Brain-derived neurotrophic factor-induced potentiation of glutamate and GABA release: different dependency on signaling pathways and neuronal activity

The mechanisms underlying BDNF-modulated neurotransmitter release remain elusive. Here, we found that 24-h exposure of postnatal cortical neurons to BDNF potentiated depolarization-evoked glutamate and GABA release in a protein synthesis-dependent manner. BDNF-potentiated glutamate release occurred through the PLC-gamma and MAPK pathways. The expression of synapsin I, synaptotagmin, and synaptophysin, but not of syntaxin or SNAP25, increased through the PLC-gamma and MAPK pathways. In contrast, BDNF-up-regulated GABA release and GAD65/67 expression depended on MAPK. Furthermore, neuronal activity was necessary for the up-regulation of glutamate release and synapsin I, synaptotagmin, and synaptophysin expression, but not of GABA or GAD65/67. PLC-gamma inhibitor attenuated BDNF-stimulated long-lasting MAPK activation. As BDNF rapidly potentiates glutamatergic transmission through PLC-gamma (J. Biol. Chem. 277, (2002) 6520-6529), PLC-gamma-mediated neuronal activity might sustain MAPK activation, resulting in BDNF-potentiated glutamate release. In conclusion, BDNF potentiates the excitatory and inhibitory system separately, which may be important for the regulation of synaptic plasticity.     

Perinatal Oxygen Restriction Does Not Result in Reduced Rat Frontal Cortex Synaptophysin Protein Levels at Adulthood as Opposed to Postmortem Findings in Schizophrenia

Synaptophysin, a synaptic vesicle protein and a marker for synaptic density has been found to be reduced in postmortem prefrontal cortex of schizophrenia patients, consistent with evidence for synaptic deficits in schizophrenia. The contribution of both genetic and environmental factors to the etiology of schizophrenia is well established, and obstetric complications have been suggested as a non-genetic risk factor of schizophrenia. As there is only scarce evidence for a genetic linkage between synaptophysin’s chromosomal locus (Xp11.22) and schizophrenia, we hypothesized that early neonatal exposure of rat pups to oxygen restriction would result in reduced frontal cortex synaptophysin protein levels at adulthood. We studied the effects of anoxia or hypoxia on 7-day-old rats frontal cortex synaptophysin protein levels assessed by Western blotting 4 and 7 weeks following the exposure. In hypoxia- or anoxia-exposed rats, synaptophysin protein levels were elevated both 4 and 7 weeks after the exposure. Two-way ANOVA followed by post hoc LSD analysis showed that the effect was predominantly at 4 weeks after exposure and that only anoxia-exposed rats differed significantly from control rats (p = 0.019). These results are in contrast to postmortem findings in schizophrenia and suggest that reduced synaptophysin protein levels in schizophrenia patients’ postmortem brain do not result from perinatal oxygen deprivation.     

Potentiation of synaptic strength and intrinsic excitability in the nucleus accumbens after 10 days of morphine withdrawal

Neuroadaptations in the nucleus accumbens (NAc) are associated with the development of drug addiction. Plasticity in synaptic strength and intrinsic excitability of NAc medium spiny neurons (MSNs) play critical roles in addiction induced by different classes of abused drugs. However, it is unknown whether morphine exposure influences synaptic strength, intrinsic excitability or both in NAc. Here we show that chronic withdrawal (10 days after the last injection) from repeated morphine exposure elicited potentiation in both glutamatergic synaptic strength and intrinsic excitability of MSNs in NAc shell (NAcSh). The potentiation of synaptic strength was demonstrated by an increase in the frequency of miniature excitatory postsynaptic currents (mEPSCs), a decrease in the paired-pulse ratio (PPR), and an increase in the ratio of α-amino-3-hydroxy-5-methyl-isoxazole propionic acid receptors (AMPAR)- to N-methyl-D-aspartate receptors (NMDAR)-mediated currents. The potentiation of intrinsic excitability was mediated by inhibition of the sustained potassium currents via extrasynaptic NMDAR activation. The function of the presynaptic group II metabotropic glutamate receptors (mGluR2/3) was downregulated, enhancing the probability of glutamate release on synaptic terminals during chronic morphine withdrawal. Pretreatment with the mGluR2/3 agonist LY379268 completely blocked potentiation of both synaptic strength and intrinsic excitability. These results suggest that chronic morphine withdrawal downregulates mGluR2/3 to induce potentiation of MSN glutamatergic synapse via increased glutamate release, leading to potentiation of intrinsic excitability. Such potentiation of both synaptic strength and intrinsic excitability might contribute to neuroadaptations induced by morphine application.     

