GABAergic actions mediate opposite ethanol effects on dopaminergic neurons in the anterior and posterior ventral tegmental area

It is known that the posterior ventral tegmental area (p-VTA) differs from the anterior VTA (a-VTA) in that rats learn to self-administer ethanol into the p-VTA, but not into the a-VTA. Because activation of VTA dopaminergic neurons by ethanol is a cellular mechanism underlying the reinforcement of ethanol consumption, we hypothesized that ethanol may exert different effects on dopaminergic neurons in the p-VTA and a-VTA. In patch-clamp recordings in midbrain slices from young rats (postnatal days 22-32), we detected no significant difference in electrophysiological properties between p-VTA and a-VTA dopaminergic neurons. However, acute exposure to ethanol (21-86 mM) stimulated p-VTA dopaminergic neurons but suppressed a-VTA dopaminergic neurons. Conversely, ethanol (>21 mM) dose-dependently reduced the frequency of the GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs) generated by inhibitory neuronal firing but not miniature inhibitory postsynaptic currents (mIPSCs) in p-VTA dopaminergic neurons. By contrast, ethanol increased the frequency and amplitude of both sIPSCs and mIPSCs in a-VTA dopaminergic neurons. All of these effects of ethanol were abolished by a GABA(A) receptor antagonist. There was a strong negative correlation between ethanol-evoked modulation of sIPSCs and neuronal firing in VTA dopaminergic neurons. These results indicate that GABAergic inputs play an important role in ethanol's actions in the VTA. The differential effects of ethanol on sIPSCs and neuronal firing in the p-VTA and a-VTA could be the basis for ethanol reinforcement via the p-VTA.     

Primary leiomyosarcoma of the thyroid gland with prior malignancy and radiotherapy:A case report and review of literature

BACKGROUND Leiomyosarcoma(LMS) of the thyroid gland is a rarely presented tumor that offers poor prognosis. To the best of the authors' knowledge, there currently exist only 28 known cases described in the literature(limited to English).CASE SUMMARY Herein a case is reported of a 60-year-old female patient who had an LMS of the thyroid, which was accompanied by periodic dysphonia and breathing disorder as well as the feeling of pressure in the chest and neck. At the time the disease was diagnosed, no metastases were detected. Prior to the diagnosis, the patient experienced a uterine adenocarcinoma that had been treated by surgical procedure and radiotherapy. For the LMS, a total thyroidectomy was performed,followed by radiotherapy. Since metastases were also discovered in the lungs,sternum, and femur, chemotherapy was administered as well.Immunohistochemically, the tumor cells in the thyroid indicated positively for alpha smooth muscle actin, calponin, and H-caldesmon, but were negative for CD34, p63, estrogen receptor, progesterone receptor, and Epstein-Barr virus.CONCLUSION Although the etiology of the LMS is as of yet unknown, prior malignancy and radiation should be considered as risk factors.     

Anoxia produces smaller changes in synaptic transmission, membrane potential, and input resistance in immature rat hippocampus

1. The reversible blocking effect of brief anoxia (2-4 min) on synaptic transmission was studied in submerged hippocampal slices (kept mostly at 34 degrees), obtained from adult (greater than 120 g) and very young (6-50 g) Wistar rats. Excitatory postsynaptic potentials (EPSPs) were recorded with extra- and intracellular electrodes, sometimes simultaneously: in CA1, they were evoked by stratum radiation stimulation, in CA3 by hilar stimulation. 2. In slices from adults, EPSPs in CA1 were depressed by 90% after 2 min of anoxia, and postanoxic recovery was relatively slow (one-half recovery times 4.0 +/- 0.23 min, mean +/- SE). EPSPs in CA3 were consistently more resistant, especially those generated by mossy fibers; after 2 min of anoxia, these were reduced by only 14.7 +/- 5.4%. 3. In newborn animals (PN1-4), both intra- and extracellular EPSPs (but no population spikes) could be recorded in CA1. Although smaller and more fatigable than in the adult, they were much more resistant to anoxia, after 2 min being reduced by only 44.1 +/- 8.8%; and they were not abolished even after 6-7 min. On the other hand, postanoxic recovery was very rapid, being one-half complete in 2.4 +/- 0.48 min. Only large and very prolonged (giant) depolarizing PSPs [probably inhibitory postsynaptic potentials (IPSPs)] could be recorded in CA3 neurons; they were rapidly blocked by anoxia. 4. In older pups (PN6-21), the CA1 EPSPs became progressively more sensitive to anoxia. At the end of the second week, they were as rapidly blocked as in slices from adults; but postanoxic recovery remained quicker throughout this period. In CA3, EPSPs could now be evoked that were as resistant to anoxia as in adult slices. 5. In both CA1 and CA3 neurons from adult rats, anoxia (for 2-3 min) reduced the input resistance (RN) by 45.7 +/- 6.25%. In CA1 neurons, there was most often some hyperpolarization (-7.2 +/- 1.8 mV), which was less consistent in CA3 cells. The return of O2 typically led to a second (postanoxic) phase of hyperpolarization (-7.9 +/- 1.93 mV). 6. At PN1-4, the resting potential (Vm) of most cells had to be maintained by current injection; the input resistance (RN) of CA1 neurons was 70% higher than in mature cells, and there was little time-dependent inward rectification. Anoxia produced no regular changes in Vm, and reductions in RN were very small (by only 9.6 +/- 5.0%). A postanoxic hyperpolarization was seen in only 2 neurons out of 11.(ABSTRACT TRUNCATED AT 400 WORDS)     

