Reflections on more than 30 years association with Hanns.

I first met Hanns in 1977 and soon learnt of his extraordinary ability as a researcher. He became a friend as well as a mentor providing enthusiasm for my own research. I watched closely over the years how his research uncovered details of the association of the benzodiazepines and GABA and delineated the structural composition of the GABAA receptor associated with the action of individual drugs such as antianxiety and antiepileptic agents.

Reversal of GABA-mediated inhibition of the electrically and potassium chloride evoked [3H]-GABA release from rat substantia nigra slices by DL-3-hydroxy-3-phenyl pentanamide.

The phenyl alcohol amides, DL-2-hydroxy-2-phenyl butyramide (CAS 52839-87-9), DL-3-hydroxy-3-phenyl pentanamide (CAS 131802-69-2, DL-HEPP) and DL-4-hydroxy-4-phenyl hexanamide (CAS 67880-30-2) and their fluorine and chlorine analogs, at a concentration of 100 micromol/L, did not displace [3H]-gamma-aminobutyric acid ([3H]-GABA, CAS 108158-36-7) from GABAA receptors and only weakly displaced [3H]-GABA and [3H]-CGP62349 (CAS 186986-97-0), a GABAB receptor antagonist, from GABAB receptors in rat brain crude synaptic membranes. The electrically and potassium chloride (15 mmol/L) evoked [3H]-GABA release in the presence of DL-HEPP, GABA and GABAB receptor ligands from rat brain substantia nigra (SN) slices was studied. R-Baclofen (CAS 69308-37-8) (10 micromol/L), a GABAB receptor agonist, produced an inhibition of the electrically evoked [3H]-GABA release and this inhibition was blocked by CGP 55845A (CAS 149184-22-5) (10 micromol/L), a GABAB receptor antagonist, but was not affected by DL-HEPP (100 micromol/L).

GABAB receptor: a site of therapeutic benefit.

Although the presence of functional GABAB receptors in mammalian brain has been known for more than 20 years, there is still only one therapeutic agent in use, baclofen, which mediates its effects directly via this receptor. However, activation of this receptor can produce numerous effects that might be amenable to drug development. Evidence from preclinical studies also suggests that antagonism of the GABAB receptor produces beneficial clinical effects.

Reduced inhibitory action of a GABAB receptor agonist on [3H]-dopamine release from rat ventral tegmental area in vitro after chronic nicotine administration.

Background: The activation of GABAB receptors in the ventral tegmental area (VTA) has been suggested to attenuate the rewarding properties of psychostimulants, including nicotine. However, the neurochemical mechanism that underlie this effect remains unknown. Since GABAB receptors modulate the release of several neurotransmitters in the mammalian brain, we have characterised the effect of the GABAB receptor agonist baclofen on the release of [3H]-dopamine ([3H]-DA) from VTA slices of naive rats and of rats pre-treated with nicotine.

GABA(B) receptor alterations as indicators of physiological and pharmacological function.

Given the widespread distribution of GABA(B) receptors throughout the central nervous system, and within certain peripheral organs, it is likely their selective pharmacological manipulation could be of benefit in the treatment of a variety of disorders. Studies aimed at defining the clinical potential of GABA(B) receptor agonists and antagonists have included gene deletion experiments, examination of changes in receptor binding, subunit expression and function in diseased tissue, as well as after the chronic administration of drugs. The results indicate that a functional GABA(B) receptor requires the combination of GABA(B(1)) and GABA(B(2)) subunits, that receptor function does not always correlate with subunit expression and receptor binding, and that GABA(B) receptor modifications may be associated with the clinical response to antidepressants, mood stabilizers, and GABA(B) receptor agonists and antagonists.

Reduced G-protein coupling to the GABAB receptor in the nucleus accumbens and the medial prefrontal cortex of the rat after chronic treatment with nicotine.

The effect of repeated administration of nicotine (0.4 mg/kg, daily, s.c.

Plasticity of GABA(B) receptor-mediated heterosynaptic interactions at mossy fibers after status epilepticus.

Several neurotransmitters, including GABA acting at presynaptic GABA(B) receptors, modulate glutamate release at synapses between hippocampal mossy fibers and CA3 pyramidal neurons. This phenomenon gates excitation of the hippocampus and may therefore prevent limbic seizure propagation. Here we report that status epilepticus, triggered by either perforant path stimulation or pilocarpine administration, was followed 24 hr later by a loss of GABA(B) receptor-mediated heterosynaptic depression among populations of mossy fibers.

Modification of GABA(B1) and GABA(B2) receptor subunits in the somatosensory cerebral cortex and thalamus of rats with absence seizures (GAERS).

In the present study, we have investigated GABA(B) receptor expression in somatosensory cortex (S1) and the ventrobasal (VB) and reticular (Rt) thalamic nuclei of Genetic Absence Epilepsy Rats from Strasbourg (GAERS), which represent an animal model for the human absence epilepsy. We focused our attention on the thalamocortical network because it has been demonstrated that absence seizures are generated in this specific circuit, which is under the control of several inhibitory, e.g.

Targeting thalamic nuclei is not sufficient for the full anti-absence action of ethosuximide in a rat model of absence epilepsy.

Absence epilepsy is characterised by recurrent periods of physical and mental inactivity coupled to bilateral, synchronous spike and wave discharges (SWDs) on the electroencephalogram. The mechanism of action of ethosuximide (ETX), a drug specific for absence seizures, is believed to involve a reduction in the low threshold T-type Ca(2+) current in thalamocortical and nucleus reticularis thalami (NRT) neurones, although other electrophysiological data have questioned this. Here, we employed a genetic rat model of absence seizures to investigate the effects of directly administering ETX to the thalamus.

Extracellular glutamine to glutamate ratio may predict outcome in the injured brain: a clinical microdialysis study in children.

The amino acid content of hourly microdialysis samples from nine severely head-injured children was examined. Of particular interest was the measurement of the excitatory amino acid glutamate, as high levels of this substance, which are associated with the excitotoxicity cascade, have been linked to high intracranial pressure and poor outcome in a similar study in adults. Interpretation of these data is complicated by many clinical and methodological factors and these are discussed in relation to the findings.

Extracellular glutamate in the brains of children with severe head injuries: a pilot microdialysis study.

Objective: To determine, using a microdialysis technique, the extracellular levels of glutamate and non-transmitter amino acids in the brain of children with severe head injuries.

Methods: A microdialysis probe was inserted along side the intracranial pressure (ICP) bolt in 9 children (age range 2-14 years) with severe head injuries (Glasgow coma scale<8). Dialysate samples were collected hourly and analysed, using High Performance Liquid Chromatography (HPLC), for glutamate, glutamine and various structural amino acids.

5-Hydroxytryptamine drives apoptosis in biopsylike Burkitt lymphoma cells: reversal by selective serotonin reuptake inhibitors.

Serotonin (5-HT), a well-known neurotransmitter of the central nervous system, has been implicated in diverse aspects of immune regulation. Here we show that 5-HT can efficiently drive programmed cell death in established Burkitt lymphoma (BL) lines that remain faithful to the original biopsy phenotype (group 1). Group 1 BL cells cultured in the presence of 5-HT exhibited marked suppression of DNA synthesis that was accompanied by extensive apoptosis-serotonin-driven apoptosis was complete within 24 hours, was preceded by early caspase activation, and was accompanied by a decline in mitochondrial membrane potential.