Chronic prenatal ethanol exposure alters glucocorticoid signalling in the hippocampus of the postnatal Guinea pig

The present study tested the hypothesis that chronic prenatal ethanol exposure causes long-lasting changes in glucocorticoid signalling in postnatal offspring. Pregnant guinea pigs were treated with ethanol (4 g/kg maternal body weight/day), isocaloric-sucrose/pair-feeding or water throughout gestation, and maternal saliva cortisol concentration was determined 2 h after treatment at different stages of gestation. Electrically-stimulated release of glutamate and GABA, in the presence or absence of dexamethasone, as well as glucocorticoid and mineralocorticoid receptor mRNA expression, was determined in the hippocampus and prefrontal cortex of adult offspring of treated pregnant guinea pigs. Maternal saliva cortisol concentration increased throughout pregnancy, which was associated with increased foetal plasma and amniotic fluid cortisol concentration. Ethanol administration to pregnant guinea pigs increased maternal saliva cortisol concentration during early and mid-gestation. In late gestation, ethanol administration did not increase saliva cortisol concentration above that induced by pregnancy. Chronic prenatal ethanol exposure had no effect on stimulated glutamate or GABA release, but selectively prevented dexamethasone-mediated suppression of stimulated glutamate release, and decreased expression of mineralocorticoid, but not glucocorticoid, receptor mRNA in the hippocampus of adult offspring. These data indicate that maternal ethanol administration leads to excessively increased maternal cortisol concentration that can impact negatively the developing foetal brain, leading to persistent postnatal deficits in glucocorticoid regulation of glutamate signalling in the adult hippocampus.     

Corticostriatal plasticity in the nucleus accumbens core

Small fluctuations in striatal glutamate and dopamine are required to establish goal-directed behaviors and motor learning, while large changes appear to underlie many neuropsychological disorders, including drug dependence and Parkinson's disease. A better understanding of how variations in neurotransmitter availability can modify striatal circuitry will lead to new therapeutic targets for these disorders. Here, we examined dopamine-induced plasticity in prefrontal cortical projections to the nucleus accumbens (NAc) core. We combined behavioral measures of male mice, presynaptic optical studies of glutamate release kinetics from prefrontal cortical projections, and postsynaptic electrophysiological recordings of spiny projection neurons within the NAc core. Our data show that repeated amphetamine promotes long-lasting but reversible changes along the corticoaccumbal pathway. In saline-treated mice, coincident cortical stimulation and dopamine release promoted presynaptic filtering by depressing exocytosis from glutamatergic boutons with a low-probability of release. The repeated use of amphetamine caused a frequency-dependent, progressive, and long-lasting depression in corticoaccumbal activity during withdrawal. This chronic presynaptic depression was relieved by a drug challenge which potentiated glutamate release from synapses with a low-probability of release. D1 receptors generated this synaptic potentiation, which corresponded with the degree of locomotor sensitization in individual mice. By reversing the synaptic depression, drug reinstatement may promote allostasis by returning corticoaccumbal activity to a more stable and normalized state. Therefore, dopamine-induced synaptic filtering of excitatory signals entering the NAc core in novice mice and paradoxical excitation of the corticoaccumbal pathway during drug reinstatement may encode motor learning, habit formation, and dependence.     

