Mobility behaviour and driving status of patients with mental disorders - an exploratory study.

BACKGROUND: Driving is an important activity of daily life and an integral part of mobility. However, impact of mental illness on road mobility is widely unexplored. METHOD: Driving status in 1497 psychiatric inpatients (PPs) and a clinical control group of 313 neurological inpatients (NPs) was investigated using a brief questionnaire. RESULTS: 67% of PPs (89% NPs) reported to have a valid driver's licence and 77% of them (92% NPs) reported to regularly use their cars. Within driver's license holders, patients with organic mental disorder (32%), substance dependence (37%) and psychotic disorder (40%) had the lowest proportion of current drivers. Higher educational qualification (odds ratio [OR] from 2.978 to 17.036) and being married/partnered (OR 3.049) or divorced (OR 4.840) significantly advanced the probability of possession of a driving license. Predictive factors for driving cessation were being female, an older age, drawing a pension and having an organic mental disease or schizophrenic disorder. CONCLUSION: Mental disease has a negative impact on driving status and this is especially true for illnesses frequently being accompanied by distinct cognitive impairments. Factors predicting road mobility elucidate the strong relationship with psychosocial status indicating that recovery of driving competence should be an integral goal of treatment strategies.

Correlation between distal motor latency and compound muscle action potential in amyotrophic lateral sclerosis.

OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder, characterized by a selective progressive degeneration of the motor system. Electromyography is essential for the diagnosis of ALS. The measurement of motor conduction of peripheral nerves is of major importance to recognize other possible causes of progressive muscle wasting. However, there are also pathologic changes in nerve conduction studies in ALS patients. METHODS: In this study we analysed the values of distal motor latency (DML), compound muscle action potential (CMAP) and motor nerve conduction velocity (MNCV) in 95 patients with definite ALS. RESULTS: We found slight slowing of MNCV and moderate to strong reduction of CMAP and a prolongation of DML. We found no significant correlation between MNCV and CMAP. DISCUSSION: The main finding of the present work was the negative correlation between DML and CMAP. It is interpreted as a very distal axonal damage as the main reason for prolongation of DML in ALS patients.

[Diagnosis and treatment of amyotrophic lateral sclerosis]. / Paresen-Muskelatrophien-Spastik: Denken Sie an die amyotrophe Lateralsklerose.

Like Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which a very defined population of neurons selectively degenerates. Muscular atrophy and central paresis develop in ALS patients relatively quickly--usually within months to a few years. Bulbar symptoms such as swallowing disorders and dysarthria are frequently observed in the beginning. The disease progresses steadily and without remission. The average length of survival after diagnosis is two to three years. The diagnosis is made on the basis of a characteristic group of symptoms and confirmed or substantiated through additional clinical neurological tests. Currently, the cause of the disease cannot be treated. Treatment concentrates primarily on symptomatic measures and providing supportive devices.

Molecular analysis of the interaction of the pyrazine derivatives RPR119990 and RPR117824 with human AMPA-type glutamate receptor channels.

Antagonizing glutamatergic neurotransmission by blockade of AMPA-type glutamate receptors is a promising pharmacological strategy in the treatment of neurodegenerative diseases. We investigated the interaction of two new pyrazine derivatives (RPR119990 and RPR117824) with recombinant AMPA-type glutamate receptors. Recombinant homooligomeric GluR1flop, GluR2flip, GluR2flop, GluR6, non-desensitizing GluR2 L504Y channels and heterooligomeric GluR1/2 channels were expressed in HEK293 cells. AMPA-type channels were competitively inhibited by RPR119990 or RPR117824 with an IC(50) around 10 nM, at GluR6 channels the dose-response relation of the inhibition was shifted to higher concentrations. Non-desensitizing GluR2 L504Y channels were used to further characterize the inhibition. After equilibration with the agonist a marked dose-dependent current decay upon coapplication of glutamate and RPR119990 and a dose-independent time course of recovery from block was observed. The extents of current inhibition as well as the time constant of current decay upon addition of the blocker to the test solution were dependent on agonist concentration, pointing to a competitive inhibition. Quantitative analysis of the experimental data using computerized simulations are compatible with a competitive block mechanism and provides hints to binding sites at unliganded and liganded closed states of the receptor.

GABA(A)-receptor mRNA expression in the prefrontal and temporal cortex of ALS patients.

