Biomedical subjects

H S Swartzwelder

Publications and source records attributed to H S Swartzwelder.

At least 19 recordsLinked to original sources

PubMed2001

Age-related differences in neurosteroid potentiation of muscimol-stimulated 36Cl(-) flux following chronic ethanol treatment.

Alcoholism and alcohol abuse create costly social and economic problems in many nations. Recent studies indicate that alcohol exposure during adolescence may convey unique risks for subsequent neurocognitive deficits and problem drinking. Although GABA(A) receptor function is one of the principle neurochemical targets of ethanol action in the adult brain, little is known about the effects of alcohol on this system during adolescence. Adolescent (30-day-old) and adult (90-day-old) male rats were intermittently exposed to ethanol for 1 month. At various times after the end of the exposure period, synaptoneurosomes were prepared from their cerebral cortices. GABA(A) receptor-mediated 36Cl(-) influx was measured in the absence and presence of the neurosteroid 3alpha,21-dihydroxy-5alpha-pregnan-20-one (THDOC). In tissue from ethanol-exposed animals, sensitization to the potentiating effects of the neurosteroid was apparent 5 and 12 days after ethanol withdrawal. This sensitization was more apparent at the low concentrations of THDOC in animals pretreated with ethanol as adolescents. Sensitization to the potentiating effects of a neurosteroid is an enduring phenomenon, persistent long after the acute phase of ethanol withdrawal, and may be indicative of long-term changes in GABA(A) receptor function. Enhanced neurosteroid sensitization in animals pretreated as adolescents is consistent with the notion that adolescence is a period of unique sensitivity to the effects of ethanol. This uniqueness may now be extended to the chronic effects of ethanol.

Adolescent↗

PubMed2001

Age-independent and dose-response effects of ethanol on spatial memory in rats.

Results of previous studies have shown that ethanol impairs the acquisition of spatial memory in adolescent rats at doses below those required to impair the acquisition in adults. However, the previous work did not identify doses of ethanol that failed to impair acquisition in adolescents or that impaired acquisition in both adolescent and adult animals. This was our aim in the present study. Male, Long-Evans hooded rats (adolescent and adult) were treated intraperitoneally with 0.0, 0.5, or 2.5 g/kg of ethanol 30 min before daily training on a spatial or nonspatial version of the Morris water maze task. Twenty-four hours after training on the spatial task the animals were given a 1-min probe trial. The low dose of ethanol (0.5 g/kg) failed to impair the performance of animals from either age group on any tasks. It did, however, enhance the initial rate of acquisition on the spatial task. The 2.5-g/kg dose eliminated acquisition of spatial learning in animals of both ages and significantly attenuated performance on a nonspatial task in both age groups. However, the treatment effect in the nonspatial task was eliminated with controlling for baseline performance. These results establish a low dose of ethanol (0.5 g/kg) that does not impair acquisition of spatial memory in adolescent or adult rats. Moreover, the study findings show that 2.5 g/kg of ethanol markedly impairs acquisition of spatial memory in both adolescent and adult animals.

Aging↗

PubMed2000

Prenatal choline supplementation alters hippocampal N-methyl-D-aspartate receptor-mediated neurotransmission in adult rats.

Manipulation of dietary choline levels in pregnant rats has been shown to result in enduring alterations in memory and hippocampal function of the offspring, but the mechanisms underlying these effects remain unclear. Hippocampal slices were prepared from adult rats that were offspring of dams fed control, choline supplemented, or choline deficient diets on days 12-17 of gestation. N-methyl-D-aspartate (NMDA) receptor-mediated population excitatory postsynaptic potentials (pEPSPs) were pharmacologically isolated and evoked using electrical stimulus pulses applied to s. radiatum of area CA1. Evoked NMDA receptor-mediated pEPSPs were enhanced in slices from prenatally choline supplemented relative to controls in both male and female rats. The greatest differences occurred at the low end of the input-output curve, among responses that were less than 60% of maximal. These results are discussed in the context of previous behavioral and electrophysiological studies.

