Radan Čapek

Reversal of the activity-dependent suppression of GABA-mediated inhibition in hippocampal slices from γ-vinyl GABA (vigabatrin)-pretreated rats

The antiepileptic drug, gamma-vinyl GABA (GVG, vigabatrin), is an irreversible inhibitor of GABA-transaminase, the enzyme responsible for the breakdown of GABA. In hippocampal slices prepared from rats pretreated with either an anticonvulsant dose of GVG (1500 mg/kg) or saline, electrophysiological recordings were performed in order to examine the effects of GVG pretreatment on GABAergic neurotransmission. Although GVG had no effect on the effectiveness of GABA-mediated inhibition when elicited by a single stimulus, it reversed the activity-dependent depression of inhibition which is typically observed when inhibitory pathways are activated repetitively by a train of stimuli delivered at low frequency. Similarly, GVG pretreatment prevented the progressive decline in the amplitude of monosynaptic inhibitory postsynaptic potentials (IPSPs) during low-frequency stimulation of inhibitory interneurons. Thus, in slices from GVG pretreated rats, the amplitudes of both the fast and slow components of the last of a series of IPSPs evoked by a 5 Hz, 4 s train were maintained at 91.5 +/- 6.6% and 87.7 +/- 6.5%, respectively, compared to 61.1 +/- 3.9% and 57.1 +/- 5.0% in control slices. Finally, in slices from GVG pretreated rats, we observed a reduction in the ability of the GABA(B) receptor agonist, baclofen, to decrease the amplitude of monosynaptic inhibitory postsynaptic currents. These results suggest that GVG may produce its frequency-dependent actions by reducing the function of release regulating presynaptic GABA(B) autoreceptors. The frequency-dependent reinforcement of inhibition by GVG may importantly contribute to the anticonvulsant effectiveness of this compound.

12-Month Cognitive Outcomes of Major and Minor Depression in Older Medical Patients

OBJECTIVE To examine the temporal relationship between depression diagnoses and cognitive function in older medical patients. DESIGN Prospective cohort study with repeated follow-up assessments at 3, 6, and 12 months after hospitalization. SETTING The medical services of two acute care hospitals in Montreal, Quebec, Canada. PARTICIPANTS Two hundred eighty-one medical inpatients aged 65 and older without apparent cognitive impairment at study entry. MEASUREMENTS Diagnostic Interview Schedule for depression and Mini-Mental State Examination (MMSE) for cognitive function. RESULTS At study entry, 121 (43.1%) and 51 (18.1%) patients, respectively, met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for major or minor depression. Based on a mixed effects regression model, depression diagnoses were associated with poorer cognitive function, independent of age, education, baseline cognitive and physical function, cardiovascular diseases and other comorbidities, previous history of depression and antidepressant treatment, and fluctuation in the severity of depression symptoms over time. On average across three follow-up assessments, patients with major or minor depression, respectively, had a 0.8 (95% confidence interval: 0.1-1.5) and 1.0 (0.3-1.8) point lower performance on the MMSE than those without depression. In contrast, there was no significant association when depression diagnoses and cognitive function were assessed over shorter intervals or cross-sectionally. A general linear regression model yielded consistent results, with adjusted effect estimates of 0.9 (0.03-0.8) for major and 1.5 (0.5-2.5) for minor depression over 12 months. CONCLUSION A diagnosis of major or minor depression at hospital admission is an independent risk factor for poorer cognitive function during the subsequent 12 months in older medical patients.

Assessing the cumulative effects of exposure to selected benzodiazepines on the risk of fall-related injuries in the elderly.