There is evidence that excitotoxic cell death is involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). Electrophysiological and histological studies support the pathophysiological concept of an impaired inhibitory, namely GABAergic, control of the motoneurons in the cerebral cortex of ALS patients. Recently, pathological, neuropsychological and functional imaging data have challenged the view that ALS is a disorder restricted to the motor system. The aim of our study was to investigate the expression of the most abundant GABA(A)-receptor subunit mRNAs and the GABA synthesizing enzyme glutamic acid decarboxylase (GAD) in the prefrontal, temporal, occipital and cerebellar cortex of ALS patients compared to tissue of control persons. We performed in situ hybridization histochemistry (ISH) on human post-mortem cortex sections of ALS patients (n=5) and age-matched controls with no history of neurological disease (n=5). In the prefrontal and temporal cortex of ALS patients, we detected significantly reduced mRNA expression of the alpha1-subunit, while the GABA synthesizing enzyme glutamic acid decarboxylase (GAD) was significantly upregulated in these regions. In the occipital and cerebellar cortex, we did not see disease-specific differences of the mRNA expression of the investigated subunits.

Two mechanisms of action of the adamantane derivative IEM-1460 at human AMPA-type glutamate receptors.

1. Antagonizing glutamatergic neurotransmission by blockade of AMPA-type glutamate receptors (GluR) is a promising pharmacological strategy for neuroprotection in neurodegenerative diseases and acute treatment of stroke. 2. We investigated the interaction of the adamantane derivative IEM-1460 with human wild-type and mutant AMPA-type GluR channels. Different recombinant homooligomeric human AMPA-type GluR channels and a rat nondesensitizing mutant GluR (GluR2 L504Y) channel were expressed in HEK293 cells and investigated using the patch-clamp technique in combination with ultrafast agonist application. 3. When IEM-1460 was coapplied with glutamate, an open channel block mechanism was observed at slow desensitizing GluR2 flip (>/=0.1 mM IEM-1460) and nondesensitizing GluR2 L504Y channels (>/=1 microM IEM-1460). 4. A competitive block of AMPA-type channels was observed with IC(50) values for the dose block curves of 0.1 mM IEM-1460 at human unmutated and 10 microM IEM-1460 at mutant GluR channels. 5. Nondesensitizing GluR2 L504Y channels were used to further characterize the block mechanism. After equilibration with the agonist, a current decay upon coapplication of glutamate and IEM-1460 was observed. The recovery from block was independent of the glutamate and IEM-1460 concentration. The extent of current inhibition as well as the time constant of current decay upon addition of the blocker to the test solution were dependent on agonist concentration; this strongly points to an additional competitive-like block mechanism of IEM-1460 at human AMPA-type GluR channels. 6. The data were interpreted in the frame of a molecular scheme with two binding sites of IEM-1460 at the receptor, one at the unliganded resting and the other at the fully liganded open state of the channels.

Structural features of phenol derivatives determining potency for activation of chloride currents via alpha(1) homomeric and alpha(1)beta heteromeric glycine receptors.

Phenol derivatives constitute a family of neuroactive compounds. The aim of our study was to identify structural features that determine their modulatory effects at glycine receptors. We investigated the effects of four methylated phenol derivatives and two halogenated analogues on chloride inward currents via rat alpha(1) and alpha(1)beta glycine receptors, heterologously expressed in HEK 293. All compounds potentiated the effect of a submaximal glycine concentration in both alpha(1) homomeric and alpha(1)beta glycine receptors. While the degree of maximum potentiation of the glycine 10 microM effect in alpha(1)beta receptors was not different between the compounds, the halogenated compounds achieved half-maximum potentiating effects in the low microM range -- at more than 20-fold lower concentrations compared with their nonhalogenated analogues (P<0.0001). The coactivating effect was over-ridden by inhibitory effects at concentrations >300 microM in the halogenated compounds. Neither the number nor the position of the methyl groups significantly affected the EC(50) for coactivation. Only the bimethylated compounds 2,6 and 3,5 dimethylphenol (at concentrations >1000 microM) directly activated both alpha(1) and alpha(1)beta receptors up to 30% of the maximum response evoked by 1000 microM glycine. These results show that halogenation in the para position is a crucial structural feature for the potency of a phenolic compound to positively modulate glycine receptor function, while direct activation is only seen with high concentrations of compounds that carry at least two methyl groups. The presence of the beta subunit is not required for both effects.

