Substance P in the anterior thalamic paraventricular nucleus: promotion of ethanol drinking in response to orexin from the hypothalamus

Abstract

The paraventricular nucleus of the thalamus (PVT) appears to participate in drug addiction. Recent evidence in rats shows that ethanol drinking is increased by orexin/hypocretin (OX) afferents from the hypothalamus, acting specifically in the anterior (aPVT) rather than posterior (pPVT) PVT subregion. The present study sought to identify neuropeptides transcribed within the PVT, which themselves might contribute to ethanol drinking and possibly mediate the actions of OX. We discovered that substance P (SP) in the aPVT can stimulate intermittent access ethanol drinking, similar to OX, and that SP receptor (NK1R) antagonists in this subregion reduce ethanol drinking. As with OX, this effect is site-specific, with SP in the pPVT or dorsal third ventricle having no effect on ethanol drinking, and it is behaviorally specific, with SP in the aPVT reducing the drinking of sucrose and stimulating it in the pPVT. A close relationship between SP and OX was demonstrated by a stimulatory effect of local OX injection on SP mRNA and peptide levels, specifically in the aPVT but not pPVT, and also a stimulatory effect of OX on SP expression in isolated thalamic neurons, reflecting postsynaptic actions. A functional relationship between OX and SP in the aPVT is suggested by our additional finding that ethanol drinking induced by OX is blocked by a local NK1R antagonist administered at a subthreshold dose. These results, suggesting that SP in the aPVT mediates the stimulatory effect of OX on ethanol drinking, identifies a new role for SP in the control of this behavior.

Paraventricular Thalamic Control of Food Intake and Reward: Role of Glucagon-Like Peptide-1 Receptor Signaling

“…Recent studies are beginning to show differential behavioral effects when targeting the anterior PVT (aPVT) vs the posterior PVT (pPVT). For example, orexin and substance P receptor signaling in the aPVT, but not the pPVT, increases alcohol intake (Barson et al, 2015(Barson et al, , 2017, and activation of aPVT → NAc pathway, but not the pPVT → NAc circuit, reduces sucrose-seeking (Do-Monte et al, 2017). Given the close proximity of mPVT to the aPVT and pPVT, it is possible that the effects observed in the present study may include the aPVT and/or pPVT.…”

Orexin/Hypocretin System: Role in Food and Drug Overconsumption

“…The OX1R antagonists reduce drinking in the dark when injected into the nucleus accumbens shell, central nucleus of the amygdala, or ventral tegmental area (Lei et al, 2016; Olney, Navarro, & Thiele, 2017) and intermittent access alcohol drinking when injected into the medial prefrontal cortex, but not the anterior insular cortex and substantia nigra (Lei et al, 2016; Srinivasan et al, 2012) or the paraventricular thalamus (Barson et al, 2015). This is in contrast to the OX2R antagonist TCS OX2 29, which reduces two-bottle choice alcohol drinking when injected into the paraventricular thalamus where OX-B increases it to a greater extent than an equimolar dose of OX-A (Barson et al, 2015; Barson et al, 2017), but which has no effect on drinking in the dark when injected into the nucleus accumbens shell, central nucleus of the amygdala, or ventral tegmental area (Lei et al, 2016; Olney et al, 2017). This evidence supports the idea that alcohol drinking is stimulated by OX1R in multiple limbic brain regions, while OX2R is most active in the paraventricular thalamus where it specifically promotes high-level drinking.…”

An arbiter model of motivational selection

“…PVT has been implicated in a remarkably diverse range of functions including arousal (Colavito et al, 2015), stress (Bhatnagar, 2003;Bhatnagar and Dallman, 1999;Bhatnagar et al, 2002;Hsu et al, 2014), fear (Beas et al, 2018;Do-Monte et al, 2015;Penzo et al, 2015;Zhu et al, 2018), appetitive learning (Otis et al, 2017;Otis et al, 2019;Zhu et al, 2018), incentive salience (Campus et al, 2019;Haight and Flagel, 2014;Haight et al, 2015;Haight et al, 2017), relapse to drug seeking (Dayas et al, 2007;Dayas et al, 2008;Hamlin et al, 2009;James et al, 2011;James et al, 2010;James and Dayas, 2013;Marchant et al, 2010;Martin-Fardon and Boutrel, 2012;Matzeu et al, 2017;Matzeu et al, 2015), opiate withdrawal (Zhu et al, 2016) , drinking and feeding (Barson et al, 2015;Barson et al, 2017;Ong et al, 2017). We argue that PVT is implicated in these diverse functions because they have in common the need for motivational selection and PVT is a key component of the circuitry arbitrating this selection.…”