Synaptic pathology in prefrontal cortex is present only with severe dementia in Alzheimer disease

Synaptic pathology is proposed to be integral to the clinical expression of Alzheimer disease (AD). Most studies have assessed only the vesicle protein synaptophysin as a measure of synaptic integrity. The interrelationships of synaptophysin, other presynaptic proteins, the cholinergic system, and severity of dementia in AD remain unclear. We studied the presynaptic proteins synaptophysin, syntaxin and SNAP-25, along with choline acetyltransferase (ChAT) activity in prefrontal cortex (BA 46) samples from 18 subjects with AD and 16 controls. Mean values of presynaptic protein immunoreactivities were significantly reduced, by 21%-28%, and ChAT activity was reduced by 41% in the AD groups. Synaptic protein immunoreactivity and ChAT activity were correlated with Mini-Mental State Examination scores obtained 1 yr prior to death. When AD cases were subgrouped into mild/moderate and severe illness at time of death, all differences in presynaptic proteins and ChAT activity were significant between controls and severe cases. However, no significant differences were detected in BA 46 between controls and mild/moderate cases. Considerable synaptic reserve or plasticity remains in BA 46 until the late stages of AD. Synaptophysin and ChAT appear to be more vulnerable in severe AD than are syntaxin or SNAP-25.     

Decreased expression of nardilysin in SH-SY5Y cells under ethanol stress and reduced density of nardilysin-expressing neurons in brains of alcoholics

There is evidence for a genetic link between the metalloendopeptidase nardilysin and alcohol dependence, but the functional implication of the enzyme in alcoholism is unknown. Interestingly, some of the enzyme's substrates and interaction partners are altered in neural and non-neural tissues under the influence of ethanol consumption. To learn more about putative roles of nardilysin in alcohol dependence we studied the expression of the enzyme protein in human neuroblastoma cells under chronic ethanol exposure as well as in four brain regions of alcoholics and matched controls.     

Chronic morphine treatment switches the effect of dopamine on excitatory synaptic transmission from inhibition to excitation in pyramidal cells of the basolateral amygdala

Dopaminergic signaling in the basolateral amygdala (BLA) is important for drug-stimulus learning that triggers relapse to drug-seeking behavior. However, little is known about adaptive changes in this signaling pathway upon chronic morphine treatment. In this paper, we observed the influence of chronic morphine treatment on the effect of dopamine (DA) on the excitatory transmission in the pyramidal cells of BLA in slices with the whole-cell patch-clamp method. We also studied its mechanism and significance with pharmacological approaches combined with biochemical and behavioral techniques. The results showed that chronic morphine exposure switched the effect of DA on the excitatory synaptic transmission from inhibition to excitation; the chronic morphine-induced switching action on the effect of DA was due to its influence on D1 receptors; the site of the effect of chronic morphine treatment on D1 receptors was at presynaptic locus; chronic morphine treatment induced a significant increase in the amount of D1 receptor expression in the synaptosomes and synaptosomal membrane fraction from BLA; the enhancement of presynaptic glutamate release by D1 receptor agonist upon chronic morphine treatment was dependent on the activation of cAMP-dependent protein kinase; and the intra-BLA injection of D1 receptor antagonist canceled the conditioned place aversion (CPA) in morphine-dependent rats. In conclusion, chronic morphine treatment switches the effect of DA on the excitatory synaptic transmission from inhibition to excitation by the presynaptic D1 receptor amount increase-mediated glutamate release in the pyramidal cells of BLA and the blockade of D1 receptors in BLA cancels CPA in morphine-dependent rats.     

Synaptophysin and chromogranin A immunoreactivities in senile plaques of Alzheimer''s disease

Immunolabelling for synaptophysin and chromogranin A, two polypeptides associated with small clear and large dense core synaptic vesicles respectively, has been performed on tissue sections of the temporal cortex in Alzheimer's disease in combination with anti-A4 amyloid labelling. The dystrophic neurites in many senile plaques were observed to be labelled by the anti-synaptophysin or anti-chromogranin A antibodies. Some diffuse amyloid deposits, demonstrated by antibodies against synthetic amyloid A4 peptides, were associated with a punctuate increase in synaptophysin or chromogranin A immunoreactivity. The labelling of dystrophic plaque neurites may reflect the accumulation in these processes of synaptic vesicles or material derived from them. We suggest also that the punctuate increase in synaptophysin and chromogranin A immunoreactivities associated with some A4 amyloid deposits may be an early event reflecting neuronal dysfunction.     

