Pharmacologic antagonism of ghrelin receptors attenuates development of nicotine induced locomotor sensitization in rats

Abstract

Aims Ghrelin (GHR) is an orexigenic gut peptide that interacts with ghrelin receptors (GHR-Rs) to modulate brain reinforcement circuits. Systemic GHR infusions augment cocaine stimulated locomotion and conditioned place preference (CPP) in rats, whereas genetic or pharmacological ablation of GHR-Rs has been shown to attenuate the acute locomotor-enhancing effects of nicotine, cocaine, amphetamine and alcohol and to blunt the CPP induced by food, alcohol, amphetamine and cocaine in mice. The stimulant nicotine can induce CPP and like amphetamine and cocaine, repeated administration of nicotine induces locomotor sensitization in rats. A key issue is whether pharmacological antagonism of GHR-Rs would similarly attenuate nicotine-induced locomotor sensitization. Method To examine the role of GHR-Rs in the behavioral sensitizing effects of nicotine, adult male rats were injected with either 0, 3 or 6 mg/kg of the GHR-R receptor antagonist JMV 2959 (i.p.) and 20 minutes later with either vehicle or 0.4 mg/kg nicotine hydrogen tartrate (s.c.) on each of 7 consecutive days. Results Rats treated with nicotine alone showed robust locomotor sensitization, whereas rats pretreated with JMV 2959 showed significantly attenuated nicotine-induced hyperlocomotion. Conclusions These results suggest that GHR-R activity is required for the induction of locomotor sensitization to nicotine and complement an emerging literature implicating central GHR systems in drug reward/reinforcement.

Ghrelin and ghrelin receptor modulation of psychostimulant action

“…Ghrelin receptors have been localized on neurons within the ventral tegmental area (Guan et al, 1997; Abizaid, 2009), which in turn project via the mesolimbic dopamine (DA) pathway to multiple brain regions including the nucleus accumbens (NACc), the amygdala, prefrontal cortex and hippocampus (Fields et al, 2007). Modulation of the mesolimbic dopamine system by ghrelin is likely involved in the capacity of ghrelin to elicit eating and food-related reinforcement (Dickson et al, 2011; Egecioglu et al, 2011; Skibicka and Dickson, 2011) and also plays a key role in the behavioral activating and reward/reinforcement properties of drugs of abuse such as cocaine and nicotine (Jerlhag et al, 2010; Dickson et al, 2011; Wellman et al, 2011, 2012). Finally, ghrelin receptors located on cells of the PVN may play a key role in activation of the hypothalamic-pituitary-adrenal (HPA) axis (Asakawa et al, 2001; Patterson et al, 2010; Cabral et al, 2012), which suggests a role for ghrelin in stress.…”

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).…”

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

“…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.…”