Phenotypical Screening on Neuronal Plasticity in Hippocampal-Prefrontal Cortex Connectivity Reveals an Antipsychotic with a Novel Profile.

Dysfunction in the hippocampus-prefrontal cortex (H-PFC) circuit is a critical determinant of schizophrenia. Screening of pyridazinone-risperidone hybrids on this circuit revealed EGIS 11150 (S 36549). EGIS 11150 induced theta rhythm in hippocampal slice preparations in the stratum lacunosum molecular area of CA1, which was resistant to atropine and prazosin.

New Directions for Surgical Ablation Treatment of Obsessive Compulsive Disorder.

Although there are effective treatments available for many, probably most, patients with OCD, a significant number do not respond, or fail to experience a sustained beneficial response. For patients with such chronic, disabling and 'treatment-refractory' OCD, neurosurgical treatments may be considered. The best-established neurosurgical treatments are so-called ablative procedures, where targeted lesions are created with the intention of interrupting and modifying specific circuitry functions.

Selective inhibition of extra-synaptic α5-GABA receptors by S44819, a new therapeutic agent.

In the mammalian central nervous system (CNS) GABA receptors (GABARs) mediate neuronal inhibition and are important therapeutic targets. GABARs are composed of 5 subunits, drawn from 19 proteins, underpinning expression of 20-30 GABAR subtypes. In the CNS these isoforms are heterogeneously expressed and exhibit distinct physiological and pharmacological