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Biomedical subjects

H Möhler

Publications and source records attributed to H Möhler.

At least 19 recordsLinked to original sources
PubMed2006

GABA(A) receptor diversity and pharmacology.

Because of its control of spike-timing and oscillatory network activity, gamma-aminobutyric acid (GABA)-ergic inhibition is a key element in the central regulation of somatic and mental functions. The recognition of GABA(A) receptor diversity has provided molecular tags for the analysis of distinct neuronal networks in the control of specific pharmacological and physiological brain functions. Neurons expressing alpha(1)GABA(A) receptors have been found to mediate sedation, whereas those expressing alpha(2)GABA(A) receptors mediate anxiolysis. Furthermore, associative temporal and spatial memory can be regulated by modulating the activity of hippocampal pyramidal cells via extrasynaptic alpha(5)GABA(A) receptors. In addition, neurons expressing alpha(3)GABA(A) receptors are instrumental in the processing of sensory motor information related to a schizophrenia endophenotype. Finally, during the postnatal development of the brain, the maturation of GABAergic interneurons seems to provide the trigger for the experience-dependent plasticity of neurons in the visual cortex, with alpha(1)GABA(A) receptors setting the time of onset of a critical period of plasticity. Thus, particular neuronal networks defined by respective GABA(A) receptor subtypes can now be linked to the regulation of various clearly defined behavioural patterns. These achievements are of obvious relevance for the pharmacotherapy of certain brain disorders, in particular sleep dysfunctions, anxiety disorders, schizophrenia and diseases associated with memory deficits.

Animals↗
PubMed2005

A schizophrenia-related sensorimotor deficit links alpha 3-containing GABAA receptors to a dopamine hyperfunction.

Overactivity of the dopaminergic system in the brain is considered to be a contributing factor to the development and symptomatology of schizophrenia. Therefore, the GABAergic control of dopamine functions was assessed by disrupting the gene encoding the alpha3 subunit of the GABA(A) receptor. alpha3 knockout (alpha3KO) mice exhibited neither an obvious developmental defect nor apparent morphological brain abnormalities, and there was no evidence for compensatory up-regulation of other major GABA(A)-receptor subunits. Anxiety-related behavior in the elevated-plus-maze test was undisturbed, and the anxiolytic-like effect of diazepam, which is mediated by alpha2-containing GABA(A) receptors, was preserved. As a result of the loss of alpha3 GABA(A) receptors, the GABA-induced whole-cell current recorded from midbrain dopamine neurons was significantly reduced. Spontaneous locomotor activity was slightly elevated in alpha3KO mice. Most notably, prepulse inhibition of the acoustic startle reflex was markedly attenuated in the alpha3KO mice, pointing to a deficit in sensorimotor information processing. This deficit was completely normalized by treatment with the antipsychotic D2-receptor antagonist haloperidol. The amphetamine-induced hyperlocomotion was not altered in alpha3KO mice compared with WT mice. These results suggest that the absence of alpha3-subunit-containing GABA(A) receptors induces a hyperdopaminergic phenotype, including a severe deficit in sensorimotor gating, a common feature among psychiatric conditions, including schizophrenia. Hence, agonists acting at alpha3-containing GABA(A) receptors may constitute an avenue for an effective treatment of sensorimotor-gating deficits in various psychiatric conditions.

Amphetamine↗
PubMed2005

Pathophysiology and pharmacology of GABA(A) receptors.

By controlling spike timing and sculpting neuronal rhythms, inhibitory interneurons play a key role in brain function. GABAergic interneurons are highly diverse. The respective GABA(A) receptor subtypes, therefore, provide new opportunities not only for understanding GABA-dependent pathophysiologies but also for targeting of selective neuronal circuits by drugs. The pharmacological relevance of GABA(A) receptor subtypes is increasingly being recognized. A new central nervous system pharmacology is on the horizon. The development of anxiolytic drugs devoid of sedation and of agents that enhance hippocampus-dependent learning and memory has become a novel and highly selective therapeutic opportunity.

Animals↗
PubMed2005

Hippocampal alpha5 subunit-containing GABAA receptors modulate the expression of prepulse inhibition.

