Methylphenidate attenuates rats' preference for a novel spatial stimulus introduced into a familiar environment: assessment using a force-plate actometer

Abstract

Methylphenidate is a psychostimulant widely used in the treatment of attention deficit hyperactivity disorder (ADHD). Here we report a novel paradigm that affords inferences about habituation and attention to a novel stimulus in a familiar environment in a single test session without prior training of the animals. The paradigm was used to assess the effects of methylphenidate (2.5 and 5.0mg/kg, sc) in young adult, male, Long-Evans rats. Methylphenidate increased locomotor activity during the initial exposure to the test apparatus in a non-dose-related manner. However, upon introduction of a novel spatial stimulus (an alcove) in the familiar environment, methylphenidate-treatment resulted in dose-related increases in distance traveled and inhibition of long dwell times in the alcove, the latter behavior being characteristic of vehicle-treated rats' response to the alcove condition. These results demonstrate the utility of this paradigm in the elucidation of the behavioral effects of a drug commonly used in the treatment of ADHD. Findings also suggest that species-typical response preferences in rats (e.g., refuge-seeking) may emerge in experimental settings that add spatial novelty to otherwise featureless test enclosures commonly used to assess locomotor activity.

Fig 1. Schematics of the experimental apparatus (top) and test protocol (bottom)

Fig. 2. Dose-response effects of methylphenidate on distance traveled outside the alcove as a function of 5-min time blocks within Periods 1, 2, and 3

In Periods 1 and 2 only space outside the alcove was available for occupancy by the rats. Data are presented as the group means ± SEM (n =13 per group). When error bars are not visible, the size of the plot symbol was greater than 2 SEM. Lower case alphabetic characters (a, b, c, d) represent specific means for 5-min blocks that were compared for the control group (0.0 mg/kg).

Fig. 3. Movement trajectories of individual rats shown in 5-min blocks within each of three successive periods

Representative movement trajectories are presented for three different rats from each of the treatment groups. Numbers 1 through 6 along the left side of the figure represent successive 5-min time blocks. Note that the back 1/3 of the chamber was inaccessible in Periods 1 and 2 (see Fig. 1). Inaccessible regions can be discerned by noting that no tracings are present in those regions (back third of the chamber in Periods 1 and 2, and left and right back corners in Period 3).

Fig. 4. Number of alcove visits (Panel A) and mean alcove visit duration (Panel B) for Period 3 as a function of methylphenidate dose

Data are presented as the group means ± SEM (n = 13 per group). ** P<.01 vs. vehicle control by Tukey’s post hoc test.

Fig. 5. Cumulative alcove occupancy duration as a function of elapsed time in Period 3 for vehicle control and methylphenidate dose groups

Gray symbols and gray connecting lines show individual rat data. Each individual data point marks the end of a visit or the presence of the rat in the alcove when Period 3 ended. The thick black lines indicate mean lines of best fit reflecting the rate of accumulation of alcove occupancy time during Period 3. The slope for the vehicle group was significantly (P<.01) steeper than the slopes for the two methylphenidate groups. In the plot for vehicle rats, the arrow indicates a rat that was not in the alcove when Period 3 ended, but instead was continuously located a few mm outside the alcove (as determined by inspection of its movement trajectory plot). On the x-axis, the scale markers 300, 600, 900, and 1200 s correspond to the successive 5-min blocks 15, 16, 17, and 18, respectively, of Period 3 in Fig. 2.

Fig. 6. Group average alcove visit duration as a function of ordinal position of visits in Period 3

Note that the log₁₀ scale value of 1.0 on the ordinate indicates 10 s and 2.0 represents 100 s. Data are presented as group means ± SEM. ** P<.01 vs. vehicle control by Tukey’s post hoc test.

Fig. 7. Variation in vertical force as a function of 5-min block and location within the force plate actometer during Period 3

Data are presented as group means ± SEM (n = 13 per group). “SD” in the ordinate label is an abbreviation for “standard deviation.” Sample raw data for Fz time series are shown in Fig. 8.

Fig. 8. Representative time series of vertical force variation of Fz over the first 15 s of the 4^th time block of Period 3

Data are from the same three rats whose data are shown in Fig. 3. Force data from the load plate were collected at 50 samples/sec. Inside (event line “up”) and outside (event line “down”) refer to spatial categories in the actometer (inside or outside of the alcove) where the rat was located when these data were gathered. Raw data such as these served as the basis for the quantitative assessment of force output depicted in Fig. 7