Age Factors↗

PubMed2000

Prenatal choline exposure alters hippocampal responsiveness to cholinergic stimulation in adulthood.

Manipulation of dietary choline levels during gestation results in enduring neurobehavioral changes in offspring that last into adulthood. Alterations of hippocampal function and memory are among the most striking changes. Depending upon the measures assessed, prenatal choline supplementation tends to promote excitatory synaptic efficacy in hippocampal circuits while prenatal choline deficiency diminishes it. However, the mechanisms underlying these changes remain unclear. Transverse hippocampal slices were prepared from adult offspring of dams fed choline supplemented, choline deficient, or control diets. We assessed paired-pulse inhibition, and excitatory synaptic responsiveness before and after activation of cholinergic receptors with Carbachol. Prenatally choline deficient animals yielded significantly fewer electrophysiological viable hippocampal slices than did animals from either of the other two treatment groups. Among the slices tested, there were no differences in paired pulse inhibition between the treatment groups. However, transient cholinergic activation resulted in a prolonged enhancement of the amplitude of the population EPSP (pEPSP) response in slices from prenatally choline supplemented animals. These results suggest that GABA receptor-mediated inhibition remains intact after prenatal choline manipulations, and that enhancement of the excitatory responsiveness of hippocampal circuits in slices from prenatally choline supplemented rats may be related in part to an increase in cholinergic tone within the CA1 circuit.

Animals↗

PubMed2000

Binge pattern ethanol exposure in adolescent and adult rats: differential impact on subsequent responsiveness to ethanol.

BACKGROUND: Recent evidence indicates that adolescent animals are more sensitive than adults to the disruptive effects of acute ethanol exposure on spatial learning. It is not yet known whether adolescent animals are also more sensitive than adults to the enduring neurobehavioral effects of repeated ethanol exposure. In this study, animals were exposed to ethanol in a binge-pattern during either adolescence or adulthood. At a time when all subjects were adults, spatial working memory was examined in the absence and presence of an acute ethanol challenge. METHODS: Rats were exposed to ethanol (5.0 g/kg intraperitoneally) or isovolumetric saline at 48 hr intervals over 20 days. Exposure began on either postnatal day 30 (adolescent group) or 70 (adult group). Twenty days after the final injection, a time at which all animals were adults, the subjects were tested on an elevated plus maze and then were trained to perform a spatial working memory task on an eight-arm radial maze. At the beginning of each session of training on the working memory task, subjects retrieved food rewards on four of the eight arms. After a delay, subjects were placed on the maze and allowed to retrieve food from the remaining four arms. RESULTS: Prior exposure to ethanol did not influence behavior on the plus maze. Performance of the groups did not differ during acquisition of the spatial working memory task with a 5 min delay or during subsequent testing with a 1 hr delay. However, animals treated with ethanol during adolescence exhibited larger working memory impairments during an ethanol challenge (1.5 g/kg intraperitoneally) than subjects in the other three groups. CONCLUSIONS: The findings indicate that binge pattern exposure to ethanol during adolescence enhances responsiveness to the memory-impairing effects of ethanol in adulthood.

Aging↗

PubMed1999

Choline availability to the developing rat fetus alters adult hippocampal long-term potentiation.

Supplementation with choline during pregnancy in rats causes a long-lasting improvement of visuospatial memory of the offspring. To determine if the behavioral effects of choline are related to physiological changes in hippocampus, the effect of perinatal choline supplementation or deficiency on long-term potentiation (LTP) was examined in hippocampal slices of 6-8 and 12-14 month old rats born to dams consuming a control, choline-supplemented, or a choline-free diet during pregnancy. Stimulating and recording electrodes were placed in stratum radiatum of area CA1 to record extracellular population excitatory postsynaptic potentials (pEPSPs). To induce LTP, a theta-like stimulus train was generated. The amplitude of the stimulus pulses was set at either 10% or 50% of the stimulus intensity which had induced the maximal pEPSP slope on the input/output curve. We found that at both ages, a significantly smaller percentage of slices from perinatally choline-deficient rats displayed LTP after 10% stimulus intensity (compared with control and choline-supplemented rats), and a significantly larger percentage of slices from choline-supplemented rats displayed LTP at 50% stimulus intensity (compared with control and choline-deficient rats). Results reveal that alterations in the availability of dietary choline during discrete periods of development lead to changes in hippocampal electrophysiology that last well into adulthood. These changes in LTP threshold may underlie the observed enhancement of visuospatial memory seen after prenatal choline supplementation and point to the importance of choline intake during pregnancy for development of brain and memory function.

