An Unusual Case of Cryoglobulinemic Vasculitis and Acute Disseminating Encephalomyelitis in a 21-Year-Old Caucasian Male.

Cryoglobulinemic vasculitis and acute disseminated encephalomyelitis (ADEM) are characterized by damage to either blood vessels or grey matter. For both diseases, infections can be an etiology. In cryoglobulinemic vasculitis, the initial insult causes damage to the glomerulus, and in the case of ADEM, damage leads to a central nervous system demyelinating disorder. Infective endocarditis can be associated with both diseases and can be challenging to diagnose. Individuals on antibiotics may present with negative blood cultures, making underlying infective endocarditis difficult to diagnose. In this report, we describe a 21-year-old male who presented to the hospital after an assault with splenic laceration and was subsequently found to have infective endocarditis associated with cryoglobulinemic vasculitis and ADEM.

Cell-type specific expression and behavioral impact of galanin and GalR1 in the locus coeruleus during opioid withdrawal.

The neuropeptide galanin is reported to attenuate opioid withdrawal symptoms, potentially by reducing neuronal hyperactivity in the noradrenergic locus coeruleus (LC) via galanin receptor 1 (GalR1). We evaluated this mechanism by using RNAscope in situ hybridization to characterize GalR1 mRNA distribution in the dorsal pons and to compare galanin and GalR1 mRNA expression in tyrosine hydroxylase-positive (TH+) LC cells at baseline and following chronic morphine or precipitated withdrawal. We then used genetically altered mouse lines and pharmacology to test whether noradrenergic galanin (NE-Gal) modulates withdrawal symptoms. RNAscope revealed that, while GalR1 signal was evident in the dorsal pons, 80.7% of the signal was attributable to TH- neurons outside the LC. Galanin and TH mRNA were abundant in LC cells at baseline and were further increased by withdrawal, whereas low basal GalR1 mRNA expression was unaltered by chronic morphine or withdrawal. Naloxone-precipitated withdrawal symptoms in mice lacking NE-Gal (GalcKO-Dbh ) were largely similar to WT littermates, indicating that loss of NE-Gal does not exacerbate withdrawal. Complementary experiments using NE-Gal overexpressor mice (NE-Gal OX) and systemic administration of the galanin receptor agonist galnon revealed that increasing galanin signaling also failed to alter behavioral withdrawal, while suppressing noradrenergic transmission with the alpha-2 adrenergic receptor agonist clonidine attenuated multiple symptoms. These results indicate that galanin does not acutely attenuate precipitated opioid withdrawal via an LC-specific mechanism, which has important implications for the general role of galanin in regulation of somatic and affective opioid responses and LC activity.

Loss of ß-arrestin2 in D2 cells alters neuronal excitability in the nucleus accumbens and behavioral responses to psychostimulants and opioids.

Psychostimulants and opioids increase dopamine (DA) neurotransmission, activating D1 and D2 G protein-coupled receptors. ß-arrestin2 (ßarr2) desensitizes and internalizes these receptors and initiates G protein-independent signaling. Previous work revealed that mice with a global or cell-specific knockout of ßarr2 have altered responses to certain drugs; however, the effects of ßarr2 on the excitability of medium spiny neurons (MSNs), and its role in mediating the rewarding effects of drugs of abuse are unknown. D1-Cre and D2-Cre transgenic mice were crossed with floxed ßarr2 mice to eliminate ßarr2 specifically in cells containing either D1 (D1ßarr2-KO ) or D2 (D2ßarr2-KO ) receptors. We used slice electrophysiology to characterize the role of ßarr2 in modulating D1 and D2 nucleus accumbens MSN intrinsic excitability in response to DA and tested the locomotor-activating and rewarding effects of cocaine and morphine in these mice. Eliminating ßarr2 attenuated the ability of DA to inhibit D2-MSNs and altered the DA-induced maximum firing rate in D1-MSNs. While D1ßarr2-KO mice had mostly normal drug responses, D2ßarr2-KO mice showed dose-dependent reductions in acute locomotor responses to cocaine and morphine, attenuated locomotor sensitization to cocaine, and blunted cocaine reward measured with conditioned place preference. Both D2ßarr2-KO and D1ßarr2-KO mice displayed an enhanced conditioned place preference for the highest dose of morphine. These results indicate that D1- and D2-derived ßarr2 functionally contribute to DA-induced changes in MSN intrinsic excitability and behavioral responses to psychostimulants and opioids dose-dependently.

Noradrenergic Transmission at Alpha1-Adrenergic Receptors in the Ventral Periaqueductal Gray Modulates Arousal.

BACKGROUND: Dysregulation of arousal is symptomatic of numerous psychiatric disorders. Previous research has shown that the activity of dopamine (DA) neurons in the ventral periaqueductal gray (vPAG) tracks with arousal state, and lesions of vPAGDA cells increase sleep. However, the circuitry controlling these wake-promoting DA neurons is unknown. METHODS: This study combined designer receptors exclusively activated by designer drugs (DREADDs), behavioral pharmacology, electrophysiology, and immunoelectron microscopy in male and female mice to elucidate mechanisms in the vPAG that promote arousal. RESULTS: Activation of locus coeruleus projections to the vPAG or vPAGDA neurons induced by DREADDs promoted arousal. Similarly, agonist stimulation of vPAG alpha1-adrenergic receptors (α1ARs) increased latency to fall asleep, whereas α1AR blockade had the opposite effect. α1AR stimulation drove vPAGDA activity in a glutamate-dependent, action potential-independent manner. Compared with other dopaminergic brain regions, α1ARs were enriched on astrocytes in the vPAG, and mimicking α1AR transmission specifically in vPAG astrocytes via Gq-DREADDS was sufficient to increase arousal. In general, the wake-promoting effects observed were not accompanied by hyperactivity. CONCLUSIONS: These experiments revealed that vPAG α1ARs increase arousal, promote glutamatergic input onto vPAGDA neurons, and are abundantly expressed on astrocytes. Activation of locus coeruleus inputs, vPAG astrocytes, or vPAGDA neurons increase sleep latency but do not produce hyperactivity. Together, these results support an arousal circuit whereby noradrenergic transmission at astrocytic α1ARs activates wake-promoting vPAGDA neurons via glutamate transmission.