Prepulse inhibition (PPI) refers to the phenomenon in which a low-intensity prepulse stimulus attenuates the reflexive response to a succeeding startle-eliciting pulse stimulus. The hippocampus, among other structures, is believed to play an important role in the modulation of PPI expression. In alpha5(H105R) mutant mice, the expression of the alpha5 subunit-containing GABA(A) receptors in the hippocampus is reduced. Here, we report that PPI was attenuated, and spontaneous locomotor activity was increased in alpha5(H105R) mutant mice. These effects were apparent in both genders. Thus, alpha5 subunit-containing GABA(A) receptors, which are located extrasynaptically and are thought to mediate tonic inhibition, are important regulators of the expression of PPI and locomotor exploration. Post-mortem analyses of schizophrenia brains have consistently revealed structural abnormalities of a developmental origin in the hippocampus. There may be a possibility that such abnormalities include disturbance of alpha5 GABA(A) receptor function or distribution, given that schizophrenia patients are known to exhibit a PPI deficit. Our data further highlight that the potential use of alpha5-selective inverse agonists to treat hippocampal-related mnemonic dysfunction needs to be considered against the possibility that such compounds may be adversely associated with deficient sensorimotor gating.

Acoustic Stimulation↗
PubMed2004

Specific GABA(A) circuits in brain development and therapy.

GABAergic interneurons are highly diverse and operate with a corresponding diversity of GABA(A) receptor subtypes in controlling behaviour. In this article, we review the significance of GABA(A) receptor heterogeneity for neural circuit development and central nervous system pharmacology. GABA(A) receptor subtypes were identified as selective targets for behavioural actions of benzodiazepines and of selected intravenous anesthetic agents using point mutations which render a specific receptor subtype insensitive to the action of the respective drugs and also by novel subtype-selective ligands. The pharmacological separation of anxiolysis and sedation guides the development of novel anxiolytics, while inverse agonism at extrasynaptic GABA(A) receptors involved in learning and memory is currently being evaluated as a novel therapeutic principle for symptomatic memory enhancement.

Anesthetics↗
PubMed2002

Trace fear conditioning involves hippocampal alpha5 GABA(A) receptors.

The heterogeneity of gamma-aminobutyric acid type A (GABA(A)) receptors contributes to the diversity of neuronal inhibition in the regulation of information processing. Although most GABA(A) receptors are located synaptically, the small population of alpha5GABA(A) receptors is largely expressed extrasynaptically. To clarify the role of the alpha5GABA(A) receptors in the control of behavior, a histidine-to-arginine point mutation was introduced in position 105 of the murine alpha5 subunit gene, which rendered the alpha5GABA(A) receptors diazepam-insensitive. Apart from an incomplete muscle relaxing effect, neither the sedative, anticonvulsant, nor anxiolytic-like activity of diazepam was impaired in alpha5(H105R) mice. However, in hippocampal pyramidal cells, the point mutation resulted in a selective reduction of alpha5GABA(A) receptors, which altered the drug-independent behavior. In line with the role of the hippocampus in certain forms of associative learning, trace fear conditioning, but not delay conditioning or contextual conditioning, was facilitated in the mutant mice. Trace fear conditioning differs from delay conditioning in that the conditioned and unconditioned stimulus are separated by a time interval. Thus, the largely extrasynaptic alpha5GABA(A) receptors in hippocampal pyramidal cells are implicated as control elements of the temporal association of threat cues in trace fear conditioning.

Animals↗
PubMed2002

A new benzodiazepine pharmacology.

Classical benzodiazepine drugs are in wide clinical use as anxiolytics, hypnotics, anticonvulsants, and muscle relaxants. They act by enhancing the gamma-aminobutyric acid(A) (GABA(A)) receptor function in the central nervous system. The pharmacological relevance of the multitude of structurally diverse GABA(A) receptor subtypes has only recently been identified. Based on an in vivo point mutation strategy, alpha(1)-GABA(A) receptors were found to mediate sedation, anterograde amnesia, and part of the seizure protection, whereas alpha(2)-GABA(A) receptors, but not alpha(3)-receptors, mediate anxiolysis. Rational drug targeting to specific receptor subtypes has now become possible. Only restricted neuronal networks will be modulated by the new subtype-selective drugs. Promising new anxiolytics have already been developed. A new pharmacology of the benzodiazepine site is on the horizon.

Animals↗
PubMed2001

Grafts of adenosine-releasing cells suppress seizures in kindling epilepsy.

