The Stomach-Derived Hormone Ghrelin Increases Impulsive Behavior

Abstract

Impulsivity, defined as impaired decision making, is associated with many psychiatric and behavioral disorders, such as attention-deficit/hyperactivity disorder as well as eating disorders. Recent data indicate that there is a strong positive correlation between food reward behavior and impulsivity, but the mechanisms behind this relationship remain unknown. Here we hypothesize that ghrelin, an orexigenic hormone produced by the stomach and known to increase food reward behavior, also increases impulsivity. In order to assess the impact of ghrelin on impulsivity, rats were trained in three complementary tests of impulsive behavior and choice: differential reinforcement of low rate (DRL), go/no-go, and delay discounting. Ghrelin injection into the lateral ventricle increased impulsive behavior, as indicated by reduced efficiency of performance in the DRL test, and increased lever pressing during the no-go periods of the go/no-go test. Central ghrelin stimulation also increased impulsive choice, as evidenced by the reduced choice for large rewards when delivered with a delay in the delay discounting test. In order to determine whether signaling at the central ghrelin receptors is necessary for maintenance of normal levels of impulsive behavior, DRL performance was assessed following ghrelin receptor blockade with central infusion of a ghrelin receptor antagonist. Central ghrelin receptor blockade reduced impulsive behavior, as reflected by increased efficiency of performance in the DRL task. To further investigate the neurobiological substrate underlying the impulsivity effect of ghrelin, we microinjected ghrelin into the ventral tegmental area, an area harboring dopaminergic cell bodies. Ghrelin receptor stimulation within the VTA was sufficient to increase impulsive behavior. We further evaluated the impact of ghrelin on dopamine-related gene expression and dopamine turnover in brain areas key in impulsive behavior control. This study provides the first demonstration that the stomach-produced hormone ghrelin increases impulsivity and also indicates that ghrelin can change two major components of impulsivity-motor and choice impulsivity.

Figure 1

Ghrelin is necessary and sufficient to increase impulsive action measured in the DRL task. Impulsive action, defined as the inability to withhold a response, was assessed on the DRL 20-s schedule. Centrally injected ghrelin did not significantly alter the rewards earned in the DRL task (a) or the number of responses on the active lever (b); however, it significantly reduced the efficiency of the performance (c). Centrally injected GHSR antagonist, JMV2959, did not significantly alter the rewards earned in the DRL task (d); however, it significantly reduced the amount of active lever presses emitted to obtain the rewards (e), and it significantly increased the efficiency of the performance in the task (f). Efficiency was defined as the ratio between the rewarded responses and the total (rewarded+incorrect) responses. Data are expressed as mean±SEM. n=9–10 per each treatment group. *p<0.05, **p<0.005.

Figure 2

VTA-injected ghrelin increases impulsive action measured in the DRL task. Ghrelin microinjected into the VTA did not significantly alter the rewards earned in the DRL task (a), but it significantly increased the number of responses emitted on the active lever (b) and significantly reduced the efficiency of the performance (c). Photomicrograph of a 40-μm coronal section of rat brain illustrating the injection site and schematic representation of the VTA according to the rat brain atlas (d). Data are expressed as mean±SEM. n=7 per each treatment group. *p<0.05, **p<0.005.

Figure 3

Ghrelin increases impulsive action measured in the go/no-go task. Centrally injected ghrelin increased the number of rewards earned (a) and the number of active lever presses (b) during the go periods of the go/no-go task, indicating that ghrelin increases the motivation to obtain food rewards. However, ghrelin also increased the number of active lever presses during the no-go period (c), potentially indicating an inability to withhold a response despite the no-go cue. Ghrelin had no effect on the number of responses emitted on the inactive lever (d), which supports lack of changes in general motor activity. Number of sucrose pellets earned during the no-go trials (e). Data are expressed as mean±SEM. n=9 per each treatment group. *p<0.05.

Figure 4

Ghrelin increases impulsive choice measured in the delay discounting task. Ghrelin treatment increased the amount of large rewards obtained when offered with no delay but reduced the amount of large food rewards earned when offered under 10- or 20-s delay (a). The impulsive behavior resulted in a loss of rewards earned during the 10- and 20-s delays but not when there was no delay imposed on the large rewards (b). No significant changes in locomotor activity were detected after ghrelin treatment during the delay discounting task (c). Data are expressed as mean±SEM. n=25–26 per each treatment group. *p<0.05, **p<0.005, ***p<0.0005.

Figure 5

Ghrelin-induced changes in dopamine turnover or dopamine-related genes in the striatum, OFC, and mPFC. Ghrelin increases dopamine turnover in the nucleus accumbens (a, b) and dorsal striatum (c, d). Dopamine turnover was determined after lateral ventricle ghrelin or vehicle (aCSF) infusion. Values are expressed as mean±SEM. DOPAC, 3,4-dihydroxyphenylacetic acid; HVA, homovanilic acid. n=9–10 per group. *p<0.05, **p<0.005, ****p<0.00005. Ghrelin-induced changes in nucleus accumbens (e), dorsal striatum (f), OFC (g), and mPFC (h) gene expression. COMT, catechol-O-methyltransferase; DAT, (Slc6a3) solute carrier family 6 (neurotransmitter transporter, dopamine), member 3; Ddc, dopa decarboxylase (aromatic L-amino acid decarboxylase); Drd1, dopamine receptor D1; Drd2, dopamine receptor D2; Drd3, dopamine receptor D3; Drd5, dopamine receptor D5; and Nrg3, neuregulin-3. Data are expressed as mean±SEM. n=20–24 per each treatment group. *p<0.05.