Background Adolescent intermittent alcohol exposure (AIE) has profound effects on neuronal function. We have previously shown that AIE causes aberrant hippocampal structure and function that persists into adulthood. However, the possible contributions of astrocytes and their signaling factors remain largely unexplored. We investigated the acute and enduring effects of AIE on astrocytic reactivity and signaling on synaptic expression in the hippocampus, including the impact of the thrombospondin (TSP) family of astrocyte-secreted synaptogenic factors and their neuronal receptor, alpha2delta-1 (α2δ-1). Our hypothesis is that some of the influences of AIE on neuronal function may be secondary to direct effects on astrocytes. Methods We conducted Western blot analysis on TSPs 1–4 and α2δ-1 from whole hippocampal lysates 24hrs after the 4th and 10th dose of AIE, then 24 days after the last dose (in adulthood). We used immunohistochemistry to assess astrocyte reactivity (i.e. morphology) and synaptogenesis (i.e. co-localization of pre- and post-synaptic puncta). Results AIE reduced α2δ-1 expression, and co-localized pre- and post-synaptic puncta after the 4th ethanol dose. By the 10th dose, increased TSP2 levels were accompanied by an increase in co-localized pre- and post-synaptic puncta, while α2δ-1 returned to control levels. 24 days after the last ethanol dose (i.e. adulthood), TSP2, TSP4, and α2δ-1 expression were all elevated. Astrocyte reactivity, indicated by increased astrocytic volume and area, was also observed at that time. Conclusions Repeated ethanol exposure during adolescence results in long-term changes in specific astrocyte signaling proteins and their neuronal synaptogenic receptor. Continued signaling by these traditionally developmental factors in adulthood may represent a compensatory mechanism whereby astrocytes reopen the synaptogenic window and repair lost connectivity, and consequently contribute to the enduring maladaptive structural and functional abnormalities previously observed in the hippocampus after AIE.
These findings indicate that AIE produces long-lasting decreases in dendritic spine density and changes in Fmr1 gene expression in the hippocampal formation, suggesting morphological and epigenetic mechanisms underlying previously reported behavioral deficits after AIE. The reversal of these effects by subchronic, post-AIE donepezil treatment indicates that these AIE effects can be reversed by up-regulating cholinergic function.
Background In recent years, it has become clear that acute ethanol affects various neurobiological and behavioral functions differently in adolescent animals than in adults. However, less is known about the long-term neural consequences of chronic ethanol exposure during adolescence, and most importantly whether adolescence represents a developmental period of enhanced vulnerability to such effects. Methods We made whole cell recordings of GABAA receptor-mediated tonic inhibitory currents from dentate gyrus granule cells (DGGCs) in hippocampal slices from adult rats that had been treated with chronic intermittent ethanol (CIE) or saline during adolescence, young adulthood, or adulthood. Results CIE reduced baseline tonic current amplitude in DGGCs from animals pre-treated with ethanol during adolescence, but not in GCs from those pre-treated with ethanol during young adulthood or adulthood. Similarly, the enhancement of tonic currents by acute ethanol exposure ex vivo was increased in GCs from animals pre-treated with ethanol during adolescence, but not in those from animals pre-treated during either of the other two developmental periods. Conclusions These findings underscore our recent report that CIE during adolescence results in enduring alterations in tonic current and its acute ethanol sensitivity and establish that adolescence is a developmental period during which the hippocampal formation is distinctively vulnerable to long-term alteration by chronic ethanol exposure.
The long-term effects of intermittent ethanol exposure during adolescence (AIE) are of intensive interest and investigation. The effects of AIE on learning and memory and the neural functions that drive them are of particular interest as clinical findings suggest enduring deficits in those cognitive domains in humans after ethanol abuse during adolescence. Although studies of such deficits after AIE hold much promise for identifying mechanisms and therapeutic interventions, the findings are sparse and inconclusive. The present results identify a specific deficit in memory function after AIE and establish a possible neural mechanism of that deficit that may be of translational significance. Male rats (starting at PND-30) received exposure to AIE (5g/kg, i.g.) or vehicle and were allowed to mature into adulthood. At PND-71, one group of animals was assessed using the spatial-temporal object recognition (stOR) test to evaluate memory function. A separate group of animals was used to assess the density of cholinergic neurons in forebrain areas Ch1-4 using immunohistochemistry. AIE exposed animals manifested deficits in the temporal component of the stOR task relative to controls, and a significant decrease in the number of ChAT labeled neurons in forebrain areas Ch1-4. These findings add to the growing literature indicating long-lasting neural and behavioral effects of AIE that persist into adulthood and indicate that memory-related deficits after AIE depend upon the tasks employed, and possibly their degree of complexity. Finally, the parallel finding of diminished cholinergic neuron density suggests a possible mechanism underlying the effects of AIE on memory and hippocampal function as well as possible therapeutic or preventive strategies for AIE.
