Ghrelin influences novelty seeking behavior in rodents and men

Abstract

Recent discoveries indicate an important role for ghrelin in drug and alcohol reward and an ability of ghrelin to regulate mesolimbic dopamine activity. The role of dopamine in novelty seeking, and the association between this trait and drug and alcohol abuse, led us to hypothesize that ghrelin may influence novelty seeking behavior. To test this possibility we applied several complementary rodent models of novelty seeking behavior, i.e. inescapable novelty-induced locomotor activity (NILA), novelty-induced place preference and novel object exploration, in rats subjected to acute ghrelin receptor (growth hormone secretagogue receptor; GHSR) stimulation or blockade. Furthermore we assessed the possible association between polymorphisms in the genes encoding ghrelin and GHSR and novelty seeking behavior in humans. The rodent studies indicate an important role for ghrelin in a wide range of novelty seeking behaviors. Ghrelin-injected rats exhibited a higher preference for a novel environment and increased novel object exploration. Conversely, those with GHSR blockade drastically reduced their preference for a novel environment and displayed decreased NILA. Importantly, the mesolimbic ventral tegmental area selective GHSR blockade was sufficient to reduce the NILA response indicating that the mesolimbic GHSRs might play an important role in the observed novelty responses. Moreover, in untreated animals, a striking positive correlation between NILA and sucrose reward behavior was detected. Two GHSR single nucleotide polymorphisms (SNPs), rs2948694 and rs495225, were significantly associated with the personality trait novelty seeking, as assessed using the Temperament and Character Inventory (TCI), in human subjects. This study provides the first evidence for a role of ghrelin in novelty seeking behavior in animals and humans, and also points to an association between food reward and novelty seeking in rodents.

Figure 1. Food reward seeking and NILA are behaviorally related traits.

A. Outbred Sprague-Dawley rats were divided into high NILA (HLA, n = 8) and low NILA rats (LLA, n = 8); the NILA response of LLA rats was significantly lower compared to that of HLA rats during the 30 minute period of testing. B. Number of sugar rewards earned on a progressive ratio schedule was significantly correlated with the NILA response (n = 31). C. High NILA rats earned more sugar rewards than low NILA rats. D. NILA response was significantly correlated with the amount of work rats were willing to expand for sugar rewards. E. High NILA rats display greater lever pressing rates for sugar rewards. **P<0.005.

Figure 2. Plasma ghrelin levels in high and low NILA rats.

A. Total ghrelin levels and B. active ghrelin levels are not different in animals with low (n = 12) vs. high (n = 12) NILA. C. The same rats display a markedly different activity level in the novel environment. Data on the bar graphs represent mean ± SEM. ***P<0.0005.

Figure 3. Role of ghrelin in novelty place preference.

A. Ghrelin-treated rats tend to have slightly higher preference for exploring a novel environment. In contrast those that received GHSR antagonist display much lower preference for a novel environment as compared to the more familiar one. B. Ghrelin markedly increases and the GHSR antagonist strikingly decreases exploration of a novel environment in high NILA rats (HLA). C. When only the low NILA (LLA) rats are considered ghrelin does not significantly alter the place preference, however GHSR antagonist is still effective at reducing the preference. ***P<0.0005. Ghrelin alters the relationship between preference for novelty and NILA. D. Novelty place preference (NPP, here time spent exploring the novel environment) is not correlated with locomotor activity during NILA at baseline. E. The two traits become significantly correlated after ghrelin treatment. F. GHSR antagonist does not influence the correlation.

Figure 4. Ghrelin induces a significant preference for exploration of a novel object in rats that do not show a preference for a novel object at baseline.

GHSR blockade does not alter this behavior. ***P<0.0005.

Figure 5. Role of the VTA ghrelin and GHSR in the NILA response.

A. Rats that received the VTA directed ghrelin microinjection had an elevated NILA response after 45 min of the NILA test. B. Conversely rats that received a VTA microinjection of the GHSR antagonist JMV2959 displayed a reduced NILA response. C. Rat brain section (right) and equivalent panel from the rat brain atlas (left) showing an example of the VTA microinjection used. *P<0.05. SNR, substantia nigra, reticular part; ml, medial longitudinal fasciculus; fr, fasciculus retroflexus; VTA, ventral tegmental area.

Figure 6. The GHSR SNPs rs2948694 and rs495225 are significantly associated with novelty seeking (p = 0.002 and p = 0.026, respectively).

For both rs2948694 and rs495225, the less common G/G genotype is associated with lower scores on the personality trait novelty seeking.