BACKGROUND The use of benzodiazepines is associated with increased risk of fall-related injuries in the elderly. However, it is unclear if the risks vary across the products and how they depend on the pattern of use and dosage. Specifically, the possibility of cumulative effects of past benzodiazepine use has not been thoroughly investigated. METHODS We used the administrative database for a cohort of 23,765 new users of benzodiazepines, aged 65 years and older, in Quebec, Canada, between 1990 and 1994. The associations between the use of seven benzodiazepines and the risk of fall-related injuries were assessed using several statistical models, including a novel weighted cumulative exposure model. That model assigns to each dose taken in the past a weight that represents the importance of that dose in explaining the current risk of fall. RESULTS For flurazepam, the best-fitting model indicated a cumulative effect of doses taken in the last two weeks. Uninterrupted use of flurazepam in the past months was associated with a highly significant increase in the risk of fall-related injuries (HR = 2.83, 95% CI: 1.45-4.34). The cumulative effect of a 30-day exposure to alprazolam was 1.27 (1.13-1.42). For temazepam, the results suggested a potential withdrawal effect. CONCLUSIONS Mechanisms affecting the risk of falls differ across benzodiazepines, and may include cumulative effects of use in the previous few weeks. Thus, benzodiazepine-specific analyses that account for individual patterns of use should be preferred over simpler analyses that group different benzodiazepines together and limit exposure to current use or current dose.

Acute effects of γ-vinyl GABA (vigabatrin) on hippocampal GABAergic inhibition in vitro

The acute effects of γ-vinyl-GABA (GVG) on GABAergic inhibition were investigated in the hippocampal slice preparation using the paired-pulse test of inhibition during extracellular recordings. Superfusion of GVG (100–500 μM) for 60 min resulted in a concentration-dependent decrease in GABAergic inhibition. Slices superfused with higher concentrations of GVG (0.5–1 mM) were hyperexcitable as demonstrated by the appearance of multiple spikes. Binding studies showed that GVG (1 mM) had no effect on the binding of [3H]flunitrazepam or [3H]TBOB and displaced no more than 15% of specific [3H]GABA binding, which indicates that GVG-induced disinhibition is not mediated through an action at the GABAA receptor complex. Consistent with this suggestion is the finding that GVG (500 μM) had little effect on the inhibition of the orthodromically evoked CA1 population spike produced by the GABAA receptor agonist muscimol (10 μM), whereas this inhibition was considerably attenuated by the GABAA receptor antagonist, bicuculline methiodide (5 μM). The results of this study suggest that the acute actions of GVG on the GABAergic neurotransmitter system are not involved in its anticonvulsant effect.

Antidepressant Use and Cognitive Functioning in Older Medical Patients with Major or Minor Depression–a prospective cohort study with database linkage

Objective: The long-term cognitive effect of antidepressant medications in older persons is not well understood, especially in those with minor depression and complex medical conditions. The objective of this study is to examine this relationship in older medical patients with different depression diagnoses. Methods: 281 medical inpatients aged 65 years and older from 2 acute care hospitals in Montreal, Canada, were diagnosed as with major or minor depression or without depression according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria. They were followed up with the Mini-Mental State Examination for cognitive function and the Hamilton Depression Rating Scale for depressive symptoms at baseline and 3, 6, and 12 months after discharge. Antidepressant medication was ascertained from a provincial prescription database and quantified as cumulative exposures over each follow-up interval. Results: During the 12-month follow-up period, 1027 antidepressant prescriptions were filled. The most frequently prescribed antidepressant agents were citalopram (0.81 prescriptions per person), sertraline (0.76), and paroxetine (0.66). Antidepressant use was not associated with cognitive changes among patients with major depression or without depression but was associated with an increased Mini-Mental State Examination score in patients with minor depression (1.4 points; 95% confidence interval, 0.1-2.6), independent of change in the severity of depression symptoms, concomitant benzodiazepine or psychotropic drug use, and other potentially important confounders. Conclusions: In this cohort of older medical patients, antidepressant use for 12 months did not lead to significant cognitive impairment. The small cognitive improvement among minor depression associated with antidepressant use deserves further investigation.

Phencyclidine suppresses hippocampal long-term potentiation through stereospecific activation of phencyclidine receptors.

