Interleukin-6 attenuates serotonin 2a receptor signaling by activating the JAK-STAT pathway.

The serotonin 2A (5-HT2A) receptor and the proinflammatory cytokine, interleukin-6 (IL-6), have both been implicated in psychiatric disorders. Previously, we demonstrated that these molecules both facilitate cognitive flexibility, a prefrontal cortex-mediated executive function impaired in multiple mental illnesses. In this study, we tested the hypothesis that IL-6 influences 5-HT2A receptor signaling, providing a potential mechanism by which this cytokine may influence behavior. We first demonstrated that 5-HT2A receptors and IL-6-mediated STAT3 phosphorylation colocalize in cells of the prefrontal cortex, providing the neuroanatomical substrate for a potential interaction. In the neuronally derived A1A1 cell line, which expresses both IL-6 and 5-HT2A receptors, we found that IL-6 attenuates inositol phosphate (IP) accumulation in response to the 5-HT2 agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI), suggesting that IL-6 can regulate 5-HT2A receptor function. To identify the signaling pathway(s) that mediate this effect, we measured DOI-mediated IP accumulation in the presence of IL-6 and either the JAK-STAT inhibitor 124 [(9ß,10α,16α,23E)-2,16,20,25-tetrahydroxy-9-methyl-19-norlanosta-1,5,23-triene-3,11,22-trione], JSI-124, or the extracellular signal-regulated kinase inhibitor, 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD-98059). The IL-6 effect was blocked by JSI-124 but not PD-98059. Furthermore, silencing RNA knockdown of either JAK or STAT blocked the IL-6 effect, suggesting that IL-6-induced JAK-STAT activation can regulate 5-HT2A receptor signaling. Finally, to determine if IL-6 specifically regulates the 5-HT2A receptor system, we measured IP production mediated by another Gq-coupled receptor, bradykinin B2. IL-6 had no effect on bradykinin-mediated IP accumulation, suggesting that regulation may occur at the 5-HT2A receptor. These results may provide clues to the pathologic mechanisms underlying certain psychiatric disorders and may suggest novel therapeutic strategies for their treatment.

Alcohol potentiates multiple GABAergic inputs to dorsal striatum fast-spiking interneurons.

Parvalbumin-expressing dorsal striatal fast-spiking interneurons, comprising ∼1% of the total dorsal striatal neuronal population, are necessary for the expression of compulsive-like ethanol consumption mice. Fast-spiking interneurons are driven to fire by glutamatergic inputs derived primarily from the cortex. However, these neurons also receive substantial GABAergic input from two sources: the globus pallidus and the reticular nucleus of the thalamus. How ethanol modulates inhibitory input onto fast-spiking neurons is unclear and, more broadly, alcohol effects on GABAergic synaptic transmission onto GABAergic interneurons are understudied. Examining this, we found that acute bath application of ethanol (50 mM) potentiated GABAergic transmission from both the globus pallidus and the reticular nucleus of the thalamus onto fast-spiking interneurons in mouse of both sexes. This ethanol-induced potentiation required postsynaptic calcium and was not accompanied by a sustained change in presynaptic GABA release probability. Examining whether this ethanol effect persisted following chronic intermittent ethanol exposure, we found attenuated acute-ethanol potentiation of GABAergic transmission from both the globus pallidus and the reticular nucleus of the thalamus onto striatal fast-spiking interneurons. These data underscore the impact of ethanol on GABAergic signaling in the dorsal striatum and support the notion that ethanol may disinhibit the dorsolateral striatum.

Compulsive alcohol consumption is regulated by dorsal striatum fast-spiking interneurons.

Compulsive alcohol consumption is a core, treatment-resistant feature of alcohol use disorder. The dorsomedial and dorsolateral striatum support goal-directed and habitual action strategies, respectively. How ethanol targets dorsolateral striatum to drive compulsive consumption is poorly understood. Parvalbumin-expressing striatal fast-spiking interneurons comprise ~1% of the total neuronal striatal population, are enriched dorsolaterally and are functionally modulated by ethanol. To test whether fast-spiking interneurons are necessary for the development of compulsive ethanol consumption, we selectively ablated these neurons in adult male and female C57BL/6 J mice undergoing a voluntary chronic intermittent ethanol consumption paradigm followed by a compulsive ethanol drinking assay. Fast-spiking interneuron ablation curtailed the development of organized ethanol lick sequence behavior, reduced ethanol consumption, and abrogated compulsive consumption of ethanol with the added bitterant quinine. In contrast, fast-spiking interneuron ablation did not affect any index of water or sucrose consumption. These data causally implicate the minority striatal fast-spiking interneuron population as a key component of compulsive ethanol consumption.

