Systemic ghrelin sensitizes cocaine-induced hyperlocomotion in rats

Abstract

The feeding-relevant pathway by which food restriction (FR) augments cocaine action is unknown. Systemic administration of the 28-amino acid acylated peptide ghrelin (1−10 nMol) increases food intake in rats and circulating levels of rat ghrelin are up-regulated by FR. The present experiment examined the impact of repeated administration of ghrelin or vehicle on the subsequent capacity of cocaine to enhance locomotion in rats. Male Sprague-Dawley rats were pretreated daily for seven days with 0, 5 or 10 nMol rat ghrelin (i.p.) in the home cage. On the 8 th day, rats were transported to a testing room, placed in a locomotion chamber for 15 min, and then injected (i.p.) with 0, 7.5, or 15 mg/kg cocaine hydrochloride. Locomotor activity was monitored over a 45 min post-cocaine period. Pretreatment with 5 or 10 nMol ghrelin alone did not significantly increase basal locomotion relative to that of the 0 nMol ghrelin group. Rats pretreated with 5 nMol or 10 nMol ghrelin showed an enhanced locomotor response after treatment with 15 mg/kg cocaine relative to rats treated with 0 nMol ghrelin. These results indicate that acute injection of ghrelin, at a feeding-relevant dose, can augment the acute effects of cocaine on locomotion in rats. KeywordsFood deprivation; Locomotion; Growth Hormone Food restriction (FR) is known to augment the locomotor actions of psychostimulant drugs such as cocaine or amphetamine (Bell et al., 1997;Campbell and Carroll, 2001;Carr, 2002;Carroll and Meisch, 1980, 1981). Additionally, FR acts to facilitate the acquisition of cocaine or amphetamine self-administration (Carroll, 1985) and augments the acquisition of cocaineinduced conditioned place preference (Bell et al., 1997). When animals already trained to selfadminister cocaine are deprived of food, their daily drug intake increases and FR can facilitate the reinstatement of cocaine-seeking behavior (Carroll, 1985). Conversely, food satiation can delay the acquisition of cocaine self-administration (Carroll and Lac, 1998). These findings suggest that feeding and drug addiction may share common pathways (DiLeone et al., 2003).The neural substrate through which the hyperlocomotor and reinforcing actions of drugs such as cocaine or amphetamine are enhanced by FR remains unknown (Carr, 2002). The stomach peptide ghrelin is an endogenous ligand for the growth-hormone secretagogue receptor (Kojima et al., 1999;Tschop et al., 2000) and functions as an orexigen receptor (Ariyasu et al. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Inui et al., 2004;Naleid et al., 2005;Wren et al., 2001a;Wren et al.,...

Central administration of ghrelin alters emotional responses in rats: behavioural, electrophysiological and molecular evidence

“…Ghrelin, a stomach-derived hormone (Kojima et al, 1999), increases food intake and fat mass (Tschöp et al, 2000, Theander-Carrillo et al, 2006. Apart from the reported metabolic effects that involve hypothalamic actions it is becoming increasingly apparent that ghrelin's neurobiological actions extend to systems involved in memory (Diano et al, 2006), reward (Jerlhag et al, 2006, Jerlhag et al, 2007, Wellman et al, 2008, Jerlhag et al, 2009 and even to systems involved in the cognitive processing of visual food cues (Malik, 2008).…”

Effects of Long Acting Methylphenidate on Ghrelin Levels in Male Children with Attention Deficit Hyperactivity Disorder: An Open Label Trial

“…With that association ghrelin can affect other various reward behaviors in addition to food intake. Ghrelin augments hyperactivity and arousal due to cocaine, has antidepressant-like properties and is associated with greater alcohol consumption and craving 32,33,54,59,60 . Cocaine is a stimulant agent like methylphenidate but, unlike methylphenidate, it is illegal and has neurotoxic and addictive properties.…”

“…Cocaine is a stimulant agent like methylphenidate but, unlike methylphenidate, it is illegal and has neurotoxic and addictive properties. Systematic ghrelin sensitizes and ghrelin antagonists attenuate cocaine induced hyperlocomotion and ghrelin lowers the subthreshold of the psychogenic action of cocaine 59,60 Central ghrelin activates arousal and wakefulness like stimulant medications in the treatment of narcolepsy and ADHD. The activation of the hypothalamic neural circuit including ghrelin, orexin and NPY neurons stimulates wakefulness, arousal, motor activity and may stimulate nocturnal and binge eating 61 .…”

“…In the last few years there has been mounting evidence that ghrelin is related to psychostimulant drug addiction [30][31][32][33] . In addition, ghrelin interacts with CART (Cocaine-and Amphetamine Regulated Transcript) peptides, which are known to be important in psychostimulant addiction / rewarding / reinforcing mechanisms [81][82][83] .…”

“…Ghrelin is also involved in more complex cognitive-behavioral processes like learning, memory, reward, addiction and depressive and anxious symptoms 14,29 . In addition, it has been suggested that ghrelin (by a mechanism similar to compensatory increase to food restriction) could be important in drug, stimulant and alcohol abuseaddiction mechanisms [30][31][32][33] . As a result, it is important to design studies to investigate possible interactions between methylphenidate and ghrelin because ADHD increases the risk of drug and alcohol abuse.…”