial b over trial a and trial c
over trial b). Interestingly, we found a
significant difference between dose groups when
observing latency performance improvement from
trial b to c averaged from all ten days of
testing. On average, from trial b to c, MPH
animals were more consistent in performance
relative to control animals (Figure 4). These
results suggest that commonly prescribed doses of
MPH do not increase overall working memory
ability in non-ADHD animals. This conflicts with
the suggestion that one benefit of MPH
administration is a profound increase in working
memory ability (Greenhill et al., 1999, Greenhill
et al., 2002).  It has been suggested that
classroom teachers believe decreases in
interruptive outbursts, increases in focused
attention, and higher grades memory ability go
hand in hand (Elia et al., 1999). We suggest that
improved classroom performance might be
reinforced by a heightened linear progression in
performance improvement observed in the MPH dose
group and is not related to increased working
memory ability.
Figure 1
Figure 2
References Elia, J., Ambrosini, P. J.,
Rapoport, J. L. (1999). Drug therapy Treatment
of attention deficit-hyperactivity disorder. The
New England Journal of Medicine, 340(10),
780-788. Greenhill, L. L., Halperin, J. M.,
Abikoff, H. (1999). Stimulant medications.
Journal of the American Academy of Child
Adolescent Psychiatry, 38(5), 503-512. Greenhill,
L. L., Pliszka, S., Dulcan, M. K., Bernet, W.,
Arnold, V., Beitchman, J., et al. (2002).
Practice parameter for the use of stimulant
medications in the treatment of children,
adolescents, and adults. Journal of the American
Academy of Child Adolescent Psychiartry, 41(2),
26-49. McLaughlin, M., Blustein, J. E.,
Hoffman, J. R. (2002). The effect of treadmill
running on stress induced analgesia and spatial
learning of rats. Poster session presented at
the annual meeting of the Eastern Psychological
Association, Baltimore, MD.
Figure 3
Acknowledgements Without the support of the
following individuals this project could not have
been accomplished Anthony Cassiano, Amy
Eppolito, Jane Flinn, PhD., Craig McDonald, PhD
and Laura Smith.
Figure 4
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