Extinction blunts paraventricular thalamic contributions to heroin relapse

Giannotti, Giuseppe; Gong, Sheng; Fayette, Nicholas; Heinsbroek, Jasper A.; Orfila, James E; Herson, Paco S.; Ford, Christopher P.; Peters, Jamie

doi:10.1016/j.celrep.2021.109605

Cited by 20 publications

(35 citation statements)

References 62 publications

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“…During this final test, rats were able to respond on both heroin and food levers, which delivered the heroin- or food-related cues (on FR3) but did not deliver the rewards. Thus, this was a cue extinction test, similar to other forms of cued reinstatement [ 6 , 65 ], conducted during acute (~24 h) opioid withdrawal under conditions of competing reward-related cues. Oxytocin (1 mg/kg), the orexin antagonist DORA-12 (30 mg/kg), or vehicle were injected 30 min prior to the test.…”

Section: Resultsmentioning

confidence: 99%

Oxytocin and orexin systems bidirectionally regulate the ability of opioid cues to bias reward seeking

et al. 2022

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As opioid-related fatalities continue to rise, the need for novel opioid use disorder (OUD) treatments could not be more urgent. Two separate hypothalamic neuropeptide systems have shown promise in preclinical OUD models. The oxytocin system, originating in the paraventricular nucleus (PVN), may protect against OUD severity. By contrast, the orexin system, originating in the lateral hypothalamus (LH), may exacerbate OUD severity. Thus, activating the oxytocin system or inhibiting the orexin system are potential therapeutic strategies. The specific role of these systems with regard to specific OUD outcomes, however, is not fully understood. Here, we probed the therapeutic efficacy of pharmacological interventions targeting the orexin or oxytocin system on two distinct metrics of OUD severity in rats—heroin choice (versus choice for natural reward, i.e., food) and cued reward seeking. Using a preclinical model that generates approximately equal choice between heroin and food reward, we examined the impact of exogenously administered oxytocin, an oxytocin receptor antagonist (L-368,899), and a dual orexin receptor antagonist (DORA-12) on opioid choice. Whereas these agents did not alter heroin choice when rewards (heroin and food) were available, oxytocin and DORA-12 each significantly reduced heroin seeking in the presence of competing reward cues when no rewards were available. In addition, the number of LH orexin neurons and PVN oxytocin neurons correlated with specific behavioral economic variables indicative of heroin versus food motivation. These data identify a novel bidirectional role of the oxytocin and orexin systems in the ability of opioid-related cues to bias reward seeking.

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Section: Resultsmentioning

confidence: 99%

Oxytocin and orexin systems bidirectionally regulate the ability of opioid cues to bias reward seeking

et al. 2022

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“…Surprisingly, here we find that PVT→NAc neurons play a pervasive role in the suppression of reward-motivated behavior, and through an unexpected synaptic input to NAc PV interneurons. Other studies have focused on the role of PVT synaptic input to NAc D1- and D2-MSNs 13 , 39 , 40 , and have found unique functions of these pathways in other behaviors such as the expression of opioid withdrawal 13 and the retrieval of an opioid conditioned place preference memory 40 . Thus, discrete outputs from PVT to unique NAc cell types likely control distinct behavioral states, including the suppression of reward seeking as described here.…”

Section: Discussionmentioning

confidence: 99%

“…Our data suggest that the PVT→NAc circuit is susceptible to opioid-induced plasticity; however, studies evaluating the function of PVT→NAc neuronal activity for opioid seeking in the self-administration paradigm have remained mixed. A recent study showed that stimulation of this pathway can modestly increase opioid seeking before, but not after, extinction learning 39 . In contrast, others showed that activation of this pathway can increase opioid seeking, but only under conditions of chronic food restriction 57 .…”