Aging↗

PubMed1999

Developmental changes in seizure susceptibility during ethanol withdrawal.

It has recently been established that adolescence may represent a developmentally sensitive period with respect to the effects of ethanol, particularly within the NMDA neurotransmitter system. However, the same may also be true of the GABA system. There is evidence to suggest that the number of GABA receptors and their kinetics may change across development. The purpose of this study was to determine if GABA-mediated seizure susceptibility during ethanol withdrawal differed between adolescent and adult animals. Results indicate that adult animals pretreated with ethanol were more likely to achieve maximal tonic-clonic seizure activity and spent more time in stage 3 (or higher) seizure activity than all other groups. These data lend additional support to the contention that adolescent and adult animals differ in their susceptibility to the effects of ethanol and that this susceptibility is transmitter dependent.

Age Factors↗

PubMed1999

Age and dose-dependent effects of ethanol on the induction of hippocampal long-term potentiation.

Hippocampal long-term potentiation (LTP) is strongly associated with the acquisition of spatial memory and is attenuated by ethanol. Recent studies have shown that the inhibitory potency of ethanol against n-methyl-d-aspartate (NMDA) receptor-mediated synaptic activity is enhanced in hippocampal slices taken from juvenile rats compared to those taken from adults. In addition, ethanol has been reported to impair spatial memory acquisition at lower doses in adolescent rats compared to adults. We therefore hypothesized that the suppression of hippocampal LTP by ethanol would be more potent in hippocampal slices taken from adolescent rats compared to those taken from adults. The potency of ethanol against NMDA receptor-mediated LTP was assessed in area CA1 of hippocampal slices taken from adolescent (30 days old) and adult (90 days old) rats. In slices from adolescent rats, theta-burst stimulus trains reliably induced robust LTP in the absence of ethanol, but when the stimulus trains were presented in the presence of either 10 mM or 30 mM ethanol, LTP induction was significantly suppressed relative to controls. In contrast, there was no effect of these ethanol concentrations on the induction of LTP in hippocampal slices from adult rats. These observations indicate that ethanol suppresses LTP in the adolescent hippocampus at concentrations that do not affect than it suppresses in the adult slices, suggesting a much greater sensitivity to ethanol in adolescence.

Age Factors↗

PubMed1998

Developmental differences in the acquisition of tolerance to ethanol.

This study was designed to compare the development of tolerance to ethanol in adolescent and adult rats. Rats were pretreated with ethanol (4 g/kg) twice daily by intragastric gavage for 3 or 7 days, and then challenged with a single IP dose of ethanol (5 g/kg). Throughout the pretreatment period body temperature was measured before and after the morning dosage. During the IP challenge test we measured body temperature, duration of the loss of righting reflex, and blood ethanol level upon regaining the righting reflex. The adolescent rats that were pretreated for 7 days developed greater tolerance to the effects of ethanol on body temperature during the pretreatment period. No tolerance was observed in animals that received only 3 days of pretreatment. Ethanol decreased body temperature to a greater extent in adolescent animals than adults in response to the IP challenge dose, but there was no significant difference between control and pretreated animals in either age group. The time to regain the righting reflex was lower in adolescent rats than in adults. Post hoc analyses indicated that 7 days of ethanol pretreatment diminished the effects of the IP ethanol challenge on the loss of righting reflex in adolescent but not adult rats. Although adolescent rats regained the righting reflex with higher blood ethanol levels than adults, there was no significant effect of ethanol pretreatment on that measure. These findings indicate that the development of tolerance to the temperature regulatory effects of ethanol is more marked in the adolescent rat than in the adult. This developmental difference in ethanol sensitivity is consistent with other recent findings and suggests that adolescence may be a period of unique sensitivity to a number of the behavioral and physiological effects of ethanol.

