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Unconditioned rewarding stimuli evoke phasic increases in dopamine concentration in the nucleus accumbens (NAc) while discrete aversive stimuli elicit pauses in dopamine neuron firing and reductions in NAc dopamine concentration. The unconditioned effects of more prolonged aversive states on dopamine release dynamics are not well understood and are investigated here using the malaise-inducing agent lithium chloride (LiCl). We used fast-scan cyclic voltammetry to measure phasic increases in NAc dopamine resulting from electrical stimulation of dopamine cell bodies in the ventral tegmental area (VTA). Systemic LiCl injection reduced electrically evoked dopamine release in the NAc of both anesthetized and awake rats. As some behavioral effects of LiCl appear to be mediated through glucagon-like peptide-1 receptor (GLP-1R) activation, we hypothesized that the suppression of phasic dopamine by LiCl is GLP-1R dependent. Indeed, peripheral pretreatment with the GLP-1R antagonist exendin-9 (Ex-9) potently attenuated the LiCl-induced suppression of dopamine. Pretreatment with Ex-9 did not, however, affect the suppression of phasic dopamine release by the kappa-opioid receptor agonist, salvinorin A, supporting a selective effect of GLP-1R stimulation in LiCl-induced dopamine suppression. By delivering Ex-9 to either the lateral or fourth ventricle, we highlight a population of central GLP-1 receptors rostral to the hindbrain that are involved in the LiCl-mediated suppression of NAc dopamine release.

The adipose-derived hormone leptin signals in the medial nucleus tractus solitarius (mNTS) to suppress food intake, in part, by amplifying within-meal gastrointestinal (GI) satiation signals. Here we show that mNTS leptin receptor (LepRb) signaling also reduces appetitive and motivational aspects of feeding, and that these effects can depend on energy status. Using the lowest dose that significantly suppressed 3-h cumulative food intake, unilateral leptin (0.3 μg) administration to the mNTS (3 h before testing) reduced operant lever pressing for sucrose under increasing work demands (progressive ratio reinforcement schedule) regardless of whether animals were energy deplete (food restricted) or replete (ad libitum fed). However, in a separate test of food-motivated responding in which there was no opportunity to consume food (conditioned place preference (CPP) for an environment previously associated with a palatable food reward), mNTS leptin administration suppressed food-seeking behavior only in chronically food-restricted rats. On the other hand, mNTS LepRb signaling did not reduce CPP expression for morphine reinforcement regardless of energy status, suggesting that mNTS leptin signaling differentially influences motivated responding for food vs opioid reward. Overall results show that mNTS LepRb signaling reduces food intake and appetitive food-motivated responding independent of energy status in situations involving orosensory and postingestive contact with food, whereas food-seeking behavior independent of food consumption is only reduced by mNTS LepRb activation in a state of energy deficit. These findings reveal a novel appetitive role for LepRb signaling in the mNTS, a brain region traditionally linked with processing of meal-related GI satiation signals.

The increase in obesity prevalence highlights the need for a more comprehensive understanding of the neural systems controlling food intake; one that extends beyond food intake driven by metabolic need and considers that driven by higher-order cognitive factors. The hippocampus, a brain structure involved in learning and memory function, has recently been linked with food intake control. Here we examine whether administration of the adiposity hormone leptin to the dorsal and ventral sub-regions of the hippocampus influences food intake and memory for food. Leptin (0.1 μg) delivered bilaterally to the ventral hippocampus suppressed food intake and body weight measured 24 h after administration; a higher dose (0.4 μg) was needed to suppress intake following dorsal hippocampal delivery. Leptin administration to the ventral but not dorsal hippocampus blocked the expression of a conditioned place preference for food and increased the latency to run for food in an operant runway paradigm. Additionally, ventral but not dorsal hippocampal leptin delivery suppressed memory consolidation for the spatial location of food, whereas hippocampal leptin delivery had no effect on memory consolidation in a non-spatial appetitive response paradigm. Collectively these findings indicate that ventral hippocampal leptin signaling contributes to the inhibition of food-related memories elicited by contextual stimuli. To conclude, the results support a role for hippocampal leptin signaling in the control of food intake and food-related memory processing.