The effect of chronic thienorphine administration on long‐term potentiation and synaptic structure in rat hippocampus

Thienorphine is a new nonselective partial agonist of opioid receptors, which is currently under a Phase II clinical trial in China as a new treatment for opioid dependence. In this study, we compared the effect of thienorphine with morphine on long‐term potentiation (LTP) in the lateral perforant path (LPP)‐granule cell synapse of the rat dentate gyrus (DG). Furthermore, the effect of thienorphine on the synaptic structure of the CA1 hippocampal region and the expression of synaptophysin was investigated. Results indicated interesting differences between thienorphine and morphine on the modulation of hippocampal synaptic plasticity. Chronic thienorphine treatment facilitated LTP in the LPP‐DG cell synapses more than chronic morphine treatment. Morphometric measurement and analysis showed that chronic thienorphine administration decreased the length of the active zone and reduced the thickness of CA1 postsynaptic densities compared with the saline group (control), but were elevated compared with the morphine group. Furthermore, the expression of hippocampal synaptophysin was increased with chronic thienorphine administration but reduced with chronic morphine treatment. Taken together, our study clearly demonstrates that chronic thienorphine treatment enhances LTP, modulates hippocampal synaptic structure, and increases the expression of hippocampal synaptophysin. Therefore, further study is warranted to investigate thienorphine as a new treatment for opioid dependence. Synapse 67:779–785, 2013 . © 2013 Wiley Periodicals, Inc.     

Role of GABA<Subscript>A</Subscript> receptors in alcohol use disorders suggested by chronic intermittent ethanol (CIE) rodent model

GABAergic inhibitory transmission is involved in the acute and chronic effects of ethanol on the brain and behavior. One-dose ethanol exposure induces transient plastic changes in GABA_A receptor subunit levels, composition, and regional and subcellular localization. Rapid down-regulation of early responder δ subunit-containing GABA_A receptor subtypes mediating ethanol-sensitive tonic inhibitory currents in critical neuronal circuits corresponds to rapid tolerance to ethanol’s behavioral responses. Slightly slower, α1 subunit-containing GABA_A receptor subtypes mediating ethanol-insensitive synaptic inhibition are down-regulated, corresponding to tolerance to additional ethanol behaviors plus cross-tolerance to other GABAergic drugs including benzodiazepines, anesthetics, and neurosteroids, especially sedative-hypnotic effects. Compensatory up-regulation of synaptically localized α4 and α2 subunit-containing GABA_A receptor subtypes, mediating ethanol-sensitive synaptic inhibitory currents follow, but exhibit altered physio-pharmacology, seizure susceptibility, hyperexcitability, anxiety, and tolerance to GABAergic positive allosteric modulators, corresponding to heightened alcohol withdrawal syndrome. All these changes (behavioral, physiological, and biochemical) induced by ethanol administration are transient and return to normal in a few days. After chronic intermittent ethanol (CIE) treatment the same changes are observed but they become persistent after 30 or more doses, lasting for at least 120 days in the rat, and probably for life. We conclude that the ethanol-induced changes in GABA_A receptors represent aberrant plasticity contributing critically to ethanol dependence and increased voluntary consumption. We suggest that the craving, drug-seeking, and increased consumption in the rat model are tied to ethanol-induced plastic changes in GABA_A receptors, importantly the development of ethanol-sensitive synaptic GABA_A receptor-mediating inhibitory currents that participate in maintained positive reward actions of ethanol on critical neuronal circuits. These probably disinhibit nerve endings of inhibitory GABAergic neurons on dopamine reward circuit cells, and limbic system circuits mediating anxiolysis in hippocampus and amygdala. We further suggest that the GABA_A receptors contributing to alcohol dependence in the rat and presumably in human alcohol use disorders (AUD) are the ethanol-induced up-regulated subtypes containing α4 and most importantly α2 subunits. These mediate critical aspects of the positive reinforcement of ethanol in the dependent chronic user while alleviating heightened withdrawal symptoms experienced whenever ethanol is absent. The speculative conclusions based on firm observations are readily testable.     

