251 research outputs found
The role of acetaldehyde in mediating effects of alcohol on expression of endogenous opioid system genes in a neuroblastoma cell line
No full textEthanol (EtOH) alters neural activity through interaction with various neurotransmitters and neuromodulators. The endogenous opioid system seems to play a key role in the activities of EtOH, since the opioid antagonist naltrexone (ReVia) attenuates craving. We have investigated the transcriptional regulation of opioid system genes in response to EtOH exposure for up to 96 h in human neuroblastoma SH-SY5Y cells using quantitative real-time polymerase chain reaction. We observed a significant decrease in the expression of opioid peptide precursors (proopiomelanocortin, proenkephalin, and prodynorphin) and of the kappa opioid receptor after 48 and 72 h of EtOH exposure (10 and 40 mM). These alterations were not present when the EtOH metabolism was blocked by 4-methylpyrazole. To evaluate whether the effects evoked by EtOH were possibly due to the first product of EtOH metabolism, cells were exposed to 0.4 mM acetaldehyde. We observed the same pattern of changes for prodynorphin, proenkephalin, and the kappa opioid receptor as after 72 h exposure to EtOH. These results contribute to our understanding of EtOH action at a cellular level and provide evidence of the role of acetaldehyde in mediating some of the EtOH-induced effects
Prodynorphin gene regulation by epigenetic mechanisms following ethanol and acetaldehyde exposure in SH-SY5Y cells
No full textA role for epigenetic mechanisms in the regulation of prodynorphin expression by alcohol
No full text
A role for epigenetic mechanisms in the regulation of prodynorphin expression by alcohol
No full textBackground and Aim: Alcohol alters several neurotransmitter
systems within the brain and accumulated
evidences indicate the endogenous opioid system as an
important target of its action. We studied, in vitro and in
vivo the molecular alterations occurring in the prodynorphin
gene following different exposures to alcohol.
Methods: Human neuroblastoma SH-SY5Y cells were
exposed to low, clearly not intoxicating, and high etha-
208
European Opioid Conference 2011, Kraków, Poland
nol concentrations at different time points. Sprague
Dawley rats received alcohol intragastrically trying to
mimic human drinking that establishes tolerance and dependence
conditions. Real-time RT-PCR was used to assess
the abundance of mRNAs of interest. DNA methylation
was analyzed by Methylation Specific-Real Time
PCR and bisulfite-Pyrosequencing. Specific histone
modifications at gene promoters were evaluated by
Chromatin ImmunoPrecipitation.
Results: In the cellular model we demonstrated
a temporal relationship between selective chromatin
modifications induced by ethanol or acetaldehyde,
and changes in prodynorphin gene expression were
demonstrated. In the amygdala complex of alcoholtreated
rats differential changes in prodynorphin gene
expression changes were observed depending on the
time of exposure; consistently, we propose potential
epigenetic mechanisms responsible for these alterations,
at least upong short ethanol exposure.
Conclusion: Our findings indicate a linkage between
gene expression alterations and epigenetic modulation
in prodynorphin promoter, thus adding novel information
on how the opioid system can be affected by alcohol
in several ways. Studies are ongoing to evaluate
the chromatin remodelling in the neuroplasticity occurring
in the progression of alcohol abuse. It will be
also of value to study the ability of epigenetic modulators
in reverting dynorphin genetic/epigenetic alterations
and alcohol abuse-related behaviours. Moreover,
opioid drugs already available in alcoholism treatment
could also have possible epigenetic modulating
properties
New vistas on synaptic plasticity: the receptor mosaic hypothesis of the engram.
