Neurocircuitry basis of the opioid use disorder–post-traumatic stress disorder comorbid state: conceptual analyses using a dimensional framework

Upadhyay, Jaymin; Verrico, Christopher D.; Cay, Mariesa; Kodele, Sanda; Yammine, Luba; Koob, George F.; Schreiber, Rudy

doi:10.1016/s2215-0366(21)00008-0

Cited by 10 publications

(5 citation statements)

References 133 publications

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“…90 Similarly, whereas some observational studies find that chronic opioid use worsens PTSD outcomes, 91 there is preclinical work motivating the further study of opioid subtype-specific targeting (e.g., partial MOR1 agonism, κ-type opioid receptor [KOR1] antagonism) in the treatment of comorbid PTSD and opioid use disorders. 92 Analyses in better-powered datasets may identify drug repositioning opportunities and could use the predicted effect of associated variants on gene expression to indicate whether drug candidates would be beneficial or contraindicated in people with PTSD.…”

Section: Discussionmentioning

confidence: 99%

Discovery of 95 PTSD loci provides insight into genetic architecture and neurobiology of trauma and stress-related disorders

Nievergelt,

Maihofer,

Atkinson

et al. 2023

Preprint

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Posttraumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 novel). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (e.g.,GRIA1, GRM8, CACNA1E), developmental, axon guidance, and transcription factors (e.g.,FOXP2, EFNA5, DCC), synaptic structure and function genes (e.g.,PCLO, NCAM1, PDE4B), and endocrine or immune regulators (e.g.,ESR1, TRAF3, TANK). Additional top genes influence stress, immune, fear, and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.

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Section: Discussionmentioning

confidence: 99%

Discovery of 95 PTSD loci provides insight into genetic architecture and neurobiology of trauma and stress-related disorders

Nievergelt,

Maihofer,

Atkinson

et al. 2023

Preprint

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“…An important caveat for such potential applications is that male rats were used in the present study. Sex differences in the noradrenergic and corticotropin release factor systems have been described in rats (e.g., Cason et al, 2016;den Hartog et al, 2020), and there is significant clinical evidence for sex-and gender-related variability in PSTD and SUD (Koob, 2021;Upadhyay et al, 2021). Further work will also be needed to identify the inputs and mechanisms involved on both time-scales.…”

Section: Discussionmentioning

confidence: 99%

Regulation of cocaine seeking behavior by locus coeruleus noradrenergic activity in the ventral tegmental area is time- and contingency-dependent

et al. 2022

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Substance use disorder is linked to impairments in the ventral tegmental area (VTA) dopamine (DA) reward system. Noradrenergic (NA) inputs from locus coeruleus (LC) into VTA have been shown to modulate VTA neuronal activity, and are implicated in psychostimulant effects. Phasic LC activity controls time- and context-sensitive processes: decision making, cognitive flexibility, motivation and attention. However, it is not yet known how such temporally-distinct LC activity contributes to cocaine seeking. In a previous study we demonstrated that pharmacological inhibition of NA signaling in VTA specifically attenuates cocaine-seeking. Here, we used virally-delivered opsins to target LC neurons for inhibition or excitation, delivered onto afferents in VTA of male rats seeking cocaine under extinction conditions. Optogenetic stimulation or inhibition was delivered in distinct conditions: upon active lever press, contingently with discreet cues; or non-contingently, i.e., throughout the cocaine seeking session. Non-contingent inhibition of LC noradrenergic terminals in VTA attenuated cocaine seeking under extinction conditions. In contrast, contingent inhibition increased, while contingent stimulation reduced cocaine seeking. These findings were specific for cocaine, but not natural reward (food) seeking. Our results show that NA release in VTA drives behavior depending on timing and contingency between stimuli – context, discreet conditioned cues and reinforcer availability. We show that, depending on those factors, noradrenergic signaling in VTA has opposing roles, either driving CS-induced drug seeking, or contributing to behavioral flexibility and thus extinction.