Dissociation of synaptic zinc level and zinc transporter 3 expression during postnatal development and after sensory deprivation in the barrel cortex of mice

In the neocortex, synaptic zinc level is regulated by sensory experience. Previously, we found that trimming of mystacial vibrissae resulted in an increase of synaptic zinc level in corresponding deprived barrels in the cortex of mice. The present study focused on the relationship between synaptic zinc and zinc transporter 3 (ZnT3) protein expression in the barrel cortex of mice during postnatal development and after sensory deprivation of selected vibrissae. Using immunocytochemistry and western blot analysis, we found that ZnT3 expression is delayed as compared with the onset of synaptic zinc and presynaptic markers, such as synapsin I and synaptophysin. Further, neither long-term deprivation in young mice nor short deprivation in adult mice, that resulted in an increase of synaptic zinc level, produced alterations in ZnT3, synapsin I or synaptophysin expression in deprived barrels. These results suggest that in the barrel cortex ZnT3, synapsin I or synaptophysin are not determinant for the activity-dependent regulation of the synaptic zinc level.     

Chronic ethanol produces increased taurine transport and efflux in cultured astrocytes

Due to ethanol's low potency and low level of toxicity, high amounts of ethanol are consumed to achieve pharmacological effects. Blood levels of ethanol in chronic alcoholics may reach as high as 80-100 mM. We undertook a series of studies to determine if these high levels of ethanol stimulated osmoregulatory processes in cultured astrocytes. The uptake and efflux of taurine, the major osmoregulatory amino acid with potentially neuroprotective actions, was assessed. In addition, uptake and efflux of the excitatory amino acid aspartate was studied since astrocytes are vital in maintaining proper synaptic excitatory amino levels through uptake, metabolism, and efflux. Ethanol exposure for 96 h resulted in increased uptake of both 3H-taurine and 3H-D-asparate. There were no significant changes in transporter function at 24 h consistent with the delayed time course of transporter up-regulation seen during chronic hyperosmotic stress. Following EtOH withdrawal, efflux of preloaded 3H-taurine was significantly increased as compared to controls for up to 1 h. In contrast to the efflux profile seen during hypotonic induced swelling and regulatory volume decrease (RVD), no increased 3H-D-asparate efflux was demonstrated. Cell volume measurements suggest that inhibition of the normal RVD response be involved in the increased taurine release.     

The neurotoxicity of ethanol

ABSTRACT- Alterations in nervous system functioning following acute and chronic ethanol exposure have been studied in a great number of experimental investigations. Results from many of these investigations can be difficult to interpret, particularly since a variety of techniques and exposure models are employed. This review emphasizes those studies which, in the opinion of the author, fit into a pattern where results from studying one function of the nervous system is in accordance with results from studying another. Thus, the fluidizing effect of ethanol on the neuronal membrane - an effect which ethanol shares with anaesthetics - leads to a change in protein function which in turn affects ion transport such as Na⁺ and Ca⁺⁺ across the membrane due to changes in the ion channels. Cation influx is probably directly coupled to neurotransmitter release which is in agreement with the finding that ethanol exposure results in inhibition of Na⁺ and Ca⁺⁺ current as well as acetylcholine release. The sensitation of the dopaminergic system after ethanol exposure may also be related to the changes in cation flux, and the changes in this system probably play a crucial rôle in the development of tolerance and withdrawal symptoms. Other aspects such as impairment of protein synthesis, altered GABA function of impairment of neuron excitability and conduction are more difficult to place in proper perspective. The rôle of acetaldehyde in acute as well as chronic ethanol intoxication also remains a controversy. These may, however, be secondary phenomena to primary changes in different part of the nervous system not necessarily important in the clinical situation. Behavioural and anatomical studies particularly from recent years have shown that experimental animals develop memory disturbances following chronic exposure even when kept on sufficient diet. These findings argue strongly for a direct toxic effect of ethanol, and are furthermore compatible with behavioural changes in chronic alcoholics, dominated by memory impairment. Since it has been argued that the cholinergic system plays a significant rôle for memory function, a possible explanation for some of the psychological and anatomical deficits caused by ethanol is thus the changes in the function of the cholinergic system particularly in the hippocampal regions.     

