Augmented cocaine conditioned place preference in rats pretreated with systemic ghrelin

Abstract

The physiological mechanism through which food restriction (FR) enhances the biobehavioral actions of psychostimulants is unknown but may involve the gut peptide ghrelin. Plasma levels of ghrelin are increased by FR and reduced by eating. Moreover, systemically administered ghrelin crosses into the brain and is known to augment the locomotor-stimulating effects of cocaine [COC: Wellman et al, 2004]. This study sought to determine whether pretreatment with ghrelin (5 nmol) would enhance the rewarding properties of COC (0.0, 0.312, 0.625, or 1.25 mg/kg i.p.) as measured by conditioned place preference (CPP). Adult male Sprague-Dawley rats were given free access to both sides of a CPP chamber to determine initial side preference. The rats were then confined for 30 min to either their preferred side or non-preferred side on 8 consecutive days. When rats were confined to the least preferred side, each was injected with 0.5 ml (i.p.) of either ghrelin (5 nmol) or saline 1 h before the conditioning trial and then injected (i.p.) with one of the COC doses immediately prior to the conditioning trial. On alternate days, rats were injected with vehicle one hour before and again immediately before the conditioning trial. Place preference scores were computed as the differences in time (min) spent on the least preferred side of the chamber for the pre-test and the post conditioning test, covaried by the initial degree of preference (% time spent on the black side during the pre-test). These analyses indicated a significant interaction between ghrelin pretreatment and COC dose on changes in preference scores. Significantly higher place preference scores were noted for rats treated with either 0.312 or 0.625 mg/kg COC doses, but only when these COC doses were preceded by administration of 5 nmol ghrelin. In contrast, saline pretreated rats exhibited significant CPP at the 1.25 mg/kg COC dose, but the ghrelin pretreated group did not. These results provide partial support for the contention that ghrelin pretreatment can augment the rewarding effects of subthreshold doses of COC in a CPP procedure. Moreover, these findings are consistent with the view that ghrelin may play a role in the capacity of FR to augment psychostimulant action.

Requirement of central ghrelin signaling for alcohol reward

“…This suggests that dopamine neurons themselves express GHS-R1A and that their activity might be directly modulated by ghrelin. Consistent with this model, ghrelin has also been shown to increase the incentive value of cocaine (36,37). Direct ghrelin actions on VTA neurons would require that peripheral ghrelin signals reach the CNS, because it is not yet clear that ghrelin is expressed centrally.…”

The alcohol-induced locomotor stimulation and accumbal dopamine release is suppressed in ghrelin knockout mice

“…A role of ghrelin in reward induced by other addictive drugs has also been shown. Thus, systemic ghrelin enhances cocaine-induced locomotor stimulation as well as condition place preference in rats and high serum levels of ghrelin is associated with cocaine-seeking behaviour in rats (Wellman et al, 2005;Davis et al, 2007;Tessari et al, 2007). Moreover, GHS-1A antagonism attenuates the amphetamine-and cocaine-induced locomotor simulation, accumbal dopamine release and condition place preference in mice (Jerlhag et al, 2010b).…”

Peripherally Circulating Ghrelin Does Not Mediate Alcohol‐Induced Reward and Alcohol Intake in Rodents

“…The findings that the cholinergic–dopaminergic reward link is activated by pharmacological‐induced hyperghrelinemia (Jerlhag, 2008; Jerlhag et al., 2012) and that elevated ghrelin levels associated with craving (Addolorato et al., 2006; Koopmann et al., 2012; Leggio et al., 2012), may imply that high plasma levels of ghrelin may be needed for reward interactions. Supportively, animal studies show that hyperghrelinemia is associated with cocaine seeking and that peripheral ghrelin administration augments the cocaine‐induced conditioned place preference and locomotor stimulation (Clifford et al., 2012; Davis et al., 2007; Tessari et al., 2007; Wellman et al., 2005, 2012). Conclusively, future studies on the role of peripheral versus central ghrelin in relation to alcohol reward, intake, and craving are warranted.…”