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Antidepressants are commonly supposed to enhance serotonergic and/or noradrenergic neurotransmission by inhibition of neurotransmitter reuptake through binding to the respective neurotransmitter transporters or through inhibition of the monoamine oxidase. Using the concentration-clamp technique and measurements of intracellular Ca2+, we demonstrate that different classes of antidepressants act as functional antagonists at the human 5-HT3A receptor stably expressed in HEK 293 cells and at endogenous 5-HT3 receptors of rat hippocampal neurons and N1E-115 neuroblastoma cells. The tricyclic antidepressants desipramine, imipramine, and trimipramine, the serotonin reuptake inhibitor fluoxetine, the norepinephrine reuptake inhibitor reboxetine, and the noradrenergic and specific serotonergic antidepressant mirtazapine effectively reduced the serotonin-induced Na+- and Ca2+-currents in a dose-dependent fashion. This effect was voltage-independent and, with the exception of mirtazapine, noncompetitive. Desipramine, imipramine, trimipramine, and fluoxetine also accelerated receptor desensitization. Moclobemide and carbamazepine had no effect on the serotonin-induced cation current. By analyzing analogues of desipramine and carbamazepine, we found that a basic propylamine side chain increases the antagonistic potency of tricyclic compounds, whereas it is abolished by an uncharged carboxamide group. The antagonistic effects of antidepressants at the 5-HT3 receptor did not correlate with their effects on membrane fluidity. In conclusion, structurally different types of antidepressants modulate the function of this ligand-gated ion channel. This may represent a yet unrecognized pharmacological principle of antidepressants.Molecular Psychiatry (2003) 8, 994-1007. doi:10.1038/sj.mp.4001314 [ABSTRACT FROM AUTHOR]

Summary Background and objective The gamma-aminobutyric acid[sub A] receptor (GABA[sub A]R) is a target for anaesthetic agents. We investigated the interactions of sevoflurane with a recombinant GABA[sub A]R. Emphasis was on the mechanism of block, as relevant open-channel block by a volatile anaesthetic would possibly explain prolonged GABAergic postsynaptic currents. Methods The effect of sevoflurane on GABA-induced currents through recombinant alpha[sub 1]beta[sub 2]gamma[sub 2] GABA[sub A]R channels was studied (patch clamp; HEK293 cells). GABA 0.01 mM or 1 mM was applied alone or together with sevoflurane (0.05 mM to 5 mM). Results Currents elicited by GABA 0.01 mM were increased by low sevoflurane concentrations to 183% and decreased by high sevoflurane concentrations (>1 mM) to 34% (P<0.05). Ten- to 90%-rise times of the currents were reduced by sevoflurane concentration dependently. At GABA (1 mM), peak currents and 10-90%-rise times decreased with increasing sevoflurane concentrations. A transient current increase was induced by discontinuation of GABA and sevoflurane. Such rebound currents indicate a reversal of an open-channel block by sevoflurane. Conclusions Sevoflurane (a) increases the apparent affinity of GABA to the GABA[sub A]R, as suggested by the decreased current rise times. This explains the enhancement of the currents induced by low GABA concentrations (0.01mM). Additionally, sevoflurane (b) induces a picrotoxin-like open-channel block at the GABA[sub A]R. The reversal of the open-channel block elicits a delayed GABA response. These findings indicate at least two different sites of action of sevoflurane at this receptor that are both important for an enhanced GABAergic synaptic transmission. [ABSTRACT FROM AUTHOR]

The article focuses the antagonistic behavior of antipsychotic drugs with human serotonin type 3 (5-HT3) receptor currents in a noncompetitive manner. It indicates representative recordings of 5-HT-evoked sodium ion currents after application of serotonin and the neuroleptics.

Abstract Activation of adrenoreceptors modulates synaptic transmission in the basolateral amygdala. Here, we investigated the effects of α2 -adrenoreceptor activation on long-term depression and long-term potentiation in an in vitro slice preparation of the mouse basolateral amygdala. Field potentials and excitatory postsynaptic currents were evoked in the basolateral amygdala by stimulating the lateral amygdala. Norepinephrine (20 µm) reduced synaptic transmission and completely blocked the induction of long-term potentiation and long-term depression. The α2 -adrenoreceptor antagonist yohimbine (2 µm) reversed this effect. The α2 -adrenoreceptor agonist clonidine (10 µm) mimicked the effects of norepinephrine. The Gi/o -protein inhibitor pertussis toxin (5 µg/mL) reversed the effect of clonidine. Long-term depression was blocked in the presence of ω-conotoxin GVIA, but not ω-agatoxin IVA. Clonidine inhibited voltage-activated Ca2+ currents mediated via N- or P/Q-type Ca2+ -channels. The inhibitory action of clonidine on long-term depression was reversed when inwardly rectifying K+ -channels were blocked by Ba2+ (300 µm). The present data suggest that α2 -adrenoreceptor activation impairs the induction of long-term depression in the basolateral amygdala by a Gi/o -protein-mediated inhibition of presynaptic N-type Ca2+ -channels and activation of inwardly-rectifying K+ -channels. [ABSTRACT FROM AUTHOR]