The enduring effects of an adolescent social stressor on synaptic density, part II: Poststress reversal of synaptic loss in the cortex by adinazolam and MK-801

Experience programs synaptic development to match the needs of the environment. This process depends on the nature and timing of the experience. Exposure to stress during adolescence selectively reduces synaptic density in the prefrontal cortex (a later maturing region), while sparing hippocampal synapses (an earlier maturing region). To determine whether the anatomical effects of an adolescent social stressor in rats endures into adulthood and are reversible, male subjects were isolation or group housed between days 30 and 35 and then treated with vehicle, adinazolam, MK-801, or tianeptine between days 40 and 55. At day 60, immunohistochemistry revealed a 13.5% +/- 5.3% reduction in synaptophysin in the infralimbic cortex and cingulate gyrus in isolation-housed subjects. MK-801 and adinazolam restored cortical synaptic density to within 2% of group-housed values, suggesting that the synaptic loss induced by stress during adolescence is modulated through reduced glutamatergic activity directly by NMDA antagonism or indirectly by enhancing GABAergic activity. Tianeptine did not modulate adolescent stress effects in the prefrontal cortex. None of these drugs increased cortical synaptophysin in group-housed controls. Increased synaptophysin was observed in the group-housed condition in the hippocampus, striatum, and nucleus accumbens following drug exposure. Although stress did not decrease synaptic density in these regions, drug exposure failed to increase synaptic density when compared with the controls. Taken together, stress-induced changes in cortical, but not hippocampal, synaptic density initiated during adolescence endure into adulthood. These cortical changes can be reversed through a reduction of glutamatergic activity, but not serotonin augmentation.     

Tyrosine kinase phosphorylation of GABAA receptor subunits following chronic ethanol exposure of cultured cortical neurons of mice

Previous studies from our laboratory revealed that acute ethanol exposure inhibits phosphorylation of mitogen-activated protein (MAP) kinase and extracellular signal-regulated kinases (ERK) in mice. In the present study, we have further investigated effect of chronic administration of ethanol on tyrosine kinase phosphorylation of GABA(A) receptor subunits in the mouse cultured cortical neurons. We observed that there was an up-regulation in tyrosine kinase phosphorylation of the GABA(A) receptor beta(2) and gamma(2) subunits following chronic ethanol exposure, whereas there was no effect on alpha(1) subunit of the GABA(A) receptor in the cultured cortical neurons of mice as determined by Western blotting. These results suggest a potential role for tyrosine kinase phosphorylation of some of the GABA(A) receptor subunits in chronic ethanol-induced tolerance and dependence.     

Human immunodeficiency virus type 1 gp120 and ethanol coexposure in rat organotypic brain slice cultures: Curtailment of gp120-induced neurotoxicity and neurotoxic mediators by moderate but not high ethanol concentrations