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“…Similarly, prior studies showing reduced sensitivity at α 2 ‐ARs either used male subjects (Fox et al, 2015, 2017; McElligott et al, 2013), or used counterbalancedd males and females, but did not report on sex differences in α 2 ‐AR signaling and NA uptake (Schmidt et al, 2019). While demanding, obtaining detailed information about male/female variations in NA regulation after stress would be advantageous, as both NA and corticotropin systems exhibit sex differences in animals (Cason et al, 2016; den Hartog et al, 2020), and there is strong evidence for sex and gender as important factors influencing mental health outcomes in the clinic (Koob, 2021; Upadhyay et al, 2021). Secondly, while FSCV measurements performed in anesthetized rats in combination with pharmacological tools have provided valuable insights into catecholamine signaling in VTA, NAc, BNST, and BLA (Deal et al, 2021; Kielbinski et al, 2019; Park et al, 2017; Schmidt et al, 2019), insights from other techniques should be used to confirm and extend these findings.…”

Section: Discussionmentioning

confidence: 99%

“…Stress‐related adaptations in the catecholaminergic systems could be relevant for affective and drug use disorders (Belujon & Grace, 2017; Caccamise et al, 2021; Koob, 2021; Sofuoglu & Sewell, 2009). With α 2 ‐AR agonists being proposed for clinical use in the treatment of these disorders (Gowing et al, 2016; Sofuoglu et al, 2014; Upadhyay et al, 2021), a better understanding of neuroadaptations in the NA system across the brain could translate into future advances in treatment.…”

Section: Discussionmentioning

confidence: 99%

Acute stress modulates noradrenergic signaling in the ventral tegmental area‐amygdalar circuit

Kielbinski

Bernacka

Zajda

et al. 2022

Journal of Neurochemistry

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Noradrenergic neurotransmission is a critical mediator of stress responses. In turn, exposure to stress induces noradrenergic system adaptations, some of which are implicated in the etiology of stress-related disorders. Adrenergic receptors (ARs) in the ventral tegmental area (VTA) have been demonstrated to regulate phasic dopamine (DA) release in the forebrain, necessary for behavioral responses to conditional cues.However, the impact of stress on noradrenergic modulation of the VTA has not been previously explored. We demonstrate that ARs in the VTA regulate dopaminergic activity in the VTA-BLA (basolateral amygdala) circuit, a key system for processing stress-related stimuli; and that such control is altered by acute stress. We utilized fast-scan cyclic voltammetry to assess the effects of intra-VTA microinfusion of α 1 -AR and α 2 -AR antagonists (terazosin and RX-821002, respectively), on electrically evoked phasic DA release in the BLA in stress-naïve and stressed (unavoidable electric shocks -UES) anesthetized male Sprague-Dawley rats. In addition, we used western blotting to explore UES-induced alterations in AR protein level in the VTA. Intra-VTA terazosin or RX-821002 dose-dependently attenuated DA release in the BLA. Interestingly, UES decreased the effects of intra-VTA α 2 -AR blockade on DA release (24 h but not 7 days after stress), while the effects of terazosin were unchanged. Despite changes in α 2 -AR physiological function in the VTA, UES did not alter α 2 -AR protein levels in either intracellular or membrane fractions. These findings demonstrate that NA-ergic modulation of the VTA-BLA circuit undergoes significant alterations in response to acute stress, with α 2 -AR signaling indicated as a key target.

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Neurocircuitry basis of the opioid use disorder–post-traumatic stress disorder comorbid state: conceptual analyses using a dimensional framework

Cited by 10 publications

References 133 publications

Discovery of 95 PTSD loci provides insight into genetic architecture and neurobiology of trauma and stress-related disorders

Discovery of 95 PTSD loci provides insight into genetic architecture and neurobiology of trauma and stress-related disorders

Regulation of cocaine seeking behavior by locus coeruleus noradrenergic activity in the ventral tegmental area is time- and contingency-dependent

Acute stress modulates noradrenergic signaling in the ventral tegmental area‐amygdalar circuit

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