The convulsant effects of α-thujone, the psychotropic component of absinthe, were attributed to inhibitory actions at the GABAA receptor. Here, we investigated for the first time the 5-HT3 receptor as a potential site of the psychotropic actions of α-thujone. This cation permeable ligand-gated ion channel shows considerable homology to the GABAA receptor. We previously demonstrated that in homomeric assemblies of cloned human 5-HT3A receptor subunits, the endogenous agonist 5-HT induced desensitization via channel blockade. When the 5-HT3B receptor subunit was co-expressed, the resulting heteromeric assemblies desensitized independent from channel blockade. In the present study, patch-clamp experiments revealed an inhibitory action of α-thujone on both homomeric and heteromeric 5-HT3 receptors. This inhibitory action was mediated via channel blockade. However, it was not α-thujone itself which blocked the channel. The present experiments suggested that, in homomeric receptors, α-thujone enhanced the inherent channel-blocking potency of the natural ligand, 5-HT. In heteromeric receptors, α-thujone recruited an additional channel-blocking component of the agonist. By means of kinetic modeling, we simulated possible mechanisms by which α-thujone decreased the 5-HT-induced responses. It is suggested that α-thujone reduced 5-HT3 receptor activity by an effect on mechanisms involved in receptor desensitization, which depend on receptor subunit composition. It remains to be shown if this inhibitory action on serotonergic responses contributes to behavioral effects of α-thujone. [Copyright &y& Elsevier]

This study examines the impact of post-migration living difficulties (PMLDs) and quality of life (QoL) on the mental health of 55 young refugees who arrived in Germany either accompanied or unaccompanied. The results reveal that nearly 62% of the participants exhibited clinically significant symptoms of depression or post-traumatic stress disorder. Regression analyses indicate that psychopathology was associated with being unaccompanied and experiencing lower QoL, while QoL was associated with higher economic status and lower PMLDs. Mediation analysis further demonstrates that higher economic status and reduced PMLDs were associated with higher QoL, which, in turn, correlated with lower levels of psychopathology. These findings emphasise the importance of considering PMLDs and QoL, as well as economic status and being accompanied/unaccompanied, in the assessment and treatment of young refugees in the host country., (© 2024 John Wiley & Sons Ltd.)

Young refugees are a high-risk group for mental disorders, particularly for posttraumatic stress disorder (PTSD). Individuals with PTSD suffer from an altered time perspective with a focus on negative experiences in the past and a disregard for positive life events and the future. This study investigates time perspectives and psychological distress in 30 adolescent refugees from Syria and Afghanistan in Germany. Time perspective was assessed using the Zimbardo Time Perspective Inventory. The refugees exhibited a distorted time perspective that is common for individuals with PTSD: a high orientation toward the negative past and a low orientation toward the positive past and future. A high orientation toward the negative past was associated with high levels of general psychological distress, PTSD symptoms, and depression. A low orientation toward the future was related to high levels of anxiety. Taking time perspective and corresponding beliefs into consideration may be advantageous when treating refugees with trauma-related disorders.

Effectiveness of stabilization training for adolescent refugees with trauma-induced disorders: A randomized controlled trial Abstract. Unaccompanied minor refugees (UMR) are a group particularly vulnerable to mental illness. They pose a great challenge not only for child and youth psychiatric and psychotherapeutic care, but also for youth-welfare institutions. The study examines the effectiveness of Stabilization Training for Adolescent Refugees with Trauma Induced Disorders in inpatient youth-welfare facilities. Methods: We conducted a randomized controlled trial with pre-post design in a naturalistic setting, randomly assigning 9 housing groups for UMRs to the intervention or waiting control condition. The mental stress of 46 UMRs was assessed by both self-report and educational staff-report. Two educational staff members conducted the Stabilization Training for Adolescent Refugees with Trauma Induced Disorders as an intervention in each of the respective residential groups. Results: Participation in training led to a reduction in subjective general psychological stress. At the end of the training, psychological stress in self-judgment was significantly lower in the intervention group than in the waiting control condition. The effectiveness of the training is apparently not reflected by educational staff assessments. Conclusions: Stabilization training is a suitable instrument for the preclinical care of UMR and thus an essential basis for further psychotherapy.