Human immunodeficiency virus type 1 (HIV-1) envelope protein gp120, implicated with other retroviral proteins in acquired immunodeficiency syndrome (AIDS)-related dementia, causes neuronal degeneration by inciting cascades of neurotoxic mediators from glia. It also may facilitate neuronal glutamate (N-methyl-D-aspartate, NMDA) receptor-mediated excitotoxicity by interacting at the glycine coagonist site. The authors reported that preconditioning rat organotypic hippocampal-cortical slice cultures subchronically with ethanol at concentrations occurring during moderate drinking (20 to 30 mM) prevented gp120's induction of neurotoxic mediators and intracellular calcium, as well as neuronal death. The authors now find that the acute copresence of ethanol in moderate as opposed to high concentrations similarly blocks the retroviral protein's neurotoxic effects in brain slice cultures, assessed with lactate dehydrogenase (LDH) release and propidium iodide (PI) labeling. As with ethanol preconditioning, neuroprotection against gp120 by moderate ethanol coexposure appears secondary to abrogation of the retroviral protein's early induction of arachidonic acid (AA), glutamate, and superoxide (but not nitric oxide) elevations/release. Additionally, experiments indicate that 30 mM ethanol is sufficient to inhibit the NMDA receptor, particularly in the presence of added glycine, thus hindering potential direct neuronal stimulation by gp120. However, in contrast to moderate ethanol, 100 mM ethanol, a concentration tolerated only in chronic alcoholics, potentiates gp120-dependent neurotoxicity (PI labeling) in the hippocampal CA1 region, augments LDH release, and fails to curtail gp120's actions on AA, glutamate, and superoxide-but does suppress nitric oxide induction. The results indicate dominant roles for AA, superoxide, and glutamate-mediated oxidative stress in gp120's neurotoxic mechanism, but perhaps a less important role for NMDA receptor stimulation, which would be constrained at both ethanol concentrations employed. We suggest that ethanol's concentration-dependent, two-edged sword behavior could alter the development of dementia in HIV-1-infected individuals during social consumption or abuse. Further studies are needed to elucidate the differing apparently glial effects of the two concentrations of ethanol.     

Total ethanol consumption as a seizure risk factor in alcoholics

Population studies suggest that seizures occur in chronic alcoholics as an effect of ethanol withdrawal or ethanol toxicity. Our own studies of individuals undergoing inpatient alcohol detoxification revealed a correlation between the number of detoxifications conducted and the probability that the individual will have a seizure disorder. To establish the basis for this association we studied drinking histories, drug use, and related characteristics of 500 individuals, 83 of whom were women, who enrolled in an inpatient detoxification program. Discriminant analyses revealed a direct correlation between average daily alcohol consumption and the prevalence of seizures in the alcoholic individuals studied. This correlation was significant, but it was not as strong as that between seizure prevalence and the number of times an individual underwent inpatient detoxification. This data supports the hypothesis that seizures occur in alcoholics because of a long-term kindling effect of recurrent detoxifications and a more short-term effect of ethanol exposure.     

Differential changes in synaptic terminal protein expression between nucleus accumbens core and shell in the amphetamine-sensitized rat

Repeated, intermittent administration of psychostimulant drugs such as D-amphetamine (AMPH) produces a state of behavioral sensitization to the drug that can last up to weeks to months. The molecular basis of this enhanced sensitivity to AMPH is poorly understood; however, adaptive changes in the mesocorticolimbic dopamine system has been postulated to be of primary importance. In the present investigation we used Western blotting to examine the expression of candidate presynaptic proteins involved in regulating neurotransmitter release and synaptic plasticity. Specifically, syntaxin 1, synaptophysin and synapsin I protein levels were examined in the nucleus accumbens (Nacc) and ventral tegmental area (VTA) of Sprague-Dawley rats following AMPH-sensitization. Animals received five repeated administrations of AMPH (1.5 mg/kg, i.p. on alternate days) followed by 14 days of withdrawal. Levels of syntaxin 1 and synaptophysin were found to be significantly reduced in the Nacc core of sensitized animals compared to saline-treated and untreated controls. However, syntaxin 1 expression was significantly increased in the Nacc shell subregion of sensitized animals. No significant difference in the level of synapsin I was noted in any of the brain regions. Further, expression of none of the synaptic proteins was significantly altered in the VTA of sensitized animals. Given the importance of syntaxin and synaptophysin in learning and memory processes and in the regulation of neurotransmitter release, changes in these proteins suggest their involvement in the associative learning aspects of sensitization and differential neurotransmitter release in the Nacc subregions.