Aging↗

PubMed1998

Impairment of semantic and figural memory by acute ethanol: age-dependent effects.

Alcohol drinking is prevalent among young adults in the U.S. Moreover, heavy drinking is acknowledged by a substantial percentage of young adults in both college and military subpopulations, despite the known cognitive demands associated with these endeavors and the cognitive impairments associated with alcohol usage. We assessed the acute effects of ethanol (0.6 g/kg) on the acquisition of both semantic and figural memory in a sample of young adults from 21 to 29 years of age using a repeated-measures, placebo-controlled experimental design. Ethanol significantly impaired memory acquisition in both domains. In addition, the effect of ethanol on three of the four memory measures assessed was dependent on the age of the subjects. Subjects in a young subgroup (21 to 24 years of age) were significantly more impaired in memory measures than those in the subgroup that was 25 to 29 years of age. These results indicate a divergence of the potency of ethanol against memory acquisition across a narrow age range in early adulthood. Whereas these data are preliminary, and should be generalized cautiously, they are also consistent with a growing literature using animal models that indicates that acute ethanol is a more potent antagonist of memory and memory-related hippocampal activity in adolescent animals compared with adults.

Adult↗

PubMed1998

Prenatal dietary choline supplementation decreases the threshold for induction of long-term potentiation in young adult rats.

Choline supplementation during gestation in rats leads to augmentation of spatial memory in adulthood. We hypothesized that prenatal (E12-E17) choline supplementation in the rat would lead to an enhancement of hippocampal synaptic plasticity as assessed by long-term potentiation (LTP) at 3-4 mo of age. LTP was assessed blindly in area CA1 of hippocampal slices with first suprathreshold (above threshold for LTP generation in control slices) theta-burst stimulus trains. The magnitude of potentiation after these stimuli was not different between slices from control and prenatally choline supplemented animals. Next, threshold (reliably leading to LTP generation in control slices) or subthreshold theta-burst stimulus trains were applied to slices from control, prenatally choline-supplemented, and prenatally choline-deprived rats. Threshold level stimulus trains induced LTP in slices from both the control and choline-supplemented rats but not in those from the choline-deficient rats. Subthreshold stimulus trains led to LTP induction in slices from prenatally choline-supplemented rats only. These observations indicate that prenatal dietary manipulation of the amino acid, choline, leads to subsequent significant alterations of LTP induction threshold in adult animals.

Animals↗

PubMed1998

Differential effects of ethanol on memory in adolescent and adult rats.

Previous studies have shown that ethanol inhibits memory-related synaptic activity and plasticity more potently in hippocampal slices from immature rats, compared with those taken from adults. We therefore hypothesized that ethanol would more potently attenuate the acquisition of spatial memory in adolescents, compared with adult rats. Adult (65 days of age) and adolescent (30 days of age) male rats were given five daily trials on a spatial memory task in a Morris Water Maze. The animals from each age group were subdivided into three subgroups. Each day, thirty minutes before training, the animals in each subgroup were given an intraperitoneal injection of 1.0 g/kg of ethanol, 2.0 g/kg of ethanol, or the saline vehicle. Training continued daily until the control animals had reached a performance criterion. Ethanol treatment significantly impaired spatial memory acquisition in the adolescent rats, but did not impair acquisition in adult rats. A separate experiment with identical treatment groups showed that ethanol did not impair acquisition of a nonspatial memory task in the water maze in animals from either age group. These experiments show that the acquisition of spatial, but not nonspatial, memory is more potently impaired by ethanol in adolescent animals, compared with adults.

Aging↗

PubMed1996

Medial septal benzodiazepine receptors modulate hippocampal evoked responses and long-term potentiation.

