A systematic investigation of the differential roles for ventral tegmentum serotonin 1- and 2-type receptors on food intake in the rat

Abstract

Central serotonin (5-HT) pathways are known to influence feeding and other ingestive behaviors. Although the ventral tegmentum is important for promoting the seeking and consumption of food and drugs of abuse, the roles of 5-HT receptor subtypes in this region on food intake have yet to be comprehensively examined. In these experiments, food restricted rats were given 2-h access to rat chow; separate groups of non-restricted animals had similar access to a sweetened fat diet. Feeding and locomotor activity were monitored following ventral tegmentum stimulation or blockade of 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, or 5-HT2C receptors. 5-HT1A receptor stimulation transiently inhibited rearing behavior and chow intake in food-restricted rats, and had a biphasic effect on non-restricted rats offered the palatable diet. 5-HT1B receptor agonism transiently inhibited feeding in restricted animals, but did not affect intake of non-restricted rats. In contrast, 5-HT1B receptor antagonism decreased palatable feeding. Although stimulation of ventral tegmental 5-HT2B receptors with BW723C86 did not affect hunger-driven food intake, it significantly affected palatable feeding, with a trend for an increasing intake at 2.0µg/side but not at 5.0µg/side. Antagonism of the same receptor modestly but significantly inhibited feeding of the palatable diet at 5.0µg/side ketanserin. Neither stimulation nor blockade of 5-HT2A or 5-HT2C receptors caused prolonged effects on intake or locomotion. These data suggest that serotonin's effects on feeding within the ventral tegmentum depend upon the specific receptor targeted, as well as whether intake is motivated by food restriction or the palatable nature of the offered diet.

Keywords: Feeding; Motivation; Reward; Serotonin; Ventral tegmental area.

Figure 1

Effects of ventral tegmentum stimulation or blockade of the 5-HT_1A receptor on feeding, water intake, and locomotion. In food-restricted rats offered rat chow (top two panels), 5-HT_1A receptor stimulation (but not antagonism), dose-dependently reduced food intake within the first hour of the feeding session. By the end of the second hour, consumption was equivalent across all doses of the drug. Rearing behavior was also significantly inhibited at the 8.0 μg/side dose. The effects of ventral tegmental injections of 8-OH-DPAT were significant but more complex in non-restricted rats offered a palatable diet (bottom two panels): when rats were injected with 2.0 μg/side, there was a tendency for an increase in food intake, whereas the highest dose of the drug (8.0 μg/side) inhibited intake throughout the session. Follow-up ANOVAs at individual time points yielded significant effects on feeding between conditions by 15 minutes into the session, which lasted until the session was over. These drug effects appeared to be due to differences between the 2.0 and 8.0 μg/side conditions, as Tukey’s HSD did not yield significant differences between the vehicle injection and either drug condition when the simple effects of drug dose was tested at 5-min intervals. Statistical symbols: *p < .05, **p < .01 for drug effects; single and double crosses demark p < .05 and p < .01 for drug X time interaction effect, respectively. Plus signs along the bottom of feeding graphs indicate times when there were significant simple effects of drug on food intake across drug doses. White stars within the graphs denote significant differences from the vehicle control injection, as assessed by Tukey’s HSD. The histology figures to the right represent the injection sites for each experiment, as charted within Paxinos and Watson (1998). Black-filled circles represent agonist injection sites; gray-filled circles denote antagonist injection sites.

Figure 2

Effects of ventral tegmentum stimulation or blockade of the 5-HT_1B receptor on feeding, water intake, and locomotion. Stimulation, but not blockade, of 5-HT_1B receptors yielded a significant drug X time interaction effect on food intake in food-restricted animals. This was likely due to an inhibition of feeding early in the session after rats were treated with 4.0 μg/side of CP 93129 (top panels). This difference in food consumed was absent by the end of the 2 hr session. There was no impact of CP 93129 or GR 55562 on ambulation, rearing, or water intake in hungry animals. In contrast to the effects of the agonist on feeding in food-restricted animals, non-restricted animals offered a palatable diet showed no effects of ventral tegmentum 5-HT_1B receptor stimulation on feeding. Instead, blockade of 5-HT_1B receptors caused a modest but significant decline in intake of the sweetened fat diet, without impacting water intake or locomotor measures. Statistical symbols as for Figure 1. The photomicrographs on the right show representative placements of the injection cannulas for these experiments.

Figure 3

Neither stimulation nor blockade of 5-HT_2A receptors of the ventral tegmentum caused lasting changes in food intake or locomotion. 5-HT_2A receptor stimulation yielded a significant drug X time interaction for food-restricted rats, which was likely due to an initial slower rate of feeding during the first hour for the 10.0 μg/side dose. However, at no time during the 2-hr session did drug treatment yield significantly different intake of rat chow compared to the vehicle injection. Agonist treatment did not affect food intake of the sweetened palatable diet, and blockade of the 5-HT_2A receptor did not affect either hunger- or palatability-induced feeding. Locomotion and water intake were also unaffected by these treatments. Statistical symbols and histological figures as for Figure 1.

Figure 4

Effects of ventral tegmentum stimulation or blockade of the 5-HT_2B receptor on food intake. In the case of food-restricted rats offered free access to rat chow, neither stimulation nor blockade of the 5-HT_2B receptor affected intake across the 2-hr session (top panels). In contrast, non-restricted rats offered 2-hr access to the sweetened fat diet showed significant drug and drug X time interaction effects following 5-HT_2B receptor stimulation or antagonism of the ventral tegmentum (bottom panels). Injections of BW 723C86 caused a biphasic effect on feeding on the palatable diet, with the 2.0 μg/side dose modestly increasing food intake, and the 5.0 μg/side tending to inhibit feeding. Blockade of the same receptor with RS 127445 significantly inhibited feeding at 5.0 μg/side. Locomotion and water intake were unaffected by these treatments. Statistical symbols and histological figures as for Figure 1.

Figure 5

Neither stimulation nor blockade of 5-HT_2C receptors of the ventral tegmentum caused prolonged changes in food intake. Neither RO 60-0175 nor RS 102221 impacted feeding or locomotion across the 2-hr period, regardless of whether they were motivated by food restriction (top panels) or a palatable diet (bottom panels).