Modeling the impact of alcohol on cortical development in a dish: strategies from mapping neural stem cell fate.

During the second trimester period, neuroepithelial stem cells give birth to millions of new neuroblasts, which migrate away from their germinal zones to populate the developing brain and terminally differentiate into neurons. During this period, large numbers of cells are also eliminated by programmed cell death. Therefore, the second trimester constitutes an important critical period for neuronal proliferation, migration, differentiation and apoptosis.

Chronic ethanol exposure inhibits dopamine release via effects on the presynaptic actin cytoskeleton in PC12 cells.

An increase in nucleus accumbens dopamine release appears to mediate the "rewarding" properties of drugs of abuse. Using PC12 cells, it has been shown that chronic ethanol exposure can significantly reduce nicotine-stimulated dopamine release. Here, a novel mechanism of ethanol in regulating presynaptic dopamine release is demonstrated.

The interactive effect of alcohol and nicotine on NGF-treated pheochromocytoma cells.

Previous studies have reported that alcohol exposure reduces the number of neuronal-like pheochromocytoma (PC12) cells in culture. In this study, the interactive effect of coexposure of alcohol and nicotine on PC12 cell numbers was examined in comparison with the effect derived from alcohol or nicotine exposure individually. Moreover, the role of apoptosis in mediating changes in PC12 cell numbers was also investigated.

Chronic ethanol exposure increases microtubule content in PC12 cells.

Background: Chronic ethanol exposure has been shown to result in changes in neuronal cyto-architecture such as aberrant sprouting and alteration of neurite outgrowth. In PC12 cells, chronic ethanol treatment produces an increase in Nerve Growth Factor (NGF)-induced neurite outgrowth that appears to require the epsilon, but not delta, isoform of Protein Kinase C (PKC). Neurites contain a core of microtubules that are formed from polymerization of free-tubulin.

Ethanol modulates nicotine-induced upregulation of nAChRs.

The use of alcohol and nicotine are highly correlated, suggesting an underlying biochemical interaction. Chronic nicotine exposure results in a deactivation and subsequent upregulation of the expression of nicotinic acetylcholine receptors (nAChRs). Upregulation is thought to represent certain aspects of physical dependence on nicotine.

Melatonin inhibition of nicotine-stimulated dopamine release in PC12 cells.

Melatonin, a pineal hormone, modifies numerous physiologic processes including circadian rhythms and sleep. In specific tissues, melatonin appears to have an inverse relationship with dopamine. To examine this relationship, a pheochromocytoma cell line (PC12) was used to determine the extent of melatonin's ability to inhibit nicotine-stimulated dopamine release.

betagamma Dimers mediate synergy of dopamine D2 and adenosine A2 receptor-stimulated PKA signaling and regulate ethanol consumption.

Dopamine release is activated by ethanol and addicting drugs, but molecular mechanisms linking dopaminergic signaling to neuronal responses and drinking behavior are poorly understood. We report that dopamine-D2 receptors induce PKA Calpha translocation and increase CRE-regulated gene expression. Ethanol also activates PKA signaling.

Ethanol-induced translocation of protein kinase A occurs in two phases: control by different molecular mechanisms.

Background: Cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) regulates cellular functions. The specificity of PKA-mediated phosphorylation is determined primarily by PKA localization to sub-cellular sites. Chronic exposure to ethanol causes sustained translocation of the PKA catalytic subunit (C) from the Golgi to the nucleus in NG108-15 cells.

Uncoupling of betaIIPKC from its targeting protein RACK1 in response to ethanol in cultured cells and mouse brain.

Protein kinase C (PKC) is involved in many neuroadaptive responses to ethanol in the nervous system. PKC activation results in translocation of the enzyme from one intracellular site to another. Compartmentalization of PKC isozymes is regulated by targeting proteins such as receptors for activated C kinase (RACKs).

Ethanol reduces expression of the nerve growth factor receptor, but not nerve growth factor protein levels in the neonatal rat cerebellum.

The cerebellum is especially vulnerable to ethanol's neurotoxic effects during development, and ethanol exposure during the brain growth spurt will deplete cerebellar neurons. The mechanisms undertying this neuronal cell loss remain elusive. Nerve growth factor (NGF) is a neurotrophin that promotes cell survival in various brain areas, and there is evidence that NGF may play a role in the developing cerebellum.

The role of the neuromodulator adenosine in alcohol's actions.

The interaction between the neuromodulator adenosine and adenosine receptors on the surface of neurons modifies the neurons' responses to neurotransmitters. The activated adenosine receptors alter the levels of small signaling molecules (i.e.

Ethanol causes translocation of cAMP-dependent protein kinase catalytic subunit to the nucleus.

Short- and long-term ethanol exposures have been shown to alter cellular levels of cAMP, but little is known about the effects of ethanol on cAMP-dependent protein kinase (PKA). When cAMP levels increase, the catalytic subunit of PKA (C alpha) is released from the regulatory subunit, phosphorylates nearby proteins, and then translocates to the nucleus, where it regulates gene expression. Altered localization of C alpha would have profound effects on multiple cellular functions.

Activation of cyclic AMP-dependent protein kinase reverses tolerance of a nucleoside transporter to ethanol.

Adenosine mediates some of the acute and chronic effects of ethanol in neural cells. In cultured NG108-15 cells, ethanol inhibits adenosine uptake via a specific facilitative nucleoside transporter leading to an increase in extracellular adenosine, activation of adenosine A2 receptors and increases in intracellular cyclic AMP (cAMP). After chronic ethanol exposure, an adaptive decrease in receptor-stimulated cAMP levels occurs.

NMDA prevents alcohol-induced neuronal cell death of cerebellar granule cells in culture.

Neuronal cell loss is one of the most debilitating effects of alcohol exposure during development of the nervous system. In this study, primary cultures of neuronal cells (cerebellar granule cells) were used to examine mechanisms of alcohol-induced neuronal cell death. Previously, we established that (Pantazis et al.

Vulnerability of cerebellar granule cells to alcohol-induced cell death diminishes with time in culture.

This study examined the effects of alcohol exposure on the viability of cerebellar granule cells in culture. Continuous alcohol exposure, starting 1 day after the cultures were established, significantly reduced granule cell numbers, even with a single day of exposure to an alcohol concentration as low as 100 mg/dl. The depletion of cerebellar granule cells by alcohol was concentration-dependent (greater loss of cells at higher alcohol concentrations) and duration-dependent (greater loss of cells at longer exposure durations).

Alcohol reduces the number of pheochromocytoma (PC12) cells in culture.

Pheochromocytoma (PC12) cells were used as an in vitro neuronal cell model to examine detrimental effects of alcohol on cell numbers. Alcohol exposure (100, 200, 400, and 800 mg/dl) reduced PC12 cell numbers in a dose-dependent manner. Cells that were treated with nerve growth factor (NGF) incurred less severe reductions in numbers compared with cells that were never treated with NGF.