Neonatal onset of leptin signalling in dopamine neurones of the ventral tegmental area in the rat.

Leptin inhibits feeding by acting on hypothalamic and mesolimbic dopamine (DA) pathways involved in the homeostatic and hedonic control of energy balance. In the rodent, the neonatal period is characterised by high circulating leptin concentrations and an insensitivity to the anorectic effects of this hormone, suggesting that the modulation of these circuits by leptin is reduced during this period. The present study aimed to examine the onset of the functional ventral tegmental area (VTA) response to leptin during the neonatal period and to characterise the phenotype of leptin-responsive VTA neurones. On postnatal day (PND) 10 in pups insensitive to the anorectic effects of leptin and exclusively dependent on their mother for feeding, leptin administration failed to increase phosphorylated signal transducer of activation and transcription 3 (pSTAT3) and phosphorylated extracellular signal-regulated kinase (pERK)1/2 immunoreactivity in the midbrain. At the onset of independent feeding on PND16, leptin stimulated pSTAT3 production in the lateral parabrachial pigmented area of the midbrain, with a subset of these pSTAT3-positive neurones co-localising with tyrosine hydroxylase, a marker of DA neurones. Leptin did not increase pERK1/2 immunoreactivity in DA neurones on PND16. These results suggest that the insensitivity of PND10 pups to the anorectic effects of leptin might be mediated, at least in part, by a lack of signalling through the Janus kinase/STAT signalling pathway in VTA DA neurones in response to leptin before the onset of independent feeding.

Reduced anticipatory dopamine responses to food in rats exposed to high fat during early development.

We have previously demonstrated that exposure to high fat (HF) during early development alters the presynaptic regulation of mesolimbic dopamine (DA), and increases incentive motivation for HF food rewards. The goal of the present experiments was to examine the long-term consequences of early exposure to HF on anticipatory and consumatory nucleus accumbens (NAc) DA responses to HF food rewards. Mothers were maintained on a HF (30% fat) or control diet (CD; 5% fat) from gestation day 13 to postnatal day 22 when offspring from both diet groups were weaned and maintained on the CD until adulthood. In vivo NAc DA responses to food anticipation and consumption were measured in a Pavlovian conditioning paradigm using voltammetry in freely moving rats. HF-exposed offspring displayed reduced NAc DA responses to a tone previously paired with the delivery of HF food rewards. In an unconditioned protocol, consumatory NAc DA responses could be isolated, and were similar in HF and control offspring. These data demonstrate that exposure to HF through maternal diet during early development might program behavioral and functional responses associated with mesolimbic DA neurotransmission, thus leading to an increased HF feeding and obesity.

Maternal high-fat intake alters presynaptic regulation of dopamine in the nucleus accumbens and increases motivation for fat rewards in the offspring.

High caloric intake during early postnatal development can have long term consequences for the offspring. We previously reported that the adult offspring of dams fed a high-fat diet during the last week of gestation and throughout lactation display blunted locomotor response to amphetamine (AMP) and reduced sensitization to the drug compared to offspring of control diet dams. Here, we report that the subsensitivity of high-fat offspring to AMP's locomotor stimulant action reflects, at least in part, altered regulation of nucleus accumbens (NAc) dopamine (DA) transmission. When compared to controls, the DA response of high-fat animals to AMP, as measured with microdialysis, was attenuated in the NAc, but unaffected in the prefrontal cortex (PFC). A relatively higher activity of NAc synaptosomal DA transporter sites without changes in vesicular monoamine transporter (VMAT) uptake capacity was also observed in high-fat offspring. Moreover, ventral tegmental area (VTA) D(2) receptor mRNA levels were decreased in high-fat offspring, suggesting a reduction in DA release-regulating D(2) autoreceptors in terminal regions such as the NAc. The magnitude of locomotor response to D(2/3) receptor activation (with quinpirole) was greater in high-fat than in control animals despite having comparable postsynaptic D(2) mRNA levels in the NAc. Finally, while operant responding for a sugar-enriched food reward did not differ between diet groups, high-fat offspring displayed increased operant responding for a fat-enriched reward compared to controls. These findings add to mounting evidence that early life exposure to elevated dietary maternal fat can lead to long lasting changes in DA-mediated behavioral responses to stimulant drugs and fat-enriched foods.