Effects of propofol on recombinant AMPA receptor channels.

The interaction of the anaesthetic propofol with recombinant human AMPA-type glutamate receptor channels was investigated by a patch-clamp study using fast agonist application techniques. Despite the marked effects of propofol on inhibitory synaptic transmission and voltage gated sodium channels, there is also evidence for a specific pharmacological action on AMPA receptors. In our study, we observed a deceleration of AMPA receptor channel desensitization in the prolonged presence of glutamate and propofol that is likely to account for the enhancement of ion currents through AMPA receptor channels observed in previous studies. While there was an increase in the rate and extent of desensitization at glutamate receptor 1, glutamate receptor 2, and glutamate receptor 3 AMPA receptors, no affection of current rise time, peak current amplitude, and deactivation properties was observed. Thus, our findings point to an isolated interaction with processes that control desensitization of AMPA receptor channels rather than indicating an interaction with channel opening and closing processes due to agonist binding and unbinding. The pharmacological effect described resembles in part that of compounds like cyclothiazide and aniracetam which are known to interact with channel desensitization.

Distribution of GABAA receptor mRNA in the motor cortex of ALS patients.

The pathomechanism of amyotrophic lateral sclerosis (ALS) remains unclear. There is some evidence that excitotoxic cell death is involved in the degeneration of the motor nervous system, and that ligand-gated receptor channels play a role in the pathogenesis of the disease. Several electrophysiological and anatomical studies support the pathophysiological concept of an impaired inhibitory, namely GABAergic, control of the motoneurons in the cerebral cortex of ALS patients. The aim of our study was to investigate the expression of GABAA-receptor subunit mRNAs and the GABA synthesizing enzyme glutamic acid decarboxylase (GAD) in the motor cortex of ALS patients compared to tissue of control persons. We performed in situ hybridization histochemistry (ISH) on human postmortem motor cortex sections of ALS patients (n = 5) and age matched controls with no history of neurological disease (n = 5). The most intriguing finding was a significantly reduced mRNA expression of the alpha1-subunit in ALS patients while the level of beta1-subunit mRNA was elevated in the patients group. This may indicate specific alterations of the GABAA receptor subunit composition and result in distinct physiological and pharmacological properties of these receptors in ALS patients.

Human GABA A receptors on dopaminergic neurons in the pars compacta of the substantia nigra.

The gamma-aminobutyric acid A (GABA(A)) receptor subunit expression of the dopaminergic cells of the substantia nigra (SN) was investigated in the present study. Especially the dopaminergic cells, located in the pars compacta of SN (SNc), are of great neurologic interest, because the functional deficit and depletion of these cells are the correlate of Parkinson's disease. We used a combination of in situ hybridization histochemistry (ISH) and immunohistochemistry (IHC) on sections of human postmortem mesencephalon to investigate the expression of GABA(A) receptor subunit messenger RNAs (mRNAs) and of the receptor protein in dopaminergic SN cells. Immunohistochemical detection of tyrosine hydroxylase (TH), the pivotal enzyme of dopamine synthesis, was used to define the boundaries of SN pars reticulata (SNr) and pars compacta subregions. In SNr, all neurons were labeled by subunit-specific oligonucleotide probes and the amount of GABA(A) receptor mRNA expression was quantified as alpha(1) = beta(2) > gamma(2) > alpha(3). In contrast, in SNc, only around 25% of neurons expressed mRNA transcripts of GABA(A) receptor subunits, quantified as alpha(1) = beta(2) > gamma(2) > alpha(3) > alpha(4) = beta(3). In approximately the same percentage of neurons, which were labeled by alpha(1)-subunit-specific probe, the alpha(1)-subunit also was detected at the protein level by a specific monoclonal antibody. We, therefore, could demonstrate that a subset of dopaminergic neurons in human SNc receive inhibitory synaptic input by means of GABA(A) receptors mainly of the alpha(1)beta(2)gamma(2) subtype. This might represent a negative feedback loop between the striatum and the SNc and be a target of pharmacologic interventions in neurodegenerative diseases such as Parkinson's disease.

Competitive and open channel block of recombinant nAChR channels by different antibiotics.

