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15mgh tonegenerator4/15/2023 Furthermore, orexin receptor antagonists, particularly those acting at the orexin-1 receptor, are highly effective at blocking stimulus-driven drug-seeking for various drugs of abuse ( Martin-Fardon and Weiss, 2014 Moorman et al., 2017 Plaza-Zabala et al., 2013 Smith et al., 2009 Smith et al., 2010), but these compounds have minimal effects on drug-seeking elicited by drug priming injections ( Zhou et al., 2012). Indeed, orexin cells are recruited by discriminative and contextual stimuli previously paired with drug ( Dayas et al., 2008 Martin-Fardon et al., 2018 Moorman et al., 2016), and the magnitude of orexin cell activation is strongly correlated with drug-seeking behavior ( Harris et al., 2005 Moorman et al., 2016 Richardson and Aston-Jones, 2012). For example, the orexin system is particularly important for driving drug-seeking behavior elicited by environmental cues associated with drug use (for review, see ( James et al., 2017b)). Orexin (hypocretin) cells in the perifornical/lateral hypothalamic area (LHA) play a key role in motivated behavior ( Brodnik et al., 2018 Harris et al., 2005 James et al., 2017b James et al., 2018b Mahler et al., 2014 Sakurai, 2014). These effects are likely mediated, at least in part, by normalization of presynaptic plasticity at orexin cells that occurs as a result of cocaine exposure. Together, these data indicate that activation of group III mGluRs in LHA reduces orexin cell activity in vivo and may be an effective strategy to suppress cocaine-seeking behavior following withdrawal. Finally, using whole-cell patch-clamp recordings from identified orexin cells in orexin-GFP transgenic mice, we show that enhanced presynaptic drive to orexin cells persists for up to 14d into withdrawal and that this plasticity can be normalized by L-AP4. Importantly, L-AP4 had no effect on lever pressing for sucrose pellets or general motoric behavior. Next, we extended these findings to show that intra-LHA L-AP4 infusions reduced discriminative stimulus-driven cocaine-seeking following withdrawal. First, we verified that group III mGluRs regulate orexin cell activity in behaving animals by showing that intra-LHA infusions of the selective agonist L-(+)-2-Amino-4-phosphonobutyric acid (L-AP4) reduces c- fos expression in orexin cells following 24h food deprivation. Therefore, we focused on the group III mGluR system as a potential target to reduce orexin cell excitability in-vivo. Studies in hypothalamic slices from drug-naïve animals indicate that agonism of group III metabotropic glutamate receptors (mGluRs) reduces presynaptic glutamate release onto orexin cells. These changes may augment orexin cell reactivity to drug-related cues during abstinence and contribute to relapse-like behavior. Cocaine exposure is associated with presynaptic plasticity at LHA orexin cells such that excitatory input to orexin cells is enhanced acutely and into withdrawal. The perifornical/lateral hypothalamic area (LHA) orexin (hypocretin) system is involved in drug-seeking behavior elicited by drug-associated stimuli.
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