Double Dissociation of Monoacylglycerol Lipase Inhibition and CB1 Antagonism in the Central Amygdala, Basolateral Amygdala, and the Interoceptive Insular Cortex on the Affective Properties of Acute Naloxone-Precipitated Morphine Withdrawal in Rats

This study investigates the role of the endocannabinoid 2-arachidonyl glycerol (2-AG) in regulating acute and anticipatory nausea in rats using the conditioned gaping model. The animals were systemically pretreated with MJN110, a selective monoacylglycerol lipase (MAGL) inhibitor, to enhance endogenous levels of 2-AG. Acute nausea was assessed using the taste reactivity model in which a flavour, saccharin, was paired with the administration of the emetic agent, lithium chloride (LiCl). Anticipatory nausea was assessed using a model of contextually elicited conditioned gaping in which a context was paired with the emetic agent, LiCl. Results indicated that MJN110 at the 10.0 mg kg-1 and 20.0 mg kg-1 dosage significantly attenuated acute and anticipatory nausea, as displayed by the significant reduction in mean number of gapes. This suppression was mediated by CB1 receptor activation as displayed by reversal of such effects when MJN110 was coadministered with the CB1 receptor antagonist, SR 141716. The results suggest that enhancement of endogenous 2-AG levels by MAGL inhibition may have anti-emetic potential. Keywords: 2-arachidonyl glycerol; monoacylglycerol lipase; endocannabinoid; nausea; conditioned gaping; CB1 receptor

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Basolateral and central amygdala orchestrate how we learn whom to trust

Communications Biology ◽

10.1038/s42003-021-02815-6 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Ronald Sladky ◽

Federica Riva ◽

Lisa Anna Rosenberger ◽

Jack van Honk ◽

Claus Lamm

Keyword(s):

Nucleus Accumbens ◽

Choice Behavior ◽

Basolateral Amygdala ◽

Outcome Evaluation ◽

Reward Processing ◽

Trust Game ◽

Central Amygdala ◽

Learning Success ◽

Fmri Study ◽

Human Neuroimaging

AbstractCooperation and mutual trust are essential in our society, yet not everybody is trustworthy. In this fMRI study, 62 healthy volunteers performed a repeated trust game, placing trust in a trustworthy or an untrustworthy player. We found that the central amygdala was active during trust behavior planning while the basolateral amygdala was active during outcome evaluation. When planning the trust behavior, central and basolateral amygdala activation was stronger for the untrustworthy player compared to the trustworthy player but only in participants who actually learned to differentiate the trustworthiness of the players. Independent of learning success, nucleus accumbens encoded whether trust was reciprocated. This suggests that learning whom to trust is not related to reward processing in the nucleus accumbens, but rather to engagement of the amygdala. Our study overcomes major empirical gaps between animal models and human neuroimaging and shows how different subnuclei of the amygdala and connected areas orchestrate learning to form different subjective trustworthiness beliefs about others and guide trust choice behavior.

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In amygdala we trust: different contributions of the basolateral and central amygdala in learning whom to trust

10.1101/2021.05.03.442429 ◽

2021 ◽

Author(s):

Ronald Sladky ◽

Federica Riva ◽

Lisa Rosenberger ◽

Jack van Honk ◽

Claus Lamm

Keyword(s):