Various antibiotics may impair neuromuscular transmission, provoking symptoms of myasthenia in patients with a compromised safety margin of the synaptic transmission, but little is known about the underlying mechanisms at the molecular level. Using a modified patch-clamp technique in combination with an ultrafast system for solution exchange we investigated the functional interaction of gentamicin, penicillin G, tetracycline, erythromycin and ceftriaxone with nAChR transiently transfected into HEK293 cells as a potential molecular target. Gentamicin, penicillin G, tetracycline and erythromycin induced a combination of open channel and competitive block of nAChR channel currents whereas ceftriaxone had no effect. The IC50 for the competitive block was close to or within the range of clinically relevant concentrations. Except for erythromycin the open channel block was observed only at higher concentrations. From our in-vitro results we conclude that competitive inhibition of nAChR channels by antibiotics is an important mechanism underlying the impairment of neuromuscular transmission under clinical conditions.

Congenital myasthenic syndrome due to a novel missense mutation in the gene encoding choline acetyltransferase.

Congenital myasthenic syndromes are caused by different genetic defects affecting proteins expressed at the neuromuscular junction. Recently, the first molecular genetic defect resulting in a presynaptic congenital myasthenic syndrome has been reported: Recessive loss-of-function mutations in CHAT, the gene encoding choline acetyltransferase, were described in five congenital myasthenic syndrome families. In this study, we investigated three patients from two independent Turkish kinships. Clinically, all patients presented with moderate myasthenic symptoms including ptosis and muscle weakness with increased fatigability. Multiple episodes of sudden apnea were reported for all patients. One child suffering from a second, unrelated disorder, i.e. hepatocellular carcinoma, showed a severe myasthenic phenotype, requiring permanent ventilation. Genetically, we identified a novel missense mutation (I336T) in the CHAT gene homozygously in all three patients. Haplotype analysis revealed that the mutant allele cosegregates with the clinical phenotype in both families (maximum combined two-point LOD-score of 2.46 for D10S1793). In summary, we confirm that CHAT mutations are responsible for a clinically distinct form of congenital myasthenic syndrome, characterized by episodic apnea. Infections and stress may lead to a life-threatening failure of neuromuscular transmission in congenital myasthenic syndrome with episodic apnea. The observation of the same mutation (I336T) in two independent Turkish kinships may suggest a common origin, i.e. founder.

Block of voltage-operated sodium channels by 2,6-dimethylphenol, a structural analogue of lidocaine's aromatic tail.

1. The structural features that determine the state-dependent interaction of local anaesthetics with voltage-operated sodium channels are still a matter of debate. We have studied the blockade of sodium channels by 2,6-dimethylphenol, a phenol derivative which resembles the aromatic tail of lidocaine, etidocaine, and bupivacaine. 2. The effects of 2,6-dimethylphenol were studied on heterologously (HEK 293) expressed rat neuronal (rat brain IIA) and human skeletal muscle (hSkM1) sodium channels using whole-cell voltage-clamp experiments. 3. 2,6-Dimethylphenol was effective in blocking whole-cell sodium inward currents. Its potency was comparable to the potency of lidocaine previously obtained with similar protocols by others. The IC(50) at -70 mV holding potential was 150 and 187 microM for the skeletal muscle and the neuronal isoform, respectively. In both isoforms, the blocking potency increased with the fraction of inactivated channels at depolarized holding potentials. However, the block achieved at -70 mV with respect to -150 mV holding potential was significantly higher only in the skeletal muscle isoform. The estimated dissociation constant K(d) from the inactivated state was 25 microM and 28 microM in the skeletal muscle and the neuronal isoform, respectively. The kinetics of drug equilibration between resting and inactivated channel states were about 10 fold faster compared with lidocaine. 4. Our results show that the blockade induced by 2,6-dimethylphenol retains voltage-dependency, a typical feature of lidocaine-like local anaesthetics. This is consistent with the hypothesis that the 'aromatic tail' determines the state-dependent interaction of local anaesthetics with the sodium channel.

An improved model for the binding of lidocaine and structurally related local anaesthetics to fast-inactivated voltage-operated sodium channels, showing evidence of cooperativity.

