Cutaneous melanocytoneuroma: the first case of a distinctive intraneural tumor with dual nerve sheath and melanocytic differentiation.

Many melanocytic nevi contain areas similar to nerve sheath tumors (NST) and NSTs with melanin have been described. There are some NSTs with at least partial intraneural location, including neurofibromas, plexiform neurofibromas, granular cell tumors and the recently described, dendritic cell neurofibroma with pseudorosettes. We describe the case of an NST with melanocytic differentiation and intraneural location, for which we suggest the term 'melanocytoneuroma' (MCN). It arose in the skin of a 67-year-old woman with no previous history of melanoma or neurofibromatosis. The lesion presented as a papule and histologically consisted of a dermal nodule without junctional melanocytic activity. The lesion comprised an intraneural proliferation of large epithelioid eosinophilic cells with prominent cell borders imparting a 'plant-like' appearance. The cells were also seen within adjacent nerve twigs and were positive for S100, Melan-A, HMB-45, microphthalmia transcription factor and PGP 9.5. The lesion was entirely surrounded by an epithelial membrane antigen-positive-perineurial coat and the individual tumor cells were invested by laminin and collagen type-IV-positive basal lamina-like material. The lesion did not show any evidence of atypia and following complete excision, no recurrence has been documented. In conclusion, this unusual lesion represents an intraneural proliferation with melanocytic and nerve sheath cell differentiation, to which we have accorded the appellation, MCN

Distribution and localization of the GABAB receptor

The functional GABAB receptors (GABABRs) are formed by obligate heteromers composed of two principal subunits named GABAB1 and GABAB2. In Drosophila melanogaster three GABAB subunits have been identified: GB1, GB2 and GB3. The GB1 and GB2 subunits need to be co-expressed in Xenopus oocytes or in mammalian cell lines to produce functional GABABRs. A subfamily of potassium channel tetramerization domain-containing (KCTD8, 12, 12b, and 16) proteins that are constituents of native GABABRs were recently identified. KCTDs show a temporal and spatial distribution pattern that may contribute to the heterogeneity of native GABABRs and their pharmacological properties. Of several isoforms of the GABAB1 subunit identified to date, the most abundant in the brain are the isoforms 1a and 1b; they are co-expressed with the subunit GABAB2 and their expression differs across brain and neuronal populations. GABAB1a localizes to glutamatergic terminals and is necessary for hetero-receptor function. Both isoforms 1a and 1b are detected in dendrites, but only GABAB1b in spine heads. Electron microscopy studies show that in the central nervous system (CNS), GABAB1 and GABAB2 are both pre and postsynaptic, but mostly localize to postsynaptic sites. The GABAB1(a/b) and GABAB2 subunits show an overlapping pattern of distribution throughout the CNS with certain exceptions (i.e. caudate-putamen and cerebellum). GABABRs are also detected in Schwann cells, in several peripheral tissues, and in non-neuronal cells (cardiomyocytes and airway smooth muscle). The widespread distribution of GABABRs in the CNS and the periphery reflects their physiological, pathophysiological, and pharmacological relevance

Changes in Central Sodium and not Osmolarity or Lactate Induce Panic-Like Responses in a Model of Panic Disorder

Panic disorder is a severe anxiety disorder characterized by recurrent panic attacks that can be consistently provoked with intravenous (i.v.) infusions of hypertonic (0.5 M) sodium lactate (NaLac), yet the mechanism/CNS site by which this stimulus triggers panic attacks is unclear. Chronic inhibition of GABAergic synthesis in the dorsomedial hypothalamus/perifornical region (DMH/PeF) of rats induces a vulnerability to panic-like responses after i.v. infusion of 0.5 M NaLac, providing an animal model of panic disorder. Using this panic model, we previously showed that inhibiting the anterior third ventricle region (A3Vr; containing the organum vasculosum lamina terminalis, the median preoptic nucleus, and anteroventral periventricular nucleus) attenuates cardiorespiratory and behavioral responses elicited by i.v. infusions of NaLac. In this study, we show that i.v. infusions of 0.5 M NaLac or sodium chloride, but not iso-osmolar -mannitol, increased ‘anxiety' (decreased social interaction) behaviors, heart rate, and blood pressure responses. Using whole-cell patch-clamp preparations, we also show that bath applications of NaLac (positive control), but not lactic acid (lactate stimulus) or -mannitol (osmolar stimulus), increases the firing rates of neurons in the A3Vr, which are retrogradely labeled from the DMH/PeF and which are most likely glutamatergic based on a separate study using retrograde tracing from the DMH/PeF in combination with in situ hybridization for vesicular glutamate transporter 2. These data show that hypertonic sodium, but not hyper-osmolarity or changes in lactate, is the key stimulus that provokes panic attacks in panic disorder, and is consistent with human studies