Basolateral Amygdala ◽

Human Subjects ◽

Brain Structures ◽

Trust Game ◽

Rodent Models ◽

Mutual Trust ◽

Central Amygdala ◽

Interaction Partners ◽

Improved Learning

Human societies are built on cooperation and mutual trust, but not everybody is trustworthy. Research on rodents suggests an essential role of the basolateral amygdala (BLA) in learning from social experiences (Hernandez-Lallement J et al., 2016), which was also confirmed in human subjects with selective bilateral BLA damage as they failed to adapt their trust behavior towards trustworthy vs. untrustworthy interaction partners (Rosenberger LA et al., 2019). However, neuroimaging in neurotypical populations did not consistently report involvement of the amygdala in trust behavior. This might be explained by the difficulty of differentiating between amygdala's structurally and functionally different subnuclei, i.e., the BLA and central amygdala (CeA), which have even antagonistic features particularly in trust behavior (van Honk J et al., 2013). Here, we used fMRI of the amygdala subnuclei of neurotypical adults (n=31f/31m) engaging in the repeated trust game. Our data show that both the BLA and the CeA play a role and indeed differentially: While the BLA was most active when obtaining feedback on whether invested trust had been reciprocated or not, the CeA was most active when subjects were preparing their next trust decision. In the latter phase, improved learning was associated with higher activation differences in response to untrustworthy vs. trustworthy trustees, in both BLA and CeA. Our data not only translate to rodent models and support our earlier findings in BLA-damaged subjects, but also show the specific contributions of other brain structures in the amygdala-centered network in learning whom to trust, and better not to trust.

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Spontaneous and Naloxone-Precipitated Withdrawal Behaviors From Chronic Opiates are Accompanied by Changes in N-Oleoylglycine and N-Oleoylalanine Levels in the Brain and Ameliorated by Treatment With These Mediators

Frontiers in Pharmacology ◽

10.3389/fphar.2021.706703 ◽

2021 ◽

Vol 12 ◽

Author(s):

Samantha M. Ayoub ◽

Fabiana Piscitelli ◽

Cristoforo Silvestri ◽

Cheryl L. Limebeer ◽

Erin M. Rock ◽

...

Keyword(s):

Steady State ◽

Nucleus Accumbens ◽

Chronic Exposure ◽

Insular Cortex ◽

Morphine Withdrawal ◽

Opiate Withdrawal ◽

Microbiota Composition ◽

Sprague Dawley ◽

Self Administration ◽

Colonic Microbiota

Rationale: The endocannabinoidome mediators, N-Oleoylglycine (OlGly) and N-Oleoylalanine (OlAla), have been shown to reduce acute naloxone-precipitated morphine withdrawal affective and somatic responses.Objectives: To determine the role and mechanism of action of OlGly and OlAla in withdrawal responses from chronic exposure to opiates in male Sprague-Dawley rats.Methods: Opiate withdrawal was produced: 1) spontaneously 24 h following chronic exposure to escalating doses of morphine over 14 days (Experiments 1 and 2) and steady-state exposure to heroin by minipumps for 12 days (Experiment 3), 2) by naloxone injection during steady-state heroin exposure (Experiment 4), 3) by naloxone injection during operant heroin self-administration (Experiment 5).Results: In Experiment 1, spontaneous morphine withdrawal produced somatic withdrawal reactions. The behavioral withdrawal reactions were accompanied by suppressed endogenous levels of OlGly in the nucleus accumbens, amygdala, and prefrontal cortex, N-Arachidonylglycerol and OlAla in the amygdala, 2-arachidonoylglycerol in the nucleus accumbens, amygdala and interoceptive insular cortex, and by changes in colonic microbiota composition. In Experiment 2, treatment with OlAla, but not OlGly, reduced spontaneous morphine withdrawal responses. In Experiment 3, OlAla attenuated spontaneous steady-state heroin withdrawal responses at both 5 and 20 mg/kg; OlGly only reduced withdrawal responses at the higher dose of 20 mg/kg. Experiment 4 demonstrated that naloxone-precipitated heroin withdrawal from steady-state exposure to heroin (7 mg/kg/day for 12 days) is accompanied by tissue-specific changes in brain or gut endocannabinoidome mediator, including OlGly and OlAla, levels and colonic microbiota composition, and that OlAla (5 mg/kg) attenuated behavioural withdrawal reactions, while also reversing some of the changes in brain and gut endocannabinoidome and gut microbiota induced by naloxone. Experiment 5 demonstrated that although OlAla (5 mg/kg) did not interfere with operant heroin self-administration on its own, it blocked naloxone-precipitated elevation of heroin self-administration behavior.Conclusion: These results suggest that OlAla and OlGly are two endogenous mediators whose brain concentrations respond to chronic opiate treatment and withdrawal concomitantly with changes in colon microbiota composition, and that OlAla may be more effective than OlGly in suppressing chronic opiate withdrawal responses.

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