1. The interaction of lidocaine-like local anaesthetics with voltage-operated sodium channels is traditionally assumed to be characterized by tighter binding of the drugs to depolarized channels. As inactivated and drug-bound channels are both unavailable on depolarization, an indirect approach is required to yield estimates for the dissociation constants from channels in inactivated states. The established model, originally described by Bean et al., describes the difference in affinity between resting and inactivated states in terms of the concentration dependence of the voltage shift in the availability curve. We have tested the hypothesis that this model, which assumes a simple Langmuir relationship, could be improved by introducing a Hill-type exponent, which would take into account potential sources of cooperativity. 2. Steady-state block by lidocaine was studied in heterologously (HEK 293) expressed human skeletal muscle sodium channels and compared with experimental data previously obtained for 2,6-dimethylphenol, 3,5-dimethyl-4-chlorophenol, and 4-chlorophenol. Cells were clamped to membrane potentials from -150 to -5 mV, and a subsequent test pulse was used to assess the number of channels available to open. 3. All compounds shifted the voltage dependence of channel availability in the direction of negative prepulse potentials. Prediction of the concentration dependence of the voltage shift in the availability curve was improved by the modified model, as shown by a marked reduction in the residual sum of squares. 4. For all compounds, the Hill-type exponent was significantly greater than one. These results could be interpreted in the light of the contemporary hypothesis that lidocaine functions as an allosteric gating effector to enhance sodium channel inactivation by strengthening the latch mechanism of inactivation, which is considered to be a particle-binding process allosterically coupled to activation. Alternatively, they could be interpreted by postulating additional binding sites for lidocaine on fast-inactivated sodium channels.

Kinetic analysis of the agonistic and blocking properties of pentobarbital on recombinant rat alpha(1)beta(2)gamma(2S) GABA(A) receptor channels.

Barbiturates have three different effects on the GABA(A) receptor channels: coactivation, direct activation, and blockage. We investigated the activation and blockage of the GABA(A) receptor channels by pentobarbital using the alpha(1)beta(2)gamma(2S) GABA(A) receptor channels transiently expressed in HEK293 cells in combination with the ultrafast application of agonists. The peak current amplitude of the pentobarbital activated ionic current proportionally increased to the first power of the pentobarbital concentration (Hill coefficient approximately 0.7), indicating that one binding step of pentobarbital at alpha(1)beta(2)gamma(2S) GABA(A) receptor channels can describe the experimental dose-response relation. The maximum peak current amplitude occurred at 1 mM pentobarbital and decreased at higher concentrations due to an open channel block. After the end of the pentobarbital pulses, rebound currents due to transition from the open-blocked to the open state of the receptor were observed. A kinetic scheme was constructed allowing the quantitative analysis of the pentobarbital activated ionic currents through GABA(A) receptor channels.

Two different modes of action of pentobarbital at glycine receptor channels.

Glycine receptor channels are pentameric ligand-gated ion channels which respond to the binding of inhibitory transmitters by opening of a chloride-selective central pore. Pentobarbital is widely used as an anticonvulsive, hypnotic and anaesthetic drug. In the present study, the interaction between pentobarbital and glycine receptor channels was studied on outside-out patches of human embryonic kidney (HEK) 293 cells expressing alpha(1)beta glycine receptor channels. Currents elicited by 0.03 mM glycine were enhanced by pentobarbital showing potentiation of alpha(1)beta glycine receptor channels. In the presence of 1 mM glycine+pentobarbital (1 and 3 mM), desensitization was faster and the peak current amplitude decreased. After the end of glycine+pentobarbital pulses, off-currents occurred suggestive for a channel block mechanism. Pentobarbital had no agonistic effects at glycine receptor channels.

Triple stimulation technique (TST) in amyotrophic lateral sclerosis.

OBJECTIVE: The authors studied amyotrophic lateral sclerosis (ALS) patients using triple stimulation technique (TST) to detect upper motor neuron (UMN) involvement. METHODS: Nineteen ALS patients (aged 45-72 years) were enrolled in the study. According to the El Escorial criteria, 6 diagnoses were suspected or possible, 6 probable, and 7 definite. Patients were examined clinically, with conventional (single-pulse) transcranial magnetic stimulation (TMS), and with TST (on one side only). RESULTS: Among the whole group of patients, TST appeared to be more sensitive than conventional TMS techniques. In particular among suspected/possible ALS patients, TST area ratio was pathologic in 100%, while single-pulse TMS was abnormal only in 50% of cases. Overall, the use of TST area ratio was more sensitive than the analysis of TST amplitude ratio. CONCLUSIONS: The results suggest that TST might be more sensitive and useful in the diagnosis of subclinical UMN involvement than conventional TMS techniques, even if TST is performed on one side only.