Alterations in temporal processing may represent a primary cause of key symptoms in ADHD. This study is aimed at investigating the nature of time-processing alterations in ADHD and assessing the possible utility of testing time estimation for clinical diagnostics. Retrospective verbal time estimation in the range of several minutes was examined in 50 boys with ADHD and 53 boys with other mental disorders. All participants (age 7-16) attended an outpatient clinic for ADHD diagnostics. The diagnostic assessment included the WISC-IV. Subjects with ADHD made longer and less accurate duration estimates than the clinical control group. The ADHD group showed a specific WISC-IV profile with processing speed deficits. In the ADHD group there was a correlation between processing speed and quality of time estimation that was not observed in the comparison group: higher processing speed indices were related to more accurate duration estimates. The findings provide support for the presence of a faster internal clock in subjects with ADHD and lend further support to the existence of a specific WISC-IV profile in subjects with ADHD. The results show that analyzing WISC-IV profiles and time estimation tasks are useful differential diagnosis tools, particularly when it comes to distinguishing between "real ADHD" and pseudo-ADHD.

Objective: This article is the first investigation into the proportion of unaccompanied refugee minors suffering from psychiatric disorders in Germany. Method: In a retrospective study done between 2013 and 2015, any refugees showing symptoms of a psychiatric disorder during their stay in a residential refugee center were referred to an Outpatient Department of Child and Adolescent Psychiatry for diagnostic assessment. To this end, special consultation hours were arranged. Besides the diagnoses, the number of emergency consultations occurring before and after the implementation of the special consultation hours was recorded., Results: Of the 75 refugee minors (75 %) referred, 56 were suffering from a psychiatric disorder, with posttraumatic stress disorder and depression being the most common diagnoses. Following implementation of the consultation hours, the number of refugee patients initially admitted in the Child and Adolescent Psychiatry on an emergency basis fell., Conclusions: Unaccompanied refugee minors are a highly vulnerable group that poses great challenges to clinical care. The implementation of special consultation hours is a constructive option for meeting these challenges. In particular, this special offer enables improvement of crisis management in the case of emergency consultations.

Flupirtine is a centrally acting nonopioid analgesic with muscle-relaxant properties. Flupirtine has been found to activate inwardly rectifying potassium conductances and hence to indirectly inhibit the activation of NMDA receptors. NMDA receptor activation is crucial for the induction of long-term potentiation (LTP) of synaptic transmission, which is considered as cellular correlate of learning and memory and of central sensitization in chronic pain states. Although flupirtine has been widely used for the management of pain, its effects on synaptic plasticity have not yet been investigated. We, therefore, performed extracellular and whole-cell patch-clamp recordings in hippocampal slices of mice to examine the effects of flupirtine on synaptic plasticity and neuronal membrane properties. Excitatory postsynaptic potentials (EPSPs) in the CA1 region were evoked alternately by stimulating two independent Schaffer collateral-commissural inputs. LTP and long-term depression (LTD) were induced by different stimulation paradigms (100 Hz, 10 Hz, 5 Hz, and 1 Hz). Flupirtine (30 microM) diminished the degree of LTP and enhanced LTD. This effect is most likely due to the hyperpolarization of CA1 pyramidal neurons and the reduction of their input resistance found after application of flupirtine. The observed effects on synaptic strength could underly the beneficial effects of flupirtine on different types of chronic pain.

Attempts have been made to attribute the particular features of general anaesthesia such as hypnosis, analgesia, amnesia and autonomic stability to certain brain regions. In the present study, we examined the effects of the commonplace volatile anaesthetic isoflurane on synaptic transmission in an in vitro slice preparation of the murine amygdala. Despite the established role of this limbic structure in the formation of aversive memories, conditioned fear and anxiety, as well as pain processing and regulation of sympathetic tone, the influence of volatile anaesthetics on synaptic signalling has not yet been investigated in this region of the brain. Evoked postsynaptic currents were monitored from principal neurons in the basolateral nucleus of the amygdala by means of patch-clamp recording. The mixed postsynaptic currents were mediated by non-NMDA, NMDA, GABA A and GABA B receptors. Isoflurane added to the perfusion medium reduced the strength of synaptic signalling following the activation of non-NMDA, NMDA, and GABA B receptors, whereas the GABA A receptor-mediated responses were enhanced. The overall reduction of neuronal excitability was also reflected in a reduction of field potential amplitudes. Isoflurane neither changed the membrane resting potential nor the input resistance of principal neurons in the amygdala. The present results may contribute to the understanding of how stress reactions and long-lasting neuroplastic processes are suppressed under general anaesthesia.