These studies imply an important role for α4β2 nicotinic receptors in improving sustained attention under conditions that disrupt it. Very low doses of sazetidine-A or drugs with a similar profile may provide therapeutic benefit for reversing attentional impairment in patients suffering from mental disorders and/or cognitive impairment.
Rationale Sazetidine-A is a selective α4β2 nicotinic receptor desensitizing agent and partial agonist. It has been shown in previous studies to significantly reduce nicotine self-administration in rats after acute or repeated injections. However, the effects of continuous chronic infusions of sazetidine-A on maintenance of nicotine self-administration and relapse after abstinence have yet to be examined. Objectives This study evaluated the efficacy of continuous sazetidine-A infusions (sc) over a period of four weeks to reduce nicotine self-administration in male and female Sprague-Dawley rats. Methods Sazetidine-A was administered via Alzet osmotic minipumps to young adult female and male rats at doses of 0, 2 or 6 mg/kg/day for four weeks. The effects of sazetidine-A on IV nicotine self-administration were examined in repeated 3-hour sessions over the first two weeks of infusion followed by one week of forced abstinence from nicotine and one week of resumed nicotine access. Results The 6 mg/kg/day sazetidine-A dose significantly reduced overall nicotine self-administration compared with vehicle control across the sessions for both male (p<0.001) and female (p<0.05) rats. The lower 2 mg/kg/day sazetidine-A infusion dose was effective in reducing nicotine self-administration for male (p<0.001), but not female rats. No attenuation in sazetidine-A effectiveness was seen over the course of the four-week treatment. In the vehicle control group, male rats self-administered significantly (p<0.001) more nicotine than females. Conclusions The continuing effectiveness of sazetidine-A in reducing nicotine self-administration in both male and female rats supports its promise as a new treatment to help people successfully quit smoking.
Background Caffeine, alcohol and nicotine are three of the most widespread self-administered psychoactive substances, which are known to be extensively co-administered. However, little is known about the degree to which they may mutually potentiate each other’s consumption. Methods In the current set of studies, we examined in rats the effect of caffeine administration on alcohol drinking and intravenous (i.v.) self-administration of nicotine. In male alcohol-preferring P rats, caffeine (5, 10 and 20 mg/kg) or the saline vehicle was administered acutely either by subcutaneous (S.C.) injection or orally (PO) by gavage. In a chronic study, the effect of oral caffeine (5 and 20 mg/kg) on alcohol intake over a 10-day period was tested. In another experiment, the effect of acute oral administration of caffeine (20 mg/kg) or saline on saccharin intake (0.2% solution) was determined in P rats. Effects of 20 mg/kg caffeine on motor activity were also determined in P rats. Finally, the effects of acute oral caffeine administration on nicotine self-administration in Sprague-Dawley rats were also determined. Results Both routes of administration of caffeine, S.C. and PO, caused a significant dose-related decrease in alcohol intake and preference during free access to alcohol and after 4-day deprivation of alcohol. However, the low dose of 5 mg/kg caffeine increased alcohol intake. Acute oral caffeine also reduced saccharin intake. Acute systemic administration of 20 mg/kg caffeine did not exert a significant effect on motor activity. In Sprague-Dawley rats trained to self-administer i.v. nicotine, acute oral administration of caffeine significantly increased self-administration of nicotine in a dose-related manner. Conclusions These results suggest that adenosine receptor systems may play a role in both alcohol and nicotine intake and deserve further study regarding these addictions.
It is well established that astrocytes play pivotal roles in neuronal synapse formation and maturation as well as in the modulation of synaptic transmission. Despite their general importance for brain function, relatively little is known about the maturation of astrocytes during normal postnatal development, especially during adolescence, and how that maturation may influence astroglial-synaptic contact. The medial prefrontal cortex (mPFC) and dorsal hippocampus (dHipp) are critical for executive function, memory, and their effective integration. Further, both regions undergo significant functional changes during adolescence and early adulthood that are believed to mediate these functions. However, it is unclear the extent to which astrocytes change during these late developmental periods, nor is it clear whether their association with functional synapses shifts as adolescent and young adult maturation proceeds. Here we utilize an astrocyte-specific viral labeling approach paired with high resolution single cell astrocyte imaging and threedimensional reconstruction to determine whether mPFC and dHipp astrocytes have temporally distinct maturation trajectories. mPFC astrocytes, in particular, continue to mature well into emerging adulthood (postnatal day 70). Moreover, this ongoing maturation is accompanied by a substantial increase in colocalization of astrocytes with the postsynaptic neuronal marker, PSD-95. Taken
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