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 min 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.

Ghrelin and ghrelin receptor modulation of psychostimulant action

“…To further examine the interaction of FR, ghrelin and psychostimulant function, we examined the capacity of FR to enhance cocaine-induced hyper-locomotion in wild-type (WT) mice vs. GHR-null or GHR-R null mice (Clifford et al, 2011). WT, GHR null, and GHR-R null mice were either restricted to 60% of baseline caloric intake (FR) or allowed to free-feed (FF).…”

“…GHR-R null rats do not overeat in response to systemic injection (i.p. : 15 nmol) of GHR and importantly, these rats exhibit diminished induction of locomotor sensitization (relative to WT rats) when injected daily with 10 mg/kg cocaine (Clifford et al, 2011). A similar attenuation has been noted in ghrelin null mice (Abizaid et al, 2011).…”

Physiological roles revealed by ghrelin and ghrelin receptor deficient mice

“…However, cocaine-induced locomotor activity increases similarly in WT, ghrelin -/- and ghsr -/- mice during food restriction (i.e. when endogenous ghrelin levels are elevated) [9], suggesting that augmented locomotor activity associated with food restriction is not explained by increases in endogenous ghrelin.…”

GHS-R1a signaling in the DMH and VMH contributes to food anticipatory activity

“…47 GHS-R1a À / À mice did not exhibit increase in food intake or body weight gain, they rather showed reduced body weight gain. 15,16,44,48,49 Therefore, the appetite-stimulating effect of GHS-R1a knockdown in VMH is remarkable.…”