Adenosine is an inhibitor of neuronal activity in the brain. The local release of adenosine from grafted cells was evaluated as an ex vivo gene therapy approach to suppress synchronous discharges and epileptic seizures. Fibroblasts were engineered to release adenosine by inactivating the adenosine-metabolizing enzymes adenosine kinase and adenosine deaminase. After encapsulation into semipermeable polymers, the cells were grafted into the brain ventricles of electrically kindled rats, a model of partial epilepsy. Grafted rats provided a nearly complete protection from behavioral seizures and a near-complete suppression of afterdischarges in electroencephalogram recordings, whereas the full tonic-clonic convulsions in control rats remained unaltered. Thus, the local release of adenosine resulting in adenosine concentrations <25 nM at the site of action is sufficient to suppress seizure activity and, therefore, provides a potential therapeutic principle for the treatment of drug-resistant partial epilepsies.

Adenosine↗
PubMed2001

GABA(B)-receptor isoforms molecular architecture and distribution.

The slow component of GABAergic inhibition in the brain is mediated by the metabotropic GABA(B)-receptors. Most if not all GABA(B)-receptors are heterodimers of GABA(B)R1 (GBR1) and GABA(B)R2 (GBR2) proteins. Distinctive receptor isoforms are based on the presence of two GBR1 splice variants termed GBR1a and GBR1b. Both were found to be associated with GBR2 suggesting that the isoforms GBR1a/GBR2 and GBR1b/GBR2 represent the vast majority of GABA(B)-receptors in the brain. The two isoforms differed strikingly in their pattern of expression on the regional, cellular and subcellular level. These results point to distinct funcional roles of the two receptor isoforms.

Alternative Splicing↗
PubMed2001

Protein-chemical analysis of Bio-Oss bone substitute and evidence on its carbonate content.

The natural bone substitute Bio-Oss is used in periodontal and maxillofacial surgery to fill bone defects and permit reossification. Recent reports have suggested the presence of TGFbeta and of substantial amounts of protein in Bio-Oss and have questioned its position as a biologically inert material and its safety in clinical applications (Hönig et al., Plast Reconstr Surg 1999;103:1324; Schwartz et al., J Periodontol 2000;71:1258). Bio-Oss was therefore subjected to a detailed biochemical, histochemical and biophysical analysis. In three different types of extracts of Bio-Oss no evidence for the presence of protein based on SDS-PAGE and silver staining was detected. In addition, as shown by Western blotting, there was no immunochemical evidence for the presence of the potential growth-inducing factor TGFbeta. Furthermore, micropolished sections of Bio-Oss failed to be stained with McNeal's Tetrachrome as did microtome sections treated with Goldner's Trichrome. However, Bio-Oss was strongly stained with the protein dye Coomassie blue. This staining was virtually irreversible and is attributed to the carbonate content of Bio-Oss which was detected by thermogravimetry-mass spectrometry. Thus, within the limits of the assay conditions, Bio-Oss does not contain protein material to a measurable extent.

Blotting, Western↗
PubMed2001

GABA(A) receptor subtypes: dissecting their pharmacological functions.

The enhancement of GABA-mediated synaptic transmission underlies the pharmacotherapy of various neurological and psychiatric disorders. GABA(A) receptors are pluripotent drug targets that display an extraordinary structural heterogeneity: they are assembled from a repertoire of at least 18 subunits (alpha1-6, beta1-3, gamma1-3, delta, epsilon, theta, rho1-3). However, differentiating defined GABA(A) receptor subtypes on the basis of function has had to await recent progress in the genetic dissection of receptor subtypes in vivo. Evidence that the various actions of allosteric modulators of GABA(A) receptors, in particular the benzodiazepines, can be attributed to specific GABA(A) receptor subtypes will be discussed. Such discoveries could open up new avenues for drug development.

Animals↗
PubMed2001

GABA(A)-receptor subtypes: a new pharmacology.

The GABA(A) receptor is a pluripotent drug target mediating anxiolytic, sedative, anticonvulsant, muscle relaxant and amnesic activity. These drug actions have now been attributed to defined receptor subtypes. Thus, precise guidelines are available for the development of novel drugs with more selective action and less side effects than those currently in clinical use.

Amnesia↗
PubMed2001

Molecular targets for the myorelaxant action of diazepam.

