H. S. Swartzwelder

Prenatal exposure to ethanol decreases physiological plasticity in the hippocampus of the adult rat.

Prenatal exposure to ethanol has been associated with birth defects ranging in severity from physical dysmorphias and profound mental retardation to more subtle compromises of cognitive and behavioral function. Recent evidence has shown the hippocampus to be damaged both morphologically and neurochemically after such exposure in experimental animals. The functional implications of these changes have just recently begun to be addressed. We now report that long-term potentiation and potassium-induced excitability are decreased in hippocampal slices from adult animals exposed to ethanol in-utero. These deficits reflect a decrease in the plasticity of the hippocampal formation. This alteration may be one factor contributing to the memory and learning deficits associated with in-utero exposure to ethanol.

Differential effects of delta9-THC on learning in adolescent and adult rats.

Marijuana use remains strikingly high among young users in the U.S., and yet few studies have assessed the effects of delta9-tetrahydrocannabinol (THC) in adolescents compared to adults. This study measured the effects of THC on male adolescent and adult rats in the Morris water maze. In Experiment 1, adolescent (PD=30-32) and adult (PD=65-70) rats were treated acutely with 5.0 mg/kg THC or vehicle while trained on the spatial version of the water maze on five consecutive days. In Experiment 2, adolescent and adult rats were treated acutely with 2.5 or 10.0 mg/kg THC or vehicle while trained on either the spatial and non-spatial versions of the water maze. In Experiment 3, adolescent and adult rats were treated with 5.0 mg/kg THC or vehicle daily for 21 days, and were trained on the spatial and then the non-spatial versions of the water maze task four weeks later in the absence of THC. THC impaired both spatial and nonspatial learning more in adolescents than in adults at all doses tested. However, there were no long-lasting significant effects on either spatial or non-spatial learning in rats that had been previously exposed to THC for 21 days. This developmental sensitivity is analogous to the effects of ethanol, another commonly used recreational drug.

Seizure activity in vitro: a dual focus model

Recently, we have reported that the exposure of hippocampal slices in vitro to artificial cerebrospinal fluid (ACSF) containing no added magnesium results in ictal-like (ictaform) activity in area CA3 of the hippocampal formation. Other reports describe such activity in slices of entorhinal cortex (EC) under similar conditions. Because of the close interrelationship between the entorhinal area and the hippocampal formation, we have begun to study, in vitro, brain slices which contain both the entorhinal cortex and the hippocampal formation. In these slices, we have found that, in the magnesium-free (0-Mg2+) model, there is good electrical communication between area CA3 and the EC. Simultaneous recordings of the activity in the EC and CA3 showed that, when the circuitry linking the two areas was intact, the EC tended to initiate the ictaform activity and lead CA3. However, late in the event, CA3 could lead EC. Furthermore, interictal-like spontaneous bursting in CA3 led to a disorganized pattern of ictaform activity in EC. Finally, when the EC was separated from the hippocampal formation, both areas were capable of ictaform activity which was temporally unrelated. This model provides the opportunity to explore the relationship between two epileptogenic areas in vitro, and to compare and contrast the morphology of the ictaform activity present in both structures. As such, it may prove valuable in both pharmacological and physiological studies of seizure disorders.

Baclofen disrupts passive avoidance retention in rats

Baclofen (Lioresal, Ciba-Geigy) is an analog of the inhibitory neurotransmitter GABA and is used clinically to control spasticity. Recent studies have demonstrated that this compound produces a marked inhibition of synaptically evoked responses in area CA3 of the hippocampal slice, suggesting that this drug could influence behavior mediated by the limbic system. In the present study, male rats of the Fischer-344 strain were trained on a one-trial passive avoidance task and tested for retention 1 week later. After the training trial, separate groups of rats received either 5 or 10 mg/kg/4 ml IP of baclofen or the distilled H2O vehicle immediately, 10 min, or 60 min after training. One week later, the rats that received baclofen immediately after training reentered the test chamber with a significantly higher frequency than controls, although no differences in vacillatory responses were observed between groups. Similar effects were observed following posttrial administration of chlordiazepoxide. In a separate experiment rats were tested for locomotor activity after receiving the same doses of baclofen. Although baclofen decreased activity during a 30-min period after dosing, rats exposed to baclofen showed no significant change in activity relative to controls 1 week later. These data are consistent with the interpretation that baclofen may interfere with memory consolidation or retention.

Ethanol and magnesium ions inhibit N-methyl-D-aspartate-mediated synaptic potentials in an interactive manner

The role of magnesium ions in the inhibitory effect of ethanol on NMDA receptor-mediated population synaptic potentials (pEPSPs) in area CA1 of the hippocampus of the adult rat, was studied. The excitatory amino acid (non-NMDA) receptor antagonist, DNQX and the GABAA channel antagonist, picrotoxin, were used to pharmacologically isolate NMDA-mediated pEPSPs. In the presence of a physiological concentration of magnesium (1.0 mM), ethanol (25-100 mM) inhibited NMDA-mediated pEPSPs, with an apparent EC50 of approximately 50 mM. The ability of ethanol to inhibit NMDA-mediated pEPSPs was reduced when the slices were incubated in the absence of magnesium. Concentrations of ethanol, in the range of 50-200 mM (apparent EC50 100 mM), were required to inhibit NMDA-mediated pEPSPs, in the absence of added magnesium. Combination studies of these two antagonists indicated that the sensitivity of NMDA-mediated pEPSPs to one antagonist was not altered by the presence of the other. This finding suggests that the affinity of each antagonist binding site is not affected by the presence of the other antagonist. In the case of ethanol, its low maximum antagonist efficacy may require larger concentrations of ethanol to inhibit NMDA-mediated pEPSPs, in the absence of other non-competitive antagonists such as magnesium.