Anoxia on slow inward currents of immature hippocampal neurons

1. The effects of brief anoxia (2-4 min) on membrane currents--especially the tetrodotoxin (TTX)-insensitive, Cd2+-sensitive slow inward currents, presumed to be Ca2+ currents--were studied by single-electrode voltage clamp in CA1 and CA3 neurons in submerged hippocampal slices from adult and newborn Wistar rats (PN1-13). 2. In mature neurons, anoxia had no effect on Q-type inward relaxations, but slowly activating C-type outward currents were depressed. The most striking change was the suppression of Ca inward currents (especially the slowly inactivating L-type, by greater than 95%). This effect of anoxia was not sensitive to the N-methyl-D-aspartate (NMDA) receptor blocker, D-aminophosphonovalerate. Anoxia also reversibly abolished the NMDA-evoked inward current. 3. In neurons from newborn animals (PN1-6), Q-type inward relaxations and postanoxic outward currents were very small or undetectable. The slow inward (Ca) currents were smaller than in mature cells, but they showed a clearer separation between low-threshold, fast-inactivating and high-threshold, slowly inactivating currents. Both types of current were more resistant to anoxia (mean depression of L-type was by only 53.3 +/- 5.6%, mean +/- SE). 4. In such immature neurons, the NMDA-evoked inward currents were also more resistant to anoxia. 5. By PN7-13, increasing maturation was reflected in 1) larger voltage-dependent inward currents, 2) increasingly evident Q-type relaxations and postanoxic outward currents, and 3) near-complete blockade of inward currents by anoxia (at PN11-13, mean depression of L-type currents was by 98.5 +/- 1.5%).     

Unlike 2-deoxy-D-glucose, 3-O-methyl-D-glucose does not induce long-term potentiation in rat hippocampal slices

Equimolar replacement of 10 mM glucose by 2-deoxy-D-glucose (2-DG) causes substantial depression followed by a sharp and sustained potentiation of CA1 field EPSPs. In the present experiments, similar applications of 3-O-methyl-D-glucose, which is also taken up by cells but is not phosphorylated, had only a weak blocking action and elicited no potentiation. Possible explanations for the marked effects of 2-DG include a more rapid block of glycolysis and the production of phosphorylated derivatives of 2-DG.     

Salsolinol stimulates dopamine neurons in slices of posterior ventral tegmental area indirectly by activating μ-opioid receptors

Previous studies in vivo have shown that salsolinol, the condensation product of acetaldehyde and dopamine, has properties that may contribute to alcohol abuse. Although opioid receptors, especially the μ-opioid receptors (MORs), may be involved, the cellular mechanisms mediating the effects of salsolinol have not been fully explored. In the current study, we used whole-cell patch-clamp recordings to examine the effects of salsolinol on dopamine neurons of the ventral tegmental area (VTA) in acute brain slices from Sprague-Dawley rats. Salsolinol (0.01-1 μM) dose-dependently and reversibly increased the ongoing firing of dopamine neurons; this effect was blocked by naltrexone, an antagonist of MORs, and gabazine, an antagonist of GABA(A) receptors. We further showed that salsolinol reduced the frequency without altering the amplitude of spontaneous GABA(A) receptor-mediated inhibitory postsynaptic currents in dopamine neurons. The salsolinol-induced reduction was blocked by both naltrexone and [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin, an agonist of MORs. Thus, salsolinol excites VTA-dopamine neurons indirectly by activating MORs, which inhibit GABA neurons in the VTA. This form of disinhibition seems to be a novel mechanism underlying the effects of salsolinol.