Biology subjects

Aston-Jones, G.

Publications and source records attributed to Aston-Jones, G..

6 recordsLinked to original sources

bioRxiv2018

Activation of lateral hypothalamic group III mGluRs suppresses drug-seeking following abstinence and cocaine-associated increases in excitatory drive to orexin/hypocretin cells

The perifornical/lateral hypothalamic area (LHA) orexin (hypocretin) system is involved in drug-seeking behavior elicited by drug-associated stimuli. Cocaine exposure is associated with presynaptic plasticity at LHA orexin cells such that excitatory input to orexin cells is enhanced, both acutely and into withdrawal. These changes may augment orexin cell reactivity to drug-related cues during abstinence and contribute to relapse-like behavior. Studies in hypothalamic slices from drug-naive animals indicate that agonism of group III metabotropic glutamate receptors (mGluRs) reduces presynaptic glutamate release onto orexin cells. Therefore, we examined the group III mGluR system as a potential target to reduce orexin cell excitability in-vivo, and tested whether activating these receptors could normalize orexin cell activity following cocaine and reduce cocaine-seeking elicited by drug-associated stimuli during abstinence. First, we verified that group III mGluRs regulate orexin cell activity in vivo by showing that intra-LHA infusions of the selective agonist L-(+)-2-Amino-4-phosphonobutyric acid (L-AP4) reduces Fos expression in orexin cells following 24h food deprivation. Next, we extended these findings to show that intra-LHA L-AP4 infusions reduced discriminative stimulus-driven cocaine-seeking following withdrawal. L-AP4 had no effect on general motor activity of sucrose self-administration. 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 is normalized by L-AP4. L-AP4 had no effect on measures of postsynaptic plasticity in cocaine-exposed animals. Together, these data indicate that agonism of LHA group III mGluRs reduces orexin cell activity in-vivo and is an effective strategy to suppress cocaine-seeking behavior following withdrawal. 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.

neuroscience↗

bioRxiv2018

Orexin-1 receptor signaling in ventral pallidum mediates demand for the opioid remifentanil

Signaling at the orexin-1 receptor (Ox1R) is important for motivation for various drugs of abuse. Recently, our laboratory showed that systemic blockade of Ox1Rs decreased motivation for the potent and short-acting opioid remifentanil (Porter-Stransky et al, 2017). However, the central sites through which orexin acts to mediate motivation for opioids are not known. Here, we investigated ventral pallidum (VP) as a potential site of orexin action, as VP is a known mediator of opioid reward and is densely innervated by orexin-immunoreactive fibers. We used a within-session behavioral economics (BE) paradigm in which remifentanil price (responses/{micro}g iv remifentanil) was sequentially increased throughout the session. Rats were implanted with bilateral cannulae into VP, through which microinjections of SB334867 (SB), and orexin 1 receptor (Ox1R) antagonist, were given prior to BE testing. Rats were then extinguished and subjected to cue-induced reinstatement following intra-VP SB microinjection. We found that inhibition of Ox1R signaling in VP reduced both motivation (increased demand elasticity) for remifentanil and cued reinstatement of extinguished remifentanil-seeking without affecting baseline consumption or general locomotor activity. These effects were specific to the VP, as control injections of SB immediately dorsal to VP did not affect remifentanil-seeking. Together, these findings indicate a selective role of Ox1R signaling in VP in motivation and relapse for the opioid remifentanil.

animal behavior and cognition↗

bioRxiv2018

Demand elasticity predicts addiction endophenotypes and the therapeutic efficacy of an orexin/hypocretin-1 receptor antagonist in rats

Behavioral economics is a powerful, translational approach for measuring drug demand in both humans and animals. Here, we asked if demand for cocaine in rats with limited drug experience could be used to identify individuals most at risk of expressing an addiction phenotype following either long (LgA) or intermittent (IntA) access self-administration schedules, both of which model the transition to uncontrolled drug seeking. Moreover, because the orexin-1 receptor antagonist SB-334867 (SB) is particularly effective at reducing drug-seeking in highly motivated individuals, we asked whether demand measured after prolonged drug experience could predict SB efficacy. Demand elasticity () measured immediately following acquisition of cocaine self-administration ( baseline ) was positively correlated with assessed after 2w of LgA or IntA. Baseline also predicted the magnitude of compulsive responding for cocaine, drug seeking in initial abstinence, and cued reinstatement following LgA, IntA or standard short access (ShA). When demand was measured after LgA, IntA or ShA, predicted the same addiction endophenotypes predicted by baseline , as well as primed reinstatement and the emergence of negative emotional mood behavior following abstinence. Post-LgA/IntA/ShA also predicted the efficacy of SB, such that high demand rats showed greater reductions in motivation for cocaine following SB (10 and 30mg/kg) compared to low demand rats. Together, these findings indicate that might serve as a behavioral biomarker to predict individuals most likely to progress from controlled to uncontrolled drug use, and to identify individuals most likely to benefit from orexin-based therapies for the treatment of addiction.

neuroscience↗

bioRxiv2018

Increased number and activity of a lateral subpopulation of hypothalamic orexin/hypocretin neurons underlies the expression of an addicted state in rats