No full textThe concepts of coexistence of transmitters and of receptor-receptor interactions have increased our understanding of the integrative processes regulating synaptic homeostasis and synaptic plasticity. Depending upon the ionotropic or metabotropic characteristics of the cotransmitter, it may be mainly involved in synaptic homeostasis or synaptic plasticity, respectively. A chemical trace of the postsynaptic activity can be obtained because of the plasticity of the receptor molecules. Thus, the heuristic hypothesis is introduced that islands of receptors located on postsynaptic membranes of local circuits can be formed by means of receptor-receptor interactions favouring ordered electrotonic sequences in the local circuits. This hypothesis has been named the receptor mosaic hypothesis of the engram. The islands or clusters of receptors can then store specific and complex information and when activated by the transmitters they may induce unique changes in ion permeability and cell metabolism which, at the local circuit level, can mimic exactly a previous electrotonic sequence. They can therefore represent at least part of the engram. This hypothesis is introduced against the background of the possible existence of different types of encodings of memory
A role for epigenetic mechanisms in the regulation of prodynorphin expression by alcohol RID A-5970-2010
No full textInternalization of intracerebrally administered porcine galanin (1-29) by a discrete nerve cell population in the hippocampus of the rat
No full textIn spite of numerous studies utilizing intraventricular administration of porcine galanin (1-29), little is known about the spread and cellular distribution of exogenous galanin following intraventricular administration. In this study a discrete nerve cell body population with their dendrites became strongly galanin immunoreactive (IR) in the dorsal hippocampus following intraventricular porcine galanin (1.5 nmol/rat), Time course experiments showed that after time intervals of 10 and 20 min, but not at 60 min, scattered small-to medium-sized galanin-IR nerve cell bodies and their dendrites were present in all layers of the dorsal and ventral hippocampus. In double-immunolabeling experiments most of these nerve cells were identified as putative GABA interneurons costoring NPY-IR or somatostatin-IR in some cases. Twenty minutes after intraventricular injection of artificial cerebrospinal fluid (aCSF), only endogenous punctate and coarse galanin-IR terminals were found, but no galanin-IR cell bodies. Intrahippocampal injection of fluorophore-labeled galanin resulted in the appearance of fluorescent nerve cell bodies with the same morphology and localization as in the above experiments. Coadministration of the putative galanin antagonist M35 (0.5 nmol) and galanin (1.5 nmol) resulted in a reduced number of galanin-IR nerve cell bodies in the hippocampus of half of the rats. These findings support the existence of a population of putative hippocampal GABA interneurons with the ability to internalize and concentrate galanin and/or its fragments present in the extracellular fluid, possibly mediated by galanin receptors
The role of 5-HT(1A) receptors in learning and memory
No full textThe ascending serotonin (5-HT) neurons innervate the cerebral cortex, hippocampus, septum and amygdala, all representing brain regions associated with various domains of cognition. The 5-HT innervation is diffuse and extensively arborized with few synaptic contacts, which indicates that 5-HT can affect a large number of neurons in a paracrine mode. Serotonin signaling is mediated by 14 receptor subtypes with different functional and transductional properties. The 5-HT(1A) subtype is of particular interest, since it is one of the main mediators of the action of 5-HT. Moreover, the 5-HT(1A) receptor regulates the activity of 5-HT neurons via autoreceptors, and it regulates the function of several neurotransmitter systems via postsynaptic receptors (heteroreceptors). This review assesses the pharmacological and genetic evidence that implicates the 5-HT(1A) receptor in learning and memory. The 5-HT(1A) receptors are in the position to influence the activity of glutamatergic, cholinergic and possibly GABAergic neurons in the cerebral cortex, hippocampus and in the septohippocampal projection, thereby affecting declarative and non-declarative memory functions. Moreover, the 5-HT(1A) receptor regulates several transduction mechanisms such as kinases and immediate early genes implicated in memory formation. Based on studies in rodents the stimulation of 5-HT(1A) receptors generally produces learning impairments by interfering with memory-encoding mechanisms. In contrast, antagonists of 5-HT(1A) receptors facilitate certain types of memory by enhancing hippocampal/cortical cholinergic and/or glutamatergic neurotransmission. Some data also support a potential role for the 5-HT(1A) receptor in memory consolidation. Available results also implicate the 5-HT(1A) receptor in the retrieval of aversive or emotional memories, supporting an involvement in reconsolidation. The contribution of 5-HT(1A) receptors in cognitive impairments in various psychiatric disorders is still unclear. However, there is evidence that 5-HT(1A) receptors may play differential roles in normal brain function and in psychopathological states. Taken together, the evidence indicates that the 5-HT(1A) receptor is a target for novel therapeutic advances in several neuropsychiatric disorders characterized by various cognitive deficits
Distribution and kinetics of galanin infused into the ventral hippocampus of the rat: relationship to spatial learning
No full textA recent study has shown that ventral hippocampal galanin plays a role in spatial learning and that it has an inhibitory effect on basal acetylcholine release [Ogren S. O. et al. (1996) Neuroscience 75, 1127-1140]. The present studies were designed to compare the in vivo tissue distribution and kinetics of infused galanin (porcine) with the temporal effect of galanin on spatial learning in the rat. Daily bilateral microinfusions of galanin (1.5 nmol/side for five days) via chronic cannulae placed in the ventral hippocampus produced a significant impairment of acquisition of the spatial task when infused 20 min, but not 5 or 60 min, before the daily training session. No overall impairment of memory retention (examined 24 h after the last training session) was observed in the galanin-treated rats. These results indicate that galanin given in the ventral hippocampus produces a time-dependent effect on acquisition. Using an antibody to porcine galanin and immunohistochemistry, galanin infused in the ventral hippocampus was found to be distributed mainly within the ventral part of the hippocampus and around the infusion site. The infused galanin was rapidly cleared from the extracellular space between 5 and 20 min after infusion. Five minutes after infusion of galanin, a number of cells in the ventral hippocampus, both within and outside the zone of extracellularly located galanin, showed a positive galanin-like immunoreactivity. These cells appear morphologically to be medium-sized neurons with a similar position as cells showing neuropeptide Y-like immunoreactivity. At 20 and 60 min after infusion of galanin, no cells with detectable levels of galanin-like immunoreactivity could be seen. These results indicate that the temporal kinetics and distribution of infused galanin are of major importance for its behavioural effect in the ventral hippocampus. The rapid clearance of the infused galanin and its internalization by neuronal endocytotic mechanisms may be important for its effect on cognition
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