The paraventricular nucleus of the thalamus (PVT) has been shown to participate in hedonic feeding and is thought to influence drug seeking. This understudied nucleus contains anterior (aPVT) and posterior (pPVT) subregions, which receive dense projections from hypothalamic orexin/hypocretin (OX) but exhibit anatomical and functional differences. This study sought to characterize in Long-Evans rats the involvement of these PVT subregions and their OX receptor activity in consumption of the drug, ethanol. Compared to those maintained on water and chow only (Water Group), rats trained to drink pharmacologically-relevant levels of ethanol (Ethanol Group) showed increased neuronal activation in the PVT, specifically the aPVT but not pPVT, as indicated by c-Fos-immunoreactivity. Similar results were obtained in rats administered ethanol via oral gavage, indicating that this site-specific effect was due to ethanol exposure. In support of the involvement of OX, the Ethanol group also showed increased mRNA levels of this neuropeptide in the hypothalamus and of OX 2 receptor (OX2R) but not OX 1 receptor (OX1R), again in the aPVT but not pPVT. Similarly, ethanol gavage increased double-labeling of c-Fos with OX2R but not OX1R, specifically in the aPVT. Evidence directly supporting a role for aPVT OX2R in ethanol consumption was provided by results with local injections, showing ethanol intake to be enhanced by OX-A or OX-B in the aPVT but not pPVT and reduced by a local antagonist of OX2R but not OX1R. These results focus attention on the aPVT and specifically its OX2R in mediating a positive-feedback relationship with ethanol intake.

Obese humans and animals exhibit reduced functioning of the dopamine (DA) system in the nucleus accumbens (NAc). The question addressed here is whether this change in NAc DA can be detected in Sprague-Dawley rats that are prone to obesity on a fat-rich diet but still at normal body weight. Rats were subgrouped as “obesity-prone” (OP) or “obesity-resistant” (OR), based on their weight gain during 5 days of access to a high-fat diet, and were then shifted to a lower-fat chow diet before microdialysis testing was performed. The OP rats compared to OR rats exhibited markedly reduced basal levels of DA in the NAc. After a high-fat challenge meal, both OP and OR rats showed a significant increase in extracellular DA and its metabolites; however, the NAc DA of the OP rats still remained at reduced levels. Also, the increase in DA and metabolite levels observed in OR rats after systemic administration of a fat emulsion was not evident in the OP rats, which instead showed no change in DA and a decrease in its metabolites. These results demonstrate, first, that fat can stimulate accumbal DA release and, second, that outbred rats prone to overeating and becoming obese on a palatable, fat-rich diet exhibit reduced signaling in the mesolimbic DA system while still at normal weight, suggesting that it may be causally related to their excess consummatory behavior.

The paraventricular nucleus of the thalamus (PVT) has for decades been acknowledged to be an important node in the limbic system, but studies of emotional processing generally fail to incorporate it into their investigational framework. Here, we propose that the PVT should be considered as an integral part of the emotional processing network. Through its distinct subregions, cell populations, and connections with other limbic nuclei, the PVT participates in both major features of emotion: arousal and valence. The PVT, particularly the anterior PVT, can through its neuronal activity promote arousal, both as part of the sleep-wake cycle and in response to novel stimuli. It is also involved in reward, being both responsive to rewarding stimuli and itself affecting behavior reflecting reward, likely via specific populations of cells distributed throughout its subregions. Similarly, neuronal activity in the PVT contributes to depression-like behavior, through yet undefined subregions. The posterior PVT in particular demonstrates a role in anxiety-like behavior, generally promoting but also inhibiting this behavior. This subregion is also especially responsive to stressors, and it functions to suppress the stress response following chronic stress exposure. In addition to participating in unconditioned or primary emotional responses, the PVT also makes major contributions to conditioned emotional behavior. Neuronal activity in response to a reward-predictive cue can be detected throughout the PVT, and endogenous activity in the posterior PVT strongly predicts approach or seeking behavior. Similarly, neuronal activity during conditioned fear retrieval is detected in the posterior PVT and its activation facilitates the expression of conditioned fear. Much of this involvement of the PVT in arousal and valence has been shown to occur through the same general afferents and efferents, including connections with the hypothalamus, prelimbic and infralimbic cortices, nucleus accumbens, and amygdala, although a detailed functional map of the PVT circuits that control emotional responses remains to be delineated. Thus, while caveats exist and more work is required, the PVT, through its extensive connections with other prominent nuclei in the limbic system, appears to be an integral part of the emotional processing network.