The mRNA expression of AMPA type glutamate receptors in the primary motor cortex of patients with amyotrophic lateral sclerosis: an in situ hybridization study.

The pathogenetic mechanisms leading to progressive neurodegeneration in amyotrophic lateral sclerosis (ALS) have not been fully elucidated. One possible factor responsible for the selective motor neuron loss in the motor cortex, brain stem and spinal cord is glutamate-induced excitotoxicity particularly mediated via alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) type glutamate receptors. Data about the expression pattern of AMPA receptors in the primary motor cortex are lacking so far. The pharmacological and physiological properties of AMPA receptors are defined by the heteromeric composition of the four different receptor subunits. Different expression patterns of these subunits at motor neurons may provide a molecular basis for increased vulnerability to excitotoxic damage. Using in situ hybridization histochemistry we did not detect any significant differences in the distribution of AMPA receptor mRNA in the motor cortex of ALS patients compared to controls.

Monitoring CSF proteome alterations in amyotrophic lateral sclerosis: obstacles and perspectives in translating a novel marker panel to the clinic.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal disorder of the motor neuron system with poor prognosis and marginal therapeutic options. Current clinical diagnostic criteria are based on electrophysiological examination and exclusion of other ALS-mimicking conditions. Neuroprotective treatments are, however, most promising in early disease stages. Identification of disease-specific CSF biomarkers and associated biochemical pathways is therefore most relevant to monitor disease progression, response to neuroprotective agents and to enable early inclusion of patients into clinical trials. METHODS AND FINDINGS: CSF from 35 patients with ALS diagnosed according to the revised El Escorial criteria and 23 age-matched controls was processed using paramagnetic bead chromatography for protein isolation and subsequently analyzed by MALDI-TOF mass spectrometry. CSF protein profiles were integrated into a Random Forest model constructed from 153 mass peaks. After reducing this peak set to the top 25%, a classifier was built which enabled prediction of ALS with high accuracy, sensitivity and specificity. Further analysis of the identified peptides resulted in a panel of five highly sensitive ALS biomarkers. Upregulation of secreted phosphoprotein 1 in ALS-CSF samples was confirmed by univariate analysis of ELISA and mass spectrometry data. Further quantitative validation of the five biomarkers was achieved in an 80-plex Multiple Reaction Monitoring mass spectrometry assay. CONCLUSIONS: ALS classification based on the CSF biomarker panel proposed in this study could become a valuable predictive tool for early clinical risk stratification. Of the numerous CSF proteins identified, many have putative roles in ALS-related metabolic processes, particularly in chromogranin-mediated secretion signaling pathways. While a stand-alone clinical application of this classifier will only be possible after further validation and a multicenter trial, it could be readily used to complement current ALS diagnostics and might also provide new insights into the pathomechanisms of this disease in the future.

Selective and nonselective benzodiazepine agonists have different effects on motor cortex excitability.

Transcranial magnetic stimulation (TMS) is a useful method to study pharmacological effects on motor cortex excitability. Zolpidem is a selective agonist of the benzodiazepine receptor subtype BZ1 and has a distinct pharmacological profile compared to diazepam. To study the different effects of these two drugs on the cortical inhibitory system, TMS was performed before and after administration of a single oral dose of zolpidem (10 mg) and diazepam (5 mg) in six healthy volunteers. TMS tests included the determination of resting and active motor threshold (MT) and measurements of the amplitudes of motor evoked potentials, intracortical facilitation (ICF), short-latency intracortical inhibition (SICI), and long-latency intracortical inhibition (LICI), and determination of the cortical silent period (CSP). Both drugs were without effect on the active or resting MT and decreased the ICF. Prolongation of the CSP and enhancement of LICI only in the presence of zolpidem point to a specific BZ1-related mechanism underlying the long-lasting component of cortical inhibition. This selective modulation of the CSP and the LICI points to a specific role of BZ1 receptors in the control of inhibitory neuronal loops within the primary motor cortex.