Individuals prone to ethanol overconsumption may have preexisting neurochemical disturbances that contribute to their vulnerability. This study examined the paraventricular nucleus of the thalamus (PVT), a limbic structure recently shown to participate in ethanol intake. To identify individuals prone to ethanol overconsumption, we tested Long-Evans rats in behavioral paradigms and found high levels of vertical time (rearing behavior) in a novel activity chamber to be a consistent predictor of subsequent excessive 20 percent ethanol drinking under the intermittent access model. Examining neurochemicals in the PVT, we found before ethanol exposure that prone rats with high rearing, compared with non-prone rats, had significantly lower levels of neurotensin (NTS) mRNA and peptide in the posterior (pPVT) but not anterior (aPVT) subregion of the PVT. Our additional finding that ethanol intake has no significant impact on either rearing or NTS levels indicates that these measures, which are different in prone rats before ethanol consumption, remain stable after ethanol consumption. The possibility that NTS directly controls ethanol drinking is supported by our finding that NTS administration specifically suppresses ethanol drinking when injected into the pPVT but not aPVT, with this effect occurring exclusively in higher drinkers that presumably have lower endogenous levels of NTS. Further, an NTS antagonist in the pPVT augments intake in lower drinkers with presumably more endogenous NTS, while NTS in the pPVT inhibits novelty-induced rearing that predicts excessive drinking. Together, these results provide strong evidence that low endogenous levels of NTS in the pPVT contribute to an increased propensity toward excessive ethanol drinking.
This study characterizes the PVT neuropeptide, PACAP, and its understudied protein isoform, PACAP-27, and demonstrates that it is involved in pharmacologically relevant EtOH drinking. This indicates that PACAP-27 should be further investigated for its possible role in EtOH drinking.
Neural circuit engagement within the nucleus accumbens (NAc) shell is implicated in the regulation of both negative and positive affect. Classically, the dynorphin/kappa opioid receptor (KOR) system in the NAc was believed to promote dysphoric behavior, while dopamine was viewed as interacting with reward behavior, and KOR activation was known to inhibit dopamine release. Recently, however, both the KOR and dopamine systems have, separately, been shown to have differential effects across the rostro-caudal axis of the NAc shell on hedonic responses. Whether or not this is due to interactions between KORs and dopamine, and if it extends to other affective behaviors, remains to be determined. In this study, we examined in rats the relationship between the KOR and dopamine systems in both the rostral and caudal NAc shell using ex vivo fast scan cyclic voltammetry and the impact of KOR activation on affective behavior using approach-avoidance assays. We report here that activation of KORs in the caudal NAc shell significantly inhibits dopamine release, stimulates novelty-induced rearing behavior, increases avoidance behavior, and reduces locomotor activity. In contrast, activation of KORs in the rostral NAc shell inhibits dopamine release to a lesser extent and instead increases approach behavior. Taken together, these results indicate that there is heterogeneity across the rostro-caudal axis of the NAc shell in the effects of KOR stimulation on affective behaviors, and they suggest that this might be due to differences in KOR control over dopamine release.
The paraventricular nucleus of the thalamus (PVT) has been shown to make significant contributions to affective and motivated behavior, but a comprehensive description of the neurochemicals expressed in the cells of this brain region has never been presented. While the PVT is believed to be composed of projection neurons that primarily use as their neurotransmitter the excitatory amino acid, glutamate, several neuropeptides have also been described in this brain region. In this review article, we combine published literature with our observations from the Allen Brain Atlas to describe in detail the expression and distribution of neuropeptides in cells throughout the mouse and rat PVT, with a special focus on neuropeptides known to be involved in behavior. Several themes emerge from this investigation. First, while the majority of neuropeptides are expressed across the antero-posterior axis of the PVT, they generally exist in a gradient, in which expression is most dense but not exclusive in either the anterior or posterior PVT, although other neuropeptides display somewhat more equal expression in the anterior and posterior PVT but have reduced expression in the middle PVT. Second, we find overall that neuropeptides involved in arousal are more highly expressed in the anterior PVT, those involved in depression-like behavior are more highly expressed in the posterior PVT, and those involved in reward are more highly expressed in the medial PVT, while those involved in the intake of food and drugs of abuse are distributed throughout the PVT. Third, the pattern and content of neuropeptide expression in mice and rats appear not to be identical, and many neuropeptides found in the mouse PVT have not yet been demonstrated in the rat. Thus, while significantly more work is required to uncover the expression patterns and specific roles of individual neuropeptides in the PVT, the evidence thus far supports the existence of a diverse yet highly organized system of neuropeptides in this nucleus. Determined in part by their location within the PVT and their network of projections, the function of the neuropeptides in this system likely involves intricate coordination to influence both affective and motivated behavior.
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