Exposure to ethanol during the prenatal period contributes to increased alcohol consumption and preference in rodents and increased risk for alcoholism in humans. With studies in adult animals showing the orexigenic peptides, enkephalin (ENK), galanin (GAL) and orexin (OX), to stimulate ethanol consumption, the question addressed here is whether prenatal ethanol alters the development in utero of specific neurons that express these peptides. With reports describing suppressive effects of high doses of ethanol, we examined the offspring of dams gavaged from embryonic day 9 to parturition with a control solution or lower ethanol doses, 1 and 3 g/kg/day, known to promote ethanol consumption in the offspring. To understand underlying mechanisms, measurements were taken in postnatal offspring of the expression of ENK in the hypothalamic paraventricular nucleus (PVN) and nucleus accumbens (NAc), GAL in the PVN, and OX in the perifornical lateral hypothalamus (PFLH) using real-time qPCR and in situ hybridization, and also of the cell proliferation marker, 5-bromo-2-deoxyuridine (BrdU), and its double-labeling with either neuronal nuclei (NeuN), a marker of mature neurons, or the peptides. On postnatal day 15 (P15), after two weeks without ethanol, the offspring showed increased expression of ENK in the PVN and NAc core but not shell, GAL in the PVN, and OX in the PFLH. In these same areas, prenatal ethanol compared to control increased the density at birth (P0) of neurons expressing these peptides and at P0 and P15 of neurons double-labeling BrdU and NeuN, indicating increased neurogenesis. These BrdU-positive neurons were found to express ENK, GAL and OX, indicating that prenatal ethanol promotes neurogenesis in these specific peptide systems. There were no changes in gliogenesis or apoptosis. This increase in neurogenesis and density of peptide-expressing neurons suggests the involvement of these hypothalamic and accumbal peptide systems in mediating the increased alcohol consumption observed in prenatal ethanol-exposed offspring.

Background Specialized hypothalamic systems that increase food intake might also increase ethanol intake. To test this possibility, morphine and receptor-specific opioid agonists were microinjected in the paraventricular nucleus (PVN) of rats that had learned to drink ethanol. To cross-validate the results, naloxone methiodide (m-naloxone), an opioid antagonist, was microinjected with the expectation that it would have the opposite effect of morphine and the specific opioid agonists. Methods Sprague-Dawley rats were trained, without sugar, to drink 4% or 7% ethanol and were then implanted with chronic brain cannulas aimed at the PVN. After recovery, those drinking 7% ethanol, with food and water available, were injected with two doses each of morphine or m-naloxone. To test for receptor specificity, two doses each of the μ-receptor agonist [D-Ala2,N-Me-Phe4,Gly5-ol]-Enkephalin (DAMGO), δ-receptor agonist D-Ala-Gly-Phe-Met-NH2 (DALA), or k-receptor agonist U-50,488H were injected. DAMGO was also tested in rats drinking 4% ethanol without food or water available. As an anatomical control for drug reflux, injections were made 2 mm dorsal to the PVN. Results A main result was a significant increase in ethanol intake induced by PVN injection of morphine. The opposite effect was produced by m-naloxone. The effects of morphine and m-naloxone were exclusively on intake of ethanol, even though food and water were freely available. In the analysis with specific receptor agonists, PVN injection of the δ-agonist DALA significantly increased 7% ethanol intake without affecting food or water intake. This is in contrast to the k-agonist U-50,488H, which decreased ethanol intake, and the μ-agonist DAMGO, which had no effect on ethanol intake in the presence or absence of food and water. In the anatomical control location 2 mm dorsal to the PVN, no drug caused any significant changes in ethanol, food, or water intake, providing evidence that the active site was close to the cannula tip. Conclusions The δ-opioid receptor agonist in the PVN increased ethanol intake in strong preference over food and water, while the k-opioid agonist suppressed ethanol intake. Prior studies show that learning to drink ethanol stimulates PVN expression and production of the peptides enkephalin and dynorphin, which are endogenous agonists for the δ- and k-receptors, respectively. These results suggest that enkephalin via the δ-opioid system can function locally within a positive feedback circuit to cause ethanol intake to escalate and ultimately contribute to the abuse of ethanol. This is in contrast to dynorphin via the k-opioid system, which may act to counter this escalation. Naltrexone therapy for alcoholism may act, in part, by blocking the enkephalin-triggered positive feedback cycle.