The effects of phencyclidine and the dioxolane enantiomers, dexoxadrol and levoxadrol, on long-term potentiation in the hippocampus were compared. Field potentials were evoked by stimulation of Schaffer collaterals and recorded from the CA1 region. Long-term potentiation was induced by stimulation with a single train of 25 pulses at 50 Hz. The drugs were delivered by pressure, 1 min before tetanization. Phencyclidine and its receptors ligand, dexoxadrol, abolished the induction of long-term potentiation. Levoxadrol which has very low affinity for the phencyclidine receptor was devoid of this action although it reduced the magnitude of long-term potentiation. These results indicate that phencyclidine blocks long-term potentiation by stereospecific activation of phencyclidine receptors.

Effect of phencyclidine on inhibition in the hippocampal slice.

SummaryThe effects of phencyclidine (PCP) on synaptic transmission were studied in the hippocampal slice. Population spikes evoked by orthodromic or antidromic stimulation were recorded from CAl pyramidal cells. Bath applied PCP (10−4 M) reduced moderately both the orthodromic and antidromic population spikes. Lower concentrations, 5×10−6 to 5×10−5 M of PCP, which did not depress the population spikes, reduced inhibition of the orthodromically evoked spike in a dose dependent reversible manner. Diazepam (10−6 to 10−5 M) restored the inhibition despite the continued presence of PCP. It is suggested that PCP-induced seizures and other signs of hyperexcitability could be a result of reduced inhibition.

Attenuation of hippocampal inhibition by a NMDA (N-methyl-d-aspartate) receptor antagonist

The effects of the competitive NMDA (N-methyl-D-aspartate) receptor antagonist, APV (2-amino-5-phosphonopentanoate; AP5), were examined in the hippocampal slice preparation. APV (50-100 microM) attenuated inhibition of the orthodromically evoked population spikes in the CA1 region produced by a conditioning stimulus to the alveus or to the stratum radiatum. This suggests that NMDA receptors contribute to synaptic activation of the inhibitory interneurons by a single afferent volley.

Frequency-dependent enhancement of hippocampal inhibition by GABA uptake blockers

The effects of GABA uptake inhibitors, SKF 89976A and SKF 100330A, on recurrent inhibition were studied in the rat hippocampal slice preparation by the antidromic-orthodromic stimulation test. Population spikes evoked orthodromically by stimulation of the stratum radiatum and recorded in the CA1 pyramidal cell body layer were inhibited antidromically by stimulation of the alveus by a single pulse or by a train of pulses, either at low or at high frequency. Low frequency train conditioning produced less inhibition than a single pulse. The uptake blockers had no effect or slightly enhanced the inhibition produced by single stimuli or low frequency trains. High frequency train conditioning produced more and much longer inhibition than a single pulse. This inhibition was further substantially enhanced and prolonged by the drugs. Frequency-dependent enhancement of inhibition may be responsible for suppression of epileptiform discharges by GABA uptake blockers.

Disinhibitory effect of phencyclidine in the hippocampus in vitro: PCP receptors implicated

The effects of phencyclidine (PCP) and two dioxolane stereoisomers, dexoxadrol and levoxadrol, on hippocampal inhibition were compared. Field potentials were recorded in the CA1 pyramidal cell layer in the rat hippocampal slices in vitro. Recurrent inhibition of the population spikes evoked orthodromically by stimulation of the Schaffer collaterals was induced by antidromic conditioning stimulation at appropriate time intervals before the orthodromic stimulation. The drugs were applied by micropressure ejection in concentrations which did not affect the unconditioned population spike. After PCP or dexoxadrol administration, the orthodromically evoked population spike was much less reduced by the antidromic conditioning stimulation than before, suggesting that the recurrent inhibition was diminished. Levoxadrol had only negligible effect. Since dexoxadrol has many PCP-like pharmacological properties but levoxadrol does not, we concluded that PCP attenuates hippocampal recurrent inhibition by activating the PCP receptors. It is suggested that this action results in depression of excitatory synaptic transmission from axon collaterals to the inhibitory interneuron with possible involvement of the N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptor.