Brain reinforcement system function is ghrelin dependent: studies in the rat using pharmacological fMRI and intracranial self‐stimulation

Abstract

Ghrelin (GHR) is an orexigenic gut peptide that interacts with brain ghrelin receptors (GHR-Rs) to promote food intake. Recent research suggests that GHR acts as a modulator of motivated behavior, suggesting a direct influence of GHR on brain reinforcement circuits. In the present studies, we investigated the role of GHR and GHR-Rs in brain reinforcement function. Pharmacological Magnetic Resonance Imaging was used to spatially-resolve the functional activation produced by systemic administration of an orexigenic GHR dose. The imaging data revealed a focal activation of a network of subcortical structures that comprise brain reinforcement circuits – ventral tegmental area, lateral hypothalamus and nucleus accumbens. We next analyzed whether brain reinforcement circuits require functional GHR-Rs. To this purpose, wild type (WT) or mutant rats sustaining ENU-induced knockout of GHR-Rs (GHR-R null rats) were implanted with stimulating electrodes aimed at the lateral hypothalamus, shaped to respond for intracranial self-stimulation (ICSS) and then tested using a rate-frequency procedure to examine ICSS response patterns. WT rats were readily shaped using stimulation intensities of 75 uA, whereas GHR-R null rats required 300 uA for ICSS shaping. No differences in rate-frequency curves were noted for WT rats at 75 uA and GHR-R null rats at 300 uA. When current intensity was lowered to 100 uA, GHR-R null rats did not respond for ICSS. Taken collectively, these data suggest that systemic GHR can activate mesolimbic dopaminergic areas, and highlight a facilitative role of GHR-Rs on the activity of brain reinforcement systems.

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.…”

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.…”

“…: 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 HCl (Clifford et al, 2012). As discussed below, such rats exhibit diminished reinforcement to low-level electrical stimulation of the brain (Wellman et al, 2012). …”

Intracranial Self-Stimulation to Evaluate Abuse Potential of Drugs

“…SERT 2/2 rats were also less susceptible to LPS-induced depression of ICSS, suggesting a role for SERT in LPS-induced ICSS depression. In another study, the role of the orexigenic peptide ghrelin on motivated behavior was examined using wild-type and ghrelin receptor knockout rats responding under a hybrid frequency-rate procedure (Wellman et al, 2012). Significantly higher current intensities were required to maintain similar frequencyrate curves in the knockout rats, and these results were interpreted to suggest a role for ghrelin in basal ICSS.…”