Heroin-induced conditioned immunomodulation requires expression of IL-1β in the dorsal hippocampus

Szczytkowski, Jennifer L.; Lebonville, Christina L.; Hutson, Lee; Fuchs, Rita A.; Lysle, Donald T.

doi:10.1016/j.bbi.2013.01.076

Cited by 14 publications

(26 citation statements)

References 77 publications

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“…Physiological evidence that cytokines influence synaptic plasticity is also supported by behavioral evidence that central cytokine signaling influences learning in several paradigms, including fear conditioning (Yirmiya and Goshen 2011;Szczytkowski, Lebonville et al 2013). For example, acute administration of either TNF-α or IL-1β and chronic administration of interleukin-6 (IL-6) enhanced memory performance in a passive avoidance paradigm (Matsuda, Wen et al 1996;Yirmiya, Winocur et al 2002;Brennan, Beck et al 2004).…”

Section: Discussionmentioning

confidence: 98%

The Role of Brain Interleukin-1 in Stress-Enhanced Fear Learning

Jones

Lebonville

Barrus

et al. 2014

Neuropsychopharmacol

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Posttraumatic stress disorder (PTSD) has been shown to be associated with pro-inflammatory markers, including elevated plasma levels of interleukin-1β (IL-1β). However, the precise role of neuroinflammation and central immune signaling on the development of this debilitating psychological disorder is not known. Here, we used stress-enhanced fear learning (SEFL), an animal model of the disorder, to examine the role of central IL-1β in PTSD. The results show that the severe stressor in SEFL induces a time-dependent increase in IL-1β immunoreactivity and mRNA expression within the dentate gyrus of the dorsal hippocampus (DH). There was no increase in IL-1β in the basolateral amygdala or the perirhinal cortex. Moreover, blocking the action of IL-1β following the severe stressor with IL-1 receptor antagonist (10 μg, intracerebroventricular (i.c.v.), 24 and 48 h after the stressor) prevented the development of SEFL. To provide further support for the role of IL-1β in the development of SEFL, we show that systemic morphine, a treatment which is known to reduce both PTSD and SEFL, also reduces IL-1β expression in the DH induced by the severe stressor. These studies provide the first evidence that IL-1 is involved SEFL and suggest that IL-1 signaling in the brain may have a critical role in the development of PTSD.

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Section: Discussionmentioning

confidence: 98%

The Role of Brain Interleukin-1 in Stress-Enhanced Fear Learning

Jones

Lebonville

Barrus

et al. 2014

Neuropsychopharmacol

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“…This receptor also binds to IL-1 alpha (IL-1α) and mediates its action, so the specificity of IL-1β in mediating the effects seen cannot be concluded definitively. Previous studies have shown that IL-1β signaling is required for the expression of heroin conditioned immunosuppression to a context through knockdown of IL-1β expression using IL-1β siRNA (Szczytkowski et al, 2013). For the current experiment, IL-1β siRNA was not temporally specific enough to target processes only during or shortly after each conditioning session.…”

Section: Discussionmentioning

confidence: 99%

“…Rats received five, 60-min conditioning sessions every other day as in prior studies, which has been shown to be sufficient to generate conditioned immunosuppression to the heroin-paired context (Szczytkowski et al, 2011; Szczytkowski et al, 2013; Szczytkowski and Lysle, 2010). Each conditioning session involved heroin administration (US) immediately followed by placement into a conditioning chamber (BRS/LVE, Laurel, MD, USA; W 30.5 cm × D 24.1 cm × H 26.7 cm) that served as the conditioned stimulus (CS).…”

