Impact of food restriction and cocaine on locomotion in ghrelin- and ghrelin-receptor knockout mice

Abstract

Food restriction (FR) augments the behavioral and reinforcing effects of psychomotor stimulants such as cocaine or amphetamine; effects that may be related to the capacity of FR to increase plasma levels of ghrelin (GHR), a 28-amino acid orexigenenic peptide linked to activation of brain dopamine systems. The present study used wild-type (WT) mice or mutant mice sustaining knockout of either GHR [GHR((-/-)) ] or of the growth hormone secretagogue receptor [GHS-R((-/-)) ] and subjected to FR or not to evaluate the role of GHR and GHS-R in cocaine-stimulated locomotion. WT, GHR((-/-)) , and GHS-R((-/-)) mice were either restricted to 60% of baseline caloric intake or allowed to free-feed (FF). Mice were treated with 0, 1.25, 2.5 and 5.0 mg/kg cocaine on separate test days (in random dose order) and forward locomotion was recorded on each drug day for 45 minutes after drug dosing. Food (and water) was available immediately after (but not during) each activity test. For FF mice, there was no interaction between cocaine and GHR status on locomotion. FR-WT mice treated with saline exhibited significant increases in anticipatory locomotion (relative to FF-WT mice), whereas FR-GHS-R((-/-)) mice did not. Cocaine significantly increased locomotion in FR-GHR((-/-)) and FR-GHS-R((-/-)) mice to the levels noted in FR-WT mice. These results suggest that GHS-R activity, but not GHR activity, is required for FR to augment food-associated anticipatory locomotion, but do not support the contention that GHR pathways are required for the capacity of FR to augment the acute effect of cocaine on locomotion.

Figure 1

Mean group (+ SEM) total distance traveled scores (cm) over three successive 15 min periods after vehicle injection in WT, GHR^(-/-) and GHS-R^(-/-) mice subjected to either FF (panel A) or FR (panel B) conditions. The bar above each symbol reflects the standard error of the mean for that value.

Figure 2

Total distance traveled scores (subjected to a square root transformation and covaried for locomotion after vehicle) after cocaine injection (0, 1.25, 2.5 and 5.0 mg/kg, i.p.) in WT, GHR^(-/-) and GHS-R^(-/-) mice subjected to either FF (left panel) or FR (right panel) conditions. The bar above each symbol reflects the standard error of the mean for that value. The triple stars (*-*-*) indicate that each cocaine condition for each GHR status group was significantly different from the respective baseline condition (p < 0.05).

Figure 3

Mean group (+ SEM) stereotypy counts (subjected to a square root transformation) after cocaine injection (0, 1.25, 2.5 and 5.0 mg/kg, i.p.) in WT, GHR^(-/-) and GHS-R^(-/-) mice subjected to either FF (left panel) or FR (right panel) conditions. The bar above each symbol reflects the standard error of the mean for that value.