Diazepam is used clinically for its myorelaxant, anxiolytic, sedative, and anticonvulsant properties. Although the anxiolytic action is mediated by alpha2 gamma-aminobutyric acid A (GABA(A)) receptors, the sedative action and in part the anticonvulsant action are mediated by alpha1 GABA(A) receptors. To identify the GABA(A) receptor subtypes mediating the action of diazepam on muscle tone, we have assessed the myorelaxant properties of diazepam in alpha2(H101R) and alpha3(H126R) knock-in mice harboring diazepam-insensitive alpha2 or alpha3 GABA(A) receptors, respectively. Whereas in alpha2(H101R) mice the myorelaxant action of diazepam was almost completely abolished at doses up to 10 mg/kg, the same dose induced myorelaxation in both wild-type and alpha3(H126R) mice. It was only at a very high dose (30 mg/kg diazepam) that alpha2(H101R) mice showed partial myorelaxation and alpha3(H126R) mice were partially protected from myorelaxation compared with wild-type mice. Thus, the myorelaxant activity of diazepam seems to be mediated primarily by alpha2 GABA(A) receptors and at high concentrations also by alpha3 GABA(A) receptors.

Animals↗
PubMed2000

Molecular and neuronal substrate for the selective attenuation of anxiety.

Benzodiazepine tranquilizers are used in the treatment of anxiety disorders. To identify the molecular and neuronal target mediating the anxiolytic action of benzodiazepines, we generated and analyzed two mouse lines in which the alpha2 or alpha3 GABAA (gamma-aminobutyric acid type A) receptors, respectively, were rendered insensitive to diazepam by a knock-in point mutation. The anxiolytic action of diazepam was absent in mice with the alpha2(H101R) point mutation but present in mice with the alpha3(H126R) point mutation. These findings indicate that the anxiolytic effect of benzodiazepine drugs is mediated by alpha2 GABAA receptors, which are largely expressed in the limbic system, but not by alpha3 GABAA receptors, which predominate in the reticular activating system.

Animals↗
PubMed2000

Mechanism of action of the hypnotic zolpidem in vivo.

Zolpidem is a widely used hypnotic agent acting at the GABA(A) receptor benzodiazepine site. On recombinant receptors, zolpidem displays a high affinity to alpha 1-GABA(A) receptors, an intermediate affinity to alpha(2)- and alpha(3)-GABA(A) receptors and fails to bind to alpha(5)-GABA(A) receptors. However, it is not known which receptor subtype is essential for mediating the sedative-hypnotic action in vivo. Studying alpha1(H101R) mice, which possess zolpidem-insensitive alpha(1)-GABA(A) receptors, we show that the sedative action of zolpidem is exclusively mediated by alpha(1)-GABA(A) receptors. Similarly, the activity of zolpidem against pentylenetetrazole-induced tonic convulsions is also completely mediated by alpha(1)-GABA(A) receptors. These results establish that the sedative-hypnotic and anticonvulsant activities of zolpidem are due to its action on alpha(1)-GABA(A) receptors and not on alpha(2)- or alpha(3)-GABA(A) receptors.

Animals↗
PubMed1999

Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes.

GABA(A) (gamma-aminobutyric acid(A)) receptors are molecular substrates for the regulation of vigilance, anxiety, muscle tension, epileptogenic activity and memory functions, which is evident from the spectrum of actions elicited by clinically effective drugs acting at their modulatory benzodiazepine-binding site. Here we show, by introducing a histidine-to-arginine point mutation at position 101 of the murine alpha1-subunit gene, that alpha1-type GABA(A) receptors, which are mainly expressed in cortical areas and thalamus, are rendered insensitive to allosteric modulation by benzodiazepine-site ligands, whilst regulation by the physiological neurotransmitter gamma-aminobutyric acid is preserved. alpha1(H101R) mice failed to show the sedative, amnesic and partly the anticonvulsant action of diazepam. In contrast, the anxiolytic-like, myorelaxant, motor-impairing and ethanol-potentiating effects were fully retained, and are attributed to the nonmutated GABA(A) receptors found in the limbic system (alpha2, alpha5), in monoaminergic neurons (alpha3) and in motoneurons (alpha2, alpha5). Thus, benzodiazepine-induced behavioural responses are mediated by specific GABA(A) receptor subtypes in distinct neuronal circuits, which is of interest for drug design.

Animals↗
PubMed1999

Genetically modified animals in pharmacological research: future trends.

The recognition of molecular control elements which govern cell and organ function is essential for the development of novel drug therapies and for an understanding of drug actions. Thus, a major interest is focused on methodologies which permit the identification of novel control elements. This is of particular relevance for the identification of drug targets, the distinction of target isoforms, the differentiation of signalling pathways, the generation of disease models and toxicological testing. In this review, we discuss different classes of genetically modified animals and their potential to elucidate biological processes relevant for pharmacological research including functional genomics. Techniques which permit the time- and tissue-specific inducible regulation of gene expression present an important methodological advance.

Animals↗