BackgroundThe orexin system is important for reward-driven motivation but has not been implicated in the expression of a multi-phenotype addicted state.\n\nMethodsRats were assessed for economic demand for cocaine prior to and following 14d of short- (ShA), long- (LgA) or intermittent-access (IntA) to cocaine. Rats were also assessed for a number of other DSM- V-relevant addiction criteria following differential access conditions. Orexin system function was assessed by i) quantification of numbers and activity of orexin cells, ii) pharmacological blockade of the orexin-1 receptor, and iii) subregion-specific knockdown of orexin cell populations.\n\nResultsIntA produced a cluster of addiction-like behaviors that closely recapitulate key diagnostic criteria for addiction to a greater extent than LgA or ShA. IntA was associated with plasticity in orexin cell function, including increased number and activity of orexin-expressing neurons within the lateral hypothalamic (LH) subregion. This plasticity persisted during protracted withdrawal from cocaine for at least 6 months and was associated with enhanced incubation of craving. Selective knockdown of LH orexin neurons reversed the addicted state, and orexin-1 receptor signaling played a larger role in drug seeking after IntA.\n\nConclusionsThese data provide the first evidence that LH orexin system function extends beyond general reward seeking to play a critical role in the expression of a multi-phenotype addicted-like state. Thus, the orexin/hypocretin system is a potential novel target for pharmacotherapies designed to treat cocaine addiction. In addition, these data point to the IntA model as a preferred approach to modeling addictionlike behavior in rats.

neuroscience↗

bioRxiv2018

Serotonin signaling in hippocampus during initial cocaine abstinence drives persistent drug seeking

BackgroundThe initiation of abstinence (extinction day 1, ED1) represents a stressful event involving abstinence from drug. We showed previously that ED1 cocaine-seeking behavior is reduced by blocking 5-HT signaling in dorsal hippocampus in both male and female rats. We hypothesized that the experience of ED1 can substantially influence later relapse behavior, and that dorsal raphe serotonin (DR 5-HT) signaling to dorsal hippocampus (DH) may be involved.\n\nMethodsWe used pharmacological inhibition of dorsal hippocampus 5-HT1A/1B receptors (via WAY100,635 plus GR127935), and chemogenetic inhibition of dorsal raphe-dHPC signaling to test the roles of these pathways on cocaine-seeking 2 weeks after ED1. We also tested specific effects of 5-HT1A or 5-HT1B receptor antagonism on conditioned place preference for cocaine.\n\nResultsInhibition of DR-DH signaling via DREADDs or 5-HT1A/1B antagonists decreased ED1 drug-seeking with persistent effects on cocaine-seeking 2 weeks later, confirming the involvement of 5-HT signaling to dorsal hippocampus in driving drug-seeking persistence. Administration of a 5-HT1B antagonist alone on ED1 transiently decreased drug-associated memory performance in CPP, whereas administration of a 5-HT1A antagonist had no effect on memory but blocked CPP on a subsequent test 24h later.\n\nConclusionsWe conclude that blockade of DR inputs or 5HT1 signaling in DH on ED1 prevents recall of the drug-associated context and reduces drug seeking via antagonism of 5-HT1B receptors, and consolidates the memory of the newly non-drug context via antagonism of 5-HT1A receptors. Thus, treatments that modulate 5-HT-dependent memory mechanisms during initial abstinence may facilitate later maintenance of abstinence.

neuroscience↗

bioRxiv2018

Chemogenetic Manipulations of Ventral Tegmental Area Dopamine Neurons Reveal Multifaceted Roles in Cocaine Abuse

Ventral tegmental area (VTA) dopamine (DA) neurons perform diverse functions in motivation and cognition, but their precise roles in addiction-related behaviors are still debated. Here, we targeted VTA DA neurons for bidirectional chemogenetic modulation during specific tests of cocaine reinforcement, demand, and relapse-related behaviors, querying the roles of DA neuron inhibitory and excitatory G-protein signaling in these processes. Designer receptor stimulation of Gq-, but not Gs-signaling in DA neurons enhanced cocaine seeking via functionally distinct projections to forebrain limbic regions. In contrast, engaging inhibitory Gi/o signaling in DA neurons blunted cocaines reinforcing and priming effects, reduced stress-potentiated reinstatement, and altered cue-induced cocaine seeking strategy, but not the motivational impact of cocaine cues per se. Results demonstrate that DA neurons play several distinct roles in cocaine seeking, depending on behavioral context, G-protein signaling, and DA neuron efferent target, highlighting their multifaceted roles in addiction.\n\nSignificance StatementG-protein coupled receptors are crucial modulators of VTA dopamine neuron activity, but how metabotropic signaling impacts dopamines complex roles in reward and addiction is poorly understood. Here, we bidirectionally modulate dopamine neuron G-protein signaling with DREADDs during a variety of cocaine seeking behaviors, revealing nuanced, pathway-specific roles in cocaine reward, effortful seeking, and relapse-like behaviors. Gq- and Gs-stimulation activated dopamine neurons, but only Gq stimulation robustly enhanced cocaine seeking. Gi/o inhibitory signaling altered the response strategy employed during cued reinstatement, and reduced some, but not all types of cocaine seeking. Results show that VTA dopamine neurons modulate numerous distinct aspects of cocaine addiction- and relapse-related behaviors, and indicate potential new approaches for intervening in these processes to treat addiction.

neuroscience↗