The drug MK-801 attenuates the development, but not the expression, of long-term potentiation and stimulus train-induced bursting in hippocampal slices

Recent studies have demonstrated that (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801), a use-dependent blocker of N-methyl-D-aspartate (NMDA)-activated membrane channels, attenuates the development of long-term potentiation in vitro and kindling in vivo. Both of these phenomena are manifestations of physiological plasticity related to behavioural states and the results of these studies add to the gathering evidence for the involvement of the NMDA receptor/channel system in such processes. In the present experiment, slices of hippocampus, prepared from rats, were electrically stimulated to produce either long-term potentiation of the CA1 population spike or stimulus train-induced epileptiform bursting in area CA3. At 10 microM, MK-801 attenuated the development of long-term potentiation, but had no attenuating effect upon the previously-potentiated population spike. Similarly, 10 microM MK-801 attenuated the development of epileptiform activity in area CA3, but had little or no effect on the previously-established bursting in area CA3. These data support the suggestion that MK-801 exerts an antiepileptogenic, but not an anticonvulsant effect, at concentrations which also inhibit long-term potentiation.

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)

Developmental differences in the sensitivity of hippocampal GABAA receptor-mediated IPSCS to ethanol

BACKGROUND Ethanol consumption by juveniles and adolescents is a public health problem of massive proportions. Recent studies have indicated that adolescents may be less sedated by ethanol than adults, and may thus be able to consume more ethanol, putting them at greater risk for ethanol addiction and other negative consequences of ethanol use. However, the mechanisms underlying this developmental difference are unknown. One contributing factor may be GABAA receptor-mediated inhibition, which is known to produce sedation. Ethanol is known to enhance this inhibitory process. METHODS Using whole cell recording, we tested the response of GABAA receptor-mediated IPSCs in brain slices of rat hippocampus from animals representing three developmental stages: juvenile, early adolescent, and adult. RESULTS We found significantly greater ethanol-induced enhancement of GABA-mediated IPSPs in cells from adult animals compared to those from juvenile or adolescent animals. CONCLUSIONS We conclude that the sensitivity of GABAA receptor-mediated inhibitory processes to ethanol increases with development from the juvenile period to adulthood.

Adolescent intermittent alcohol exposure: persistence of structural and functional hippocampal abnormalities into adulthood.

BACKGROUND Human adolescence is a crucial stage of neurological development during which ethanol (EtOH) consumption is often at its highest. Alcohol abuse during adolescence may render individuals at heightened risk for subsequent alcohol abuse disorders, cognitive dysfunction, or other neurological impairments by irreversibly altering long-term brain function. To test this possibility, we modeled adolescent alcohol abuse (i.e., intermittent EtOH exposure during adolescence [AIE]) in rats to determine whether adolescent exposure to alcohol leads to long-term structural and functional changes that are manifested in adult neuronal circuitry. METHODS We specifically focused on hippocampal area CA1, a brain region associated with learning and memory. Using electrophysiological, immunohistochemical, and neuroanatomical approaches, we measured post-AIE changes in synaptic plasticity, dendritic spine morphology, and synaptic structure in adulthood. RESULTS We found that AIE-pretreated adult rats manifest robust long-term potentiation, induced at stimulus intensities lower than those required in controls, suggesting a state of enhanced synaptic plasticity. Moreover, AIE resulted in an increased number of dendritic spines with characteristics typical of immaturity. Immunohistochemistry-based analysis of synaptic structures indicated a significant decrease in the number of co-localized pre- and postsynaptic puncta. This decrease is driven by an overall decrease in 2 postsynaptic density proteins, PSD-95 and SAP102. CONCLUSIONS Taken together, these findings reveal that repeated alcohol exposure during adolescence results in enduring structural and functional abnormalities in the hippocampus. These synaptic changes in the hippocampal circuits may help to explain learning-related behavioral changes in adult animals preexposed to AIE.

Potential interactions between GABAb and cholinergic systems: baclofen augments scopolamine-induced performance deficits in the eight-arm radial maze.

Sixteen male Fischer-344N rats were trained on a eight-arm radial maze task for food reinforcement. The effects of various doses of baclofen (1.25 or 2.50 mg/kg) and scopolamine (0.188, 0.375, and 0.750 mg/kg) were determined alone and in combination. Relative to vehicle controls, baclofen alone did not affect performance in the radial arm maze (number correct in the first eight responses, total errors) or the time required to complete the maze. Scopolamine alone decreased the number of correct responses in the first eight arm choices, while increasing both the number of errors and the time necessary to complete the maze. When the two drugs were co-administered, baclofen had no effect on the number of errors or time required to complete the maze in the presence of scopolamine; however, in combination with the high dose of scopolamine, it significantly inreased the number of errors made during the first eight choices. Baclofen thus can exacerbate some radial arm maze dificits produced by an anticholinergic drug. In a subsequent experiment to test the interaction between scopolamine and baclofen using a nonlearned behavior, baclofen (1.25 and 2.5 mg/kg) did not affect motor activity, whereas all doses of scopolamine (0.188–0.75 mg/kg) increased activity. The higher dose of baclofen attenuated scopolamine-induced hypermotility by 50%, but the lower dose of baclofen was not effective. These data demonstrate pharmacological interactions between baclofen, a drug used clinically for spaticity, and a drug having anticholinergic properties.