Attenuation of cocaine‐induced locomotor sensitization in rats sustaining genetic or pharmacologic antagonism of ghrelin receptors

Abstract

Systemic infusions of the orexigenic peptide ghrelin (GHR) increase dopamine levels within the nucleus accumbens and augment cocaine stimulated locomotion and conditioned place preference in rats; observations that suggest an important role for ghrelin and GHR receptors (GHR-Rs) in drug reinforcement. In the present studies, we examined the development of cocaine locomotor sensitization in rats sustaining either pharmacologic antagonism or genetic ablation of GHR-Rs. In a pharmacologic study, adult male rats were injected (i.p.) with either 0, 3 or 6 mg/kg JMV 2959 (a GHR-R1 receptor antagonist) and 20 minutes later with either vehicle or 10 mg/kg cocaine HCl on each of 7 consecutive days. Rats pretreated with JMV 2959 showed significantly attenuated cocaine-induced hyperlocomotion. In a second study, adult wild type (WT) or mutant rats sustaining ENU-induced knockout of GHR-R (GHR-R (−/−)) received daily injections (i.p) of vehicle (0.9% saline) or 10.0 mg/kg cocaine HCl for 14 successive days. GHR-R null rats treated repeatedly with cocaine showed diminished development of cocaine locomotor sensitization relative to WT rats treated with cocaine. To verify the lack of GHR-R function in the GHR-R (−/−) rats, a separate feeding experiment was conducted in which WT rats, but not GHR-R (−/−) rats, were noted to eat more after a systemic injection of 15 nmol ghrelin than after vehicle. These results suggest that GHR-R activity is required for the induction of locomotor sensitization to cocaine and complement an emerging literature implicating central GHR systems in drug reward. Ghrelin (GHR) is an orexigenic gut peptide that is transported across the blood brain barrier and interacts with GHR receptors (GHR-R) located on ventral tegmental dopamine neurons.

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

“…This is in line with the finding that GHS-R1a antagonism reduced drug-induced locomotor activity, 40,41 although central administration of ghrelin has been reported both to decrease 42 as well as increase 43 locomotor activity. In addition to the reduction in total RWA, rats with knockdown of GHS-R1a in DMH also exhibited a decrease in normalized FAA.…”

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.…”

The Effects of Ghrelin Antagonists [D‐Lys3]‐GHRP‐6 or JMV2959 on Ethanol, Water, and Food Intake in C57BL/6J Mice

“…Using animal models, studies have shown that administration of ghrelin can increase ethanol intake, while ghrelin antagonism reduces ethanol intake (Jerlhag et al, 2009). In addition, ghrelin antagonists have been shown to significantly reduce the behavioral and physiological effects of cocaine (Clifford et al, 2012), amphetamine (Jerlhag et al, 2010), and nicotine (Wellman et al, 2011; Jerlhag and Engel, 2011). In agreement with pharmacological studies, GHSR knockout mice show reduced voluntary ethanol intake and diminished ethanol-induced conditioned place preference (Jerlhag et al, 2009).…”