Influence of body weight and type of chow on the sensitivity of rats to the behavioral effects of the direct-acting dopamine-receptor agonist quinpirole

Abstract

Rationale: Amount and type of food can alter dopamine systems and sensitivity to drugs acting on those systems.

Objectives: This study examined whether changes in body weight, food type, or both body weight and food type contribute to these effects.

Methods: Rats had free or restricted access (increasing, decreasing, or maintaining body weight) to standard (5.7% fat) or high-fat (34.3%) chow.

Results: In rats gaining weight with restricted or free access to high-fat chow, both limbs of the quinpirole yawning dose-response curve (0.0032-0.32 mg/kg) shifted leftward compared with rats eating standard chow. Restricting access to standard or high-fat chow (maintaining or decreasing body weight) decreased or eliminated quinpirole-induced yawning; within 1 week of resuming free feeding, sensitivity to quinpirole was restored, although the descending limb of the dose-response curve was shifted leftward in rats eating high-fat chow. These are not likely pharmacokinetic differences because quinpirole-induced hypothermia was not different among groups. PG01037 and L-741,626 antagonized the ascending and descending limbs of the quinpirole dose-response curve in rats eating high-fat chow, indicating D3 and D2 receptor mediation, respectively. Rats eating high-fat chow also developed insulin resistance.

Conclusions: These results show that amount and type of chow alter sensitivity to a direct-acting dopamine-receptor agonist with the impact of each factor depending on whether body weight increases, decreases, or is maintained. These data demonstrate that feeding conditions, perhaps related to insulin and insulin sensitivity, profoundly impact the actions of drugs acting on dopamine systems.

Fig. 1

Body weight (panel A) and quinpirole-induced yawning (panels B–E) in three groups of rats over the 56-day (8-week) study: Group 1, free-feeding standard chow throughout the study; Group 2, free-feeding high fat chow throughout the study; and Group 3, restricted high fat chow (body weight matched to group 1) followed by free-feeding high fat chow (the vertical dashed line separates the two phases [feed conditions] of the study). Each symbol represents the mean (± SEM) of 8 rats. Abscissa: day of study (panel A) or dose in milligrams per kilogram of body weight; “V” = vehicle (panels B–E). Ordinates: mean (± SEM) body weight in grams (panel A) and mean (± SEM) number of yawns in 10 minutes (panels B–E).

Fig. 2

Body weight (panel A) and quinpirole-induced yawning (panels B–E) in two groups of rats over the 56-day (8-week) study: Group 4, restricted access to standard chow (10 g/day) followed by free-feeding standard chow; and Group 5, restricted access to high fat chow (weight matched to group 4) followed by free-feeding high fat chow. Data shown by shaded circles and dashed lines in panels B–E are the effects of quinpirole in rats with free access to standard chow throughout the study (Group 1, Fig 1). See Fig 1 for other details.

Fig. 3

Body weight (panel A) and quinpirole-induced yawning (panels B–E) in two groups of rats over the 56-day (8-week) study: Group 6, restricted access to standard chow (weight maintained) followed by free-feeding standard chow; and Group 7, restricted access to high fat chow (weight maintained) followed by free-feeding high fat chow. Data shown by shaded circles and dashed lines in panels B–E are the effects of quinpirole in rats with free access to standard chow throughout the study (Group 1, Fig 1). See Fig 1 for other details.

Fig. 4

Quinpirole-induced hypothermia in seven groups (1–7) of rats at day 35 of the study. Data shown by closed circles in the upper panel are the same data shown by the gray circles in the middle and lower panels and show the effects of quinpirole in rats with free access to standard chow throughout the study (Group 1, Fig 1). Ordinate: mean (± SEM) change in body temperature in °C. See Fig 1 for other details

Fig. 5

Quinpirole-induced yawning when quinpirole was administered alone (Group 8, open circles) and in combination with 1.0 mg/kg L-741,626 (Group 9, closed squares) or 56 mg/kg PG01037 (Group 10, closed triangles) in rats with free access to high fat chow. Each symbol represents the mean (± SEM) of 6 rats. See Fig 1 for other details.

Fig. 6

Change in blood glucose (mean ± SEM, mg/dL; ordinate) determined once per week for 4 weeks (abscissa) in rats with free access to standard (Group 11, open bars; n = 4) or high fat (Group 12, closed bars; n = 4) chow. * = significant difference (P<0.05) pre- versus post-insulin.