Section: Discussionmentioning

confidence: 99%

An opioid-gated thalamoaccumbal circuit for the suppression of reward seeking in mice

et al. 2022

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Suppression of dangerous or inappropriate reward-motivated behaviors is critical for survival, whereas therapeutic or recreational opioid use can unleash detrimental behavioral actions and addiction. Nevertheless, the neuronal systems that suppress maladaptive motivated behaviors remain unclear, and whether opioids disengage those systems is unknown. In a mouse model using two-photon calcium imaging in vivo, we identify paraventricular thalamostriatal neuronal ensembles that are inhibited upon sucrose self-administration and seeking, yet these neurons are tonically active when behavior is suppressed by a fear-provoking predator odor, a pharmacological stressor, or inhibitory learning. Electrophysiological, optogenetic, and chemogenetic experiments reveal that thalamostriatal neurons innervate accumbal parvalbumin interneurons through synapses enriched with calcium permeable AMPA receptors, and activity within this circuit is necessary and sufficient for the suppression of sucrose seeking regardless of the behavioral suppressor administered. Furthermore, systemic or intra-accumbal opioid injections rapidly dysregulate thalamostriatal ensemble dynamics, weaken thalamostriatal synaptic innervation of downstream neurons, and unleash reward-seeking behaviors in a manner that is reversed by genetic deletion of thalamic µ-opioid receptors. Overall, our findings reveal a thalamostriatal to parvalbumin interneuron circuit that is both required for the suppression of reward seeking and rapidly disengaged by opioids.

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“…Surprisingly, here we find that PVTàNAc neurons play a pervasive role in the suppression of reward-motivated behavior, and through an unexpected synaptic input to NAc PV interneurons. Other studies have focused on the role of PVT synaptic input to NAc D1-and D2-MSNs 13,36,37 , and have found unique functions of these pathways in other behaviors such as the expression of opioid withdrawal 13 and the retrieval of an opioid conditioned place preference memory 37 . Thus, discrete outputs from PVT to unique NAc cell types likely control distinct behavioral states, including the suppression of reward seeking as described here.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, studies evaluating the function of PVTàNAc neuronal activity for opioid seeking in the self-administration paradigm have remained mixed. A recent study showed that stimulation of this pathway can modestly increase opioid seeking before, but not after, extinction learning 36 . In contrast, others showed that activation of this pathway can increase opioid seeking, but only under conditions of chronic food restriction 44 .…”

Section: Discussionmentioning

confidence: 99%

A thalamostriatal parvalbumin interneuron circuit suppresses risky reward-motivated behaviors and is disengaged by opioids

Vollmer

Green

Grant

et al. 2022

Preprint

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Suppression of dangerous or inappropriate reward-motivated behaviors is critical for survival, whereas therapeutic or recreational opioid use can unleash risky behavioral actions and addiction. Nevertheless, the neuronal systems that suppress maladaptive motivated behaviors remain unclear, and whether opioids disengage those systems is unknown. Using two-photon calcium imaging in vivo, we identify paraventricular thalamostriatal neuronal ensembles that are inhibited upon sucrose self-administration and seeking, yet these neurons are tonically active when behavior is suppressed by a fear-provoking predator odor, a pharmacological stressor, or inhibitory learning. Electrophysiological, optogenetic, and chemogenetic experiments reveal that thalamostriatal neurons innervate accumbal parvalbumin interneurons through synapses enriched with calcium permeable AMPA receptors, and activity within this circuit is necessary and sufficient for the suppression of sucrose seeking regardless of the behavioral suppressor administered. Furthermore, systemic or intra-accumbal opioid injections rapidly dysregulate thalamostriatal ensemble dynamics, weaken thalamostriatal synaptic innervation of downstream parvalbumin interneurons, and unleash reward-seeking behaviors in a manner that is reversed by genetic deletion of thalamostriatal µ-opioid receptors. Overall, our findings reveal a thalamostriatal to parvalbumin interneuron circuit for the suppression of reward seeking that is rapidly disengaged by opioid-driven inhibition of presynaptic thalamostriatal neurons.

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Extinction blunts paraventricular thalamic contributions to heroin relapse

Cited by 20 publications

References 62 publications

Oxytocin and orexin systems bidirectionally regulate the ability of opioid cues to bias reward seeking

Oxytocin and orexin systems bidirectionally regulate the ability of opioid cues to bias reward seeking

An opioid-gated thalamoaccumbal circuit for the suppression of reward seeking in mice

A thalamostriatal parvalbumin interneuron circuit suppresses risky reward-motivated behaviors and is disengaged by opioids

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