Infusion of benzodiazepine (BDZ) receptor ligands into the medial septum (MS) produces a bidirectional modulation of spatial memory retention. The present experiments sought to determine the effects of BDZ ligands upon synaptic responses and long-term potentiation (LTP) in the dentate gyrus following electrical stimulation of the angular bundle. Intraseptal infusion of the BDZ agonist, chlordiazepoxide, decreased the amplitude of the evoked population spike and increased paired-pulse facilitation at a 150-ms interstimulus interval (ISI) in a dose-dependent manner. Intraseptal infusion of the BDZ antagonist, flumazenil (10 nmol), enhanced the amplitude of the dentate population spike and also increased paired-pulse facilitation at the 150-ms ISI. There was no effect of either BDZ receptor ligand upon the slope of the rising phase of the evoked population excitatory postsynaptic potential (pEPSP). Intraseptal flumazenil also significantly enhanced the magnitude of dentate LTP induced by high-frequency stimulation of the angular bundle. Intraseptal chlordiazepoxide failed to alter LTP induction. These results indicate that intraseptal infusion of an amnestic dose of the BDZ ligand, chlordiazepoxide, decreases the excitatory responsiveness of the dentate gyrus to its synaptic input from entorhinal cortex. In contrast, the promnestic BDZ ligand, flumazenil, enhances dentate granule cell responsivity, and facilitates synaptic plasticity in the dentate gyrus network. Taken together these data suggest that the memory impairing and memory enhancing action of these compounds may be a function of their ability to alter hippocampal physiology during a critical phase of memory. The potential role of septodentate cholinergic and GABAergic projections in the present observation is discussed.

Animals↗

PubMed1996

Hippocampal long-term potentiation and spatial learning in the rat: effects of GABAB receptor blockade.

This series of experiments assessed the role of GABAB receptors in the induction of long-term potentiation in the dentate gyrus in vivo, and spatial learning and memory in three different tasks. In urethane-anesthetized rats, the GABAB receptor antagonist CGP 46381 was injected intraperitoneally at a dose which effectively suppressed GABAB-mediated paired pulse disinhibition. Theta-burst stimulation reliably produced long-term potentiation in control rats. However, GABAB receptor blockade significantly suppressed the induction of long-term potentiation in the dentate gyrus. To compare the results of the long-term potentiation experiments with behavior, we assessed the performance of rats on several spatial learning and memory tasks in the presence of CGP 46381. We found that the working memory performance of highly trained rats on the eight-arm radial maze was unaffected by CGP 46381. There was also no effect of GABAB receptor blockade on learning in the eight-arm maze using a five-trial repeated acquisition paradigm. However, when we tested spatial learning in naive rats using a mildly stressful water maze task, we found that CGP 46381 substantially impaired both the latency to find the platform and the path-length travelled in the maze during acquisition. CGP 46381-treated rats took longer to learn the location of the escape platform and travelled a greater distance over the acquisition trials. These data demonstrate that GABAB receptor blockade results in a suppression of hippocampal long-term potentiation in vivo and impairs spatial learning in a task where stress may be a component of performance.

Animals↗

PubMed1996

Differential effects of ethanol in adolescent and adult rats.

Alcohol use in children and adolescents is widespread. However, very little is known about the effects of alcohol exposure during this period of postnatal development. The goal of the present study was to compare the relative sensitivity to the sedative effects of alcohol in periadolescent and adult rats. After treatment with either 4 or 5 g/kg ethanol, both 20- and 30-day-old rats regained their righting reflex significantly earlier than 60-day old rats. In 30-day-old rats, serum ethanol concentrations (SECs) were significantly greater at the time of the recovery of the righting reflex than 60-day-old rats. Developmental differences in the effects of ethanol on locomotor activity were also observed. In 60-day-old rats, 2.5 g/kg ethanol generally decreased locomotor activity. Ethanol did not significantly alter locomotor activity in 20- and 30-day-old rats. Finally there were significant developmental differences in the pharmacokinetics of ethanol with a significant delay in the time to peak SECs in 60-day-old rats relative to 20- and 30-day-old rats. These findings indicate that peri-adolescent rats are less sensitive to the sedative effects of ethanol as they recovered their righting reflex earlier and at significantly higher SECs than adult rats.

