Feeding behavior in dopamine-deficient mice

Abstract

Mice that cannot make dopamine (DA), a condition caused by the selective inactivation of tyrosine hydroxylase in dopaminergic neurons, are born normal but gradually become hypoactive and hypophagic, and die at 3 weeks of age. We characterized the feeding and locomotor responses of these DA-deficient (DA-/-) mice to 3, 4-dihyroxy-L-phenylalanine (L-DOPA) to investigate the relationship between brain DA levels and these complex behaviors. Daily administration of L-DOPA to DA-/- mice stimulated locomotor activity that lasted 6 to 9 hr; during that time the mice consumed most of their daily food and water. The minimal dose of L-DOPA that was sufficient to elicit normal feeding behavior in the DA-/- mice also restored their striatal DA to 9.1% of that in the wild-type (WT) mice at 3 hr; then DA content declined to <1% of WT levels by 24 hr. This dose of L-DOPA induced locomotor activity that exceeded that of treated WT mice by 5- to 7-fold, suggesting that DA-/- mice are supersensitive to DA. Unexpectedly, DA-/- mice manifested a second wave of activity 24 to 48 hr after L-DOPA treatment that was equivalent in magnitude to that of WT mice and independent of DA receptor activation. The DA-/- mice approached, sniffed, and chewed food during this second period of activity, but they ate <10% of that required for sustenance. Therefore, DA-/- mice can execute behaviors necessary to seek and ingest food, but they do not eat enough to survive.

Figure 1

DA−/− mice exhibit hyperactivity immediately after l-DOPA treatment, and display a second wave of activity that occurs 30 hr after treatment. Ambulatory activity of DA−/− mice (A; n = 17] and WT mice (B; n = 8). (C and D) Black bars represent the dark cycle. Total distance traveled and amount of food consumed by DA−/− and WT mice in the first 24-hr period (C) and second 24-hr period (D) after l-DOPA treatment.

Figure 2

Low doses of l-DOPA cause hyperactivity in DA−/− mice. Individually housed DA−/− mice during the 9-hr period after administration of 10, 20, 30, 40, or 50 mg/kg or 100 mg/kg l-DOPA methyl ester were used to generate a dose-response curve. Various doses of l-DOPA were administered 24 hr after their last l-DOPA injection. (A) Ambulatory activity of WT (n = 8) and DA−/− mice (n = 8). (B) Food consumed by WT (n = 8) and DA−/− mice (n = 8).

Figure 3

Food deprivation identifies the minimal amount of DA required to sustain food consumption in DA−/− mice. Mice (n = 15) housed in groups of three were treated with 50 mg/kg l-DOPA, returned to their home cages, and food was added after 3, 6, or 9 hr of restriction. Water was available ad libitum during the food restriction studies. Amount of food and water consumed after 0 (A), 3 (B), 6 (C), or 9 (D) hr of food deprivation is shown. Black horizontal lines represent the time when food was present in the cage. (E) Total amount of food consumed when mice were food-deprived after l-DOPA treatment. (F) Water consumed by food-deprived DA−/− mice.

Figure 4

DA receptor antagonists do not block the second wave of locomotion displayed by DA−/− mice. Ambulatory activity of WT and DA−/− mice treated with 0.9% saline (open bars) or a mixture of 0.1 mg/kg SCH 23390 and 2 mg/kg haloperidol (closed bars) shown as percent of saline-elicited activity. Meters traveled ± SEM: WT saline = 24.6 ± 6.2; DA−/− saline (2–6 hr) = 281.1 ± 59.3; and DA−/− saline (26–30 hr) = 17.9 ± 6.7.

Figure 5

Amphetamine induces locomotor behavior in DA−/− mice, but amphetamine treatment does not block the second wave of activity displayed by DA −/− mice. (A) Ambulatory activity of WT and DA−/− mice given two consecutive injections of 5 mg/kg amphetamine. Arrows indicate times of amphetamine administration. (B) Amphetamine (5 mg/kg) was administered 19 hr after the l-DOPA injection and activity was monitored for an additional 36 hr. Arrow indicates time of amphetamine injection.

Figure 6

Simultaneous carbidopa and l-DOPA treatment induces stereotypy in DA−/− mice. (A) Ambulatory activity of DA −/− mice (n = 8) treated with 50 mg/kg l-DOPA (■) or a mixture of 50 mg/kg l-DOPA and 12.5 mg/kg carbidopa (□) parse by 1-hr intervals. (B) Total meters traveled and food consumed by DA−/− mice in the first 3 hr after injection of 50 mg/kg l-DOPA alone (black bars) or 50 mg/kg l-DOPA and 12.5 mg/kg carbidopa (open bars). (C) Total meters traveled and food consumed by DA−/− mice in 24 hr when treated with 50 mg/kg l-DOPA alone (black bars), a mixture of 50 mg/kg l-DOPA and 12.5 mg/kg (open bars), or 50 mg/kg l-DOPA and 25 mg/kg carbidopa (gray bars).