TrkB-dependent disinhibition of the nucleus accumbens is enhanced by ethanol.

The nucleus accumbens is a critical integration center for reward-related circuitry and is comprised primarily of medium spiny projection neurons. The dynamic balance of excitation and inhibition onto medium spiny neurons determines the output of this structure. While nucleus accumbens excitatory synaptic plasticity is well-characterized, inhibitory synaptic plasticity mechanisms and their potential relevance to shaping motivated behaviors is poorly understood. Here we report the discovery of long-term depression of inhibitory synaptic transmission in the mouse nucleus accumbens core. This long-term depression is postsynaptically expressed, tropomyosin kinase B (TrkB) receptor-mediated, and augmented in the presence of ethanol. Our findings support the emerging view that TrkB signaling regulates inhibitory synaptic plasticity and suggest this mechanism in the nucleus accumbens as a target for ethanol modulation of reward.

Levels of systemic metal ions in patients with intramedullary nails.

BACKGROUND: It is being increasingly recognized that orthopedic implants are associated with adverse tissue responses, mediated by degradation products. Recent interest has been focused on the production of metal ions from hip arthroplasty. Few studies have reviewed fracture fixation devices and their metal ion production. METHODS: 61 subjects were enlisted into the study, with 3 subgroups. 21 subjects had Russell-Taylor intramedullary tibial nails in situ for 26 (21-32) months (316LVm stainless steel), 20 subjects had TriGen intramedullary tibial nails in situ for 43 (35-51) months (Ti-6Al-4V titanium alloy), and the remaining 20 subjects did not have any implant in situ and served as controls. Blood samples were taken and serum chromium, molybdenum, titanium, aluminium, and vanadium concentrations were measured using inductively coupled plasma (ICP) techniques. RESULTS: The 3 groups were matched for age, sex, and BMI. The subjects with Russell-Taylor nails had elevated levels of chromium (0.10 microg/L) with median concentrations 2.5 times higher than those of the control group. The subjects with TriGen nails had less significantly elevated levels of titanium (6.5 microg/L). INTERPRETATION: Stainless steel implants show significant differences from titanium implants in the dissemination of metal ions. Although the levels of chromium were elevated, the overall levels were modest when compared to published data regarding metal ion release and hip arthroplasty. Intramedullary nails are, however, often used in younger patients. If not removed, they may result in prolonged exposure to metal ions.

Ketamine Corrects Stress-Induced Cognitive Dysfunction through JAK2/STAT3 Signaling in the Orbitofrontal Cortex.

Deficits in cognitive flexibility are prominent in stress-related psychiatric disorders, including depression. Ketamine has rapid antidepressant efficacy, but it is unknown if ketamine improves cognitive symptoms. In rats, 2 weeks chronic intermittent cold (CIC) stress impairs reversal learning, a form of cognitive flexibility mediated by the orbitofrontal cortex (OFC) that we have used previously to model cognitive dysfunction in depression. We have shown that activating JAK2/STAT3 signaling in the OFC rescued the CIC stress-induced reversal learning deficit. Thus, in the present study we determined whether ketamine also corrects the stress-induced reversal learning deficit, and if JAK2/STAT3 signaling is involved in this effect. A single injection of ketamine (10 mg/kg, i.p.) 24 h prior to testing rescued the CIC stress-induced reversal learning deficit. CIC stress decreased JAK2 phosphorylation in the OFC, and ketamine restored pJAK2 levels within 2 h post injection. The JAK2 inhibitor AG490 given systemically or into the OFC at the time of ketamine injection prevented its beneficial effect on reversal learning. We then tested the role of JAK2/STAT3 in ketamine-induced plasticity in the OFC. Ketamine depressed local field potentials evoked in the OFC by excitatory thalamic afferent stimulation, and this was prevented by JAK2 inhibition in the OFC. Further, in both the OFC and primary cortical neurons in culture, ketamine increased expression of the neural plasticity-related protein Arc, and this was prevented by JAK2 inhibition. These results suggest that the JAK2/STAT3 signaling pathway is a novel mechanism by which ketamine exerts its therapeutic effects on stress-induced cognitive dysfunction in the OFC.

The Role of Total Elbow Arthroplasty in Complex Distal Humeral Fractures.

Fractures of the distal humerus are routinely treated by open reduction and internal fixation in an attempt to retain a painless, stable and functional joint. However, results of fixation, even with advances in plate technology, are still dependent on screw purchase and bone quality. Reported results, over the past decade, now support consideration of primary total elbow arthroplasty, in cases of highly comminuted distal humeral fractures, especially in the elderly who have low physical demands, or in those who have significant pre-existing inflammatory joint disease resulting in marked joint destruction.