Section: Methodsmentioning

confidence: 99%

“…The effects of heroin on LPS-induced NO are also able to be conditioned to heroin-associated stimuli. Pairing heroin (US) with a distinct environmental context (CS) allows the heroin-paired context to evoke a CR in rats in that the exposure to the context alone will cause conditioned suppression of NO (Lysle and Ijames, 2002; Szczytkowski et al, 2011; Szczytkowski et al, 2013; Szczytkowski and Lysle, 2007, 2008, 2010). Research using this model has demonstrated that the basolateral amygdala, nucleus accumbens (Saurer et al, 2009; Szczytkowski and Lysle, 2008), and a circuit comprised of these regions and the ventral tegmental area is necessary for the expression of heroin conditioned immunosuppression (Szczytkowski et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…More recently, the hippocampus, a brain region heavily implicated in contextual learning (Maren and Holt, 1999; Phillips and Ledoux, 1994; Redish, 2001) has also been shown to be involved in the expression of heroin conditioned immunosuppression. Inactivation of the dorsal hippocampus (DH) using a GABA agonist cocktail, baclofen/muscimol, or knockdown of interleukin-1β (IL-1β) signaling within the DH just before testing prevented a heroin-paired context from suppressing the immune response to LPS (Szczytkowski et al, 2013). This not only suggests the requirement of the DH for the expression of heroin conditioned immunosuppression, but also implicates a novel role for brain IL-1β in this effect.…”

Section: Introductionmentioning

confidence: 99%

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Acquisition of heroin conditioned immunosuppression requires IL-1 signaling in the dorsal hippocampus

Lebonville

Jones

Hutson

et al. 2016

Brain, Behavior, and Immunity

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Opioid users experience increased incidence of infection, which may be partially attributable to both direct opiate-immune interactions and conditioned immune responses. Previous studies have investigated the neural circuitry governing opioid conditioned immune responses, but work remains to elucidate the mechanisms mediating this effect. Our laboratory has previously shown that hippocampal IL-1 signaling, specifically, is required for the expression of heroin conditioned immunosuppression following learning. The current studies were designed to further characterize the role of hippocampal IL-1 in this phenomenon by manipulating IL-1 during learning. Experiment 1 tested whether hippocampal IL-1 is also required for the acquisition of heroin conditioned immunosuppression, while Experiment 2 tested whether hippocampal IL-1 is required for the expression of unconditioned heroin immunosuppression. We found that blocking IL-1 signaling in the dorsal hippocampus with IL-1RA during each conditioning session, but not on interspersed non-conditioning days, significantly attenuated the acquisition of heroin conditioned immunosuppression. Strikingly, we found that the same IL-1RA treatment did not alter unconditioned immunosuppression to a single dose of heroin. Thus, IL-1 signaling is not a critical component of the response to heroin but rather may play a role in the formation of the association between heroin and the context. Collectively, these studies suggest that IL-1 signaling, in addition to being involved in the expression of a heroin conditioned immune response, is also involved in the acquisition of this effect. Importantly, this effect is likely not due to blocking the response to the unconditioned stimulus since IL-1RA did not affect heroin’s immunosuppressive effects.

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Considering Drug-Associated Contexts in Substance Use Disorders and Treatment Development

et al. 2020

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Environmental contexts that are reliably associated with the use of pharmacologically active substances are hypothesized to contribute to substance use disorders. In this review, we provide an updated summary of parallel preclinical and human studies that support this hypothesis. Research conducted in rats shows that environmental contexts that are reliably paired with drug use can renew extinguished drug-seeking behavior and amplify responding elicited by discrete, drug-predictive cues. Akin to drugassociated contexts, interoceptive drug stimuli produced by the psychopharmacological effects of drugs can also influence learning and memory processes that play a role in substance use disorders. Findings from human laboratory studies show that drug-associated contexts, including social stimuli, can have profound effects on cue reactivity, drug use, and drug-related cognitive expectancies. This translationally relevant research supports the idea that treatments for substance use disorders could be improved by considering drug-associated contexts as a factor in treatment interventions. We conclude this review with ideas for how to integrate drug-associated contexts into treatment-oriented research based on 4 approaches: pharmacology, brain stimulation, mindfulness-based relapse prevention, and cognitive behavioral group therapy. Throughout, we focus on alcoholand tobacco-related research, which are two of the most prevalent and commonly misused drugs worldwide for which there are known treatments.

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Heroin-induced conditioned immunomodulation requires expression of IL-1β in the dorsal hippocampus

Cited by 14 publications

References 77 publications

The Role of Brain Interleukin-1 in Stress-Enhanced Fear Learning

The Role of Brain Interleukin-1 in Stress-Enhanced Fear Learning

Acquisition of heroin conditioned immunosuppression requires IL-1 signaling in the dorsal hippocampus

Considering Drug-Associated Contexts in Substance Use Disorders and Treatment Development

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