Unlabelled: The minimum alveolar concentration (MAC) of a volatile anesthetic defines anesthetic potency in terms of a suppressed motor response to a noxious stimulus. Therefore, the MAC of an anesthetic might in part reflect depression of motor neuron excitability. In the present study we evaluated the effect of isoflurane (ISO) on neurons in the substantia gelatinosa driven synaptically by putative nociceptive inputs in an in vitro spinal cord preparation of the rat. Whole-cell patch-clamp recordings were performed in neurons with their soma in the substantia gelatinosa of transverse rat spinal cord slices. We investigated the effect of ISO on excitatory postsynaptic currents (EPSC) evoked by dorsal root stimulation (eEPSC), spontaneous (sEPSC), and miniature (mEPSC) EPSC. ISO reversibly reduced the amplitude of eEPSC to 39% +/- 22% versus control. ISO decreased the frequency of sEPSC and mEPSC to 39% +/- 26% and 63% +/- 7%. Neither the amplitudes nor the kinetics of mEPSC and sEPSC were altered by ISO. We conclude that ISO depresses glutamatergic synaptic transmission of putative nociceptive primary-afferent inputs, presumably by reducing the release of the excitatory transmitter. This effect may contribute to an antinociceptive action of volatile anesthetics at the spinal cord level., Implications: The present electrophysiological in vitro experiments provide evidence that the volatile anesthetic isoflurane reduces excitatory transmitter release at the first site of synaptic integration of nociceptive inputs, the spinal cord superficial dorsal horn. This effect may contribute to the anesthetic action of volatile anesthetics at the spinal cord level.

The convulsant effects of alpha-thujone, the psychotropic component of absinthe, were attributed to inhibitory actions at the GABAA receptor. Here, we investigated for the first time the 5-HT3 receptor as a potential site of the psychotropic actions of alpha-thujone. This cation permeable ligand-gated ion channel shows considerable homology to the GABAA receptor. We previously demonstrated that in homomeric assemblies of cloned human 5-HT,A receptor subunits. the endogenous agonist 5-HT induced desensitization via channel blockade. When the 5-HT3 B receptor subunit was co-expressed, the resulting heteromeric assemblies desensitized independent from channel blockade. In the present study, patch-clamp experiments revealed an inhibitory action of alpha-thujone on both homomeric and heteromeric 5-HT3 receptors. This inhibitory action was mediated via channel blockade. However, it was not alpha-thujone itself which blocked the channel. The present experiments suggested that, in homomeric receptors, alpha-thujone enhanced the inherent channel-blocking potency of the natural ligand. 5-HT. In heteromeric receptors, alpha-thujonerecruited an additional channel-blocking component of the agonist. By means of kinetic modeling, we simulated possible mechanisms by which alpha-thuljone decreased the 5-HT-induced responses. It is suggested that alpha-thujone reduced 5-HT3 receptor activity by an effect on mechanisms involved in receptor desensitization, which depend on receptor subunit composition. It remains to be shown if this inhibitory action on serotonergic responses contributes to behavioral effects of alpha-thujone.

Activation of adrenoreceptors modulates synaptic transmission in the basolateral amygdala. Here, we investigated the effects of alpha2-adrenoreceptor activation on long-term depression and long-term potentiation in an in vitro slice preparation of the mouse basolateral amygdala. Field potentials and excitatory postsynaptic currents were evoked in the basolateral amygdala by stimulating the lateral amygdala. Norepinephrine (20 micro m) reduced synaptic transmission and completely blocked the induction of long-term potentiation and long-term depression. The alpha2-adrenoreceptor antagonist yohimbine (2 micro m) reversed this effect. The alpha2-adrenoreceptor agonist clonidine (10 micro m) mimicked the effects of norepinephrine. The Gi/o-protein inhibitor pertussis toxin (5 micro g/mL) reversed the effect of clonidine. Long-term depression was blocked in the presence of omega-conotoxin GVIA, but not omega-agatoxin IVA. Clonidine inhibited voltage-activated Ca2+ currents mediated via N- or P/Q-type Ca2+-channels. The inhibitory action of clonidine on long-term depression was reversed when inwardly rectifying K+-channels were blocked by Ba2+ (300 micro m). The present data suggest that alpha2-adrenoreceptor activation impairs the induction of long-term depression in the basolateral amygdala by a Gi/o-protein-mediated inhibition of presynaptic N-type Ca2+-channels and activation of inwardly-rectifying K+-channels.