Age Factors↗

PubMed1995

GABAB receptors modulate synaptically-evoked responses in the rat dentate gyrus, in vivo.

We assessed the effects of systemically injected baclofen, a GABAB agonist, on single and paired-pulse responses in the dentate gyrus of urethane-anesthetized rats, in vivo. Baclofen (10 mg/kg) significantly increased the duration of single excitatory responses. This increase was blocked by the GABAB receptor antagonist, CGP 35348, indicating that baclofen was acting through GABAB receptors. To determine the mechanism underlying this increase in response duration, the NMDA antagonist, D-2-amino-5-phosphonopentanoic acid (D-APV), was administered intracerebroventricularly (i.c.v.) after baclofen. D-APV by itself had no effect on the duration of the population excitatory post-synaptic potential (EPSP). However, when infused after baclofen, D-APV blocked the baclofen induced increase in EPSP duration. This indicates the prolonged EPSP duration caused by baclofen resulted from an enhancement of an NMDA receptor mediated component of the response. We then examined the effect of baclofen on population responses to paired stimuli. Baclofen attenuated paired-pulse inhibition of population spike amplitudes at a 25 ms interstimulus interval. CGP-35348 reduced the effect of baclofen on paired-pulse inhibition, indicating that baclofen suppressed paired-pulse inhibition by acting on GABAB receptors. In contrast to its disinhibitory effect at the 25 ms interval, baclofen had an inhibitory effect on responses evoked at a 150 ms interstimulus interval. Under control conditions, we observed that when stimuli were delivered 150 ms apart, both the EPSP duration and population spike amplitude evoked by the second stimulus were enhanced. Baclofen suppressed this enhancement.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Age-dependent inhibition of long-term potentiation by ethanol in immature versus mature hippocampus.

The goal of this study was to assess the effects of ethanol on the induction of long-term potentiation (LTP) in hippocampal slices from immature versus mature rats. Population excitatory postsynaptic potentials (pEPSPs) were recorded from stratum radiatum of area CA1 of hippocampal slices using electrical stimulation of the Schaffer collateral/commissural fiber pathway. The slices were prepared from rats aged 15 to 25 or from 70 to 100 days. Long-term potentiation (LTP) of the pEPSP slope was induced using a single, theta-burst stimulus train in the presence or absence of 60 mM ethanol. Under control conditions, the stimulus train induced LTP in slices from both immature and mature animals. However, the magnitude of LTP was greater in slices from immature rats. When ethanol was present during the stimulus train, the magnitude of LTP in slices from mature animals did not differ significantly from the magnitude of LTP in control slices. However, ethanol virtually blocked the induction of LTP in slices from immature animals. These results indicate that memory-related synaptic plasticity in the hippocampus is attenuated by ethanol to a greater degree in immature versus mature animals.

Age Factors↗

PubMed1995

Differential sensitivity of NMDA receptor-mediated synaptic potentials to ethanol in immature versus mature hippocampus.

Pharmacologically isolated, NMDA receptor-mediated population EPSPs (pEPSPs) were evoked from area CA1 of hippocampal slices using electrical stimulation of the Schaffer collateral/commissural fiber pathway. Slices were prepared from rats aged 20-25 or 80-100 days. The inhibitory effects of a range of ethanol concentrations were assessed. While ethanol antagonized NMDA-mediated pEPSPs in slices from both age groups, it was significantly more potent against pEPSPs from immature versus mature hippocampi. In slices from mature animals, significant and consistent reduction of pEPSPs was observed only with the highest ethanol concentration (100 mM), whereas 10, 30, or 100 mM significantly reduced the amplitude of pEPSPs in slices from immature animals. These results indicate that NMDA-mediated synaptic activity in the hippocampus is more sensitive to the effects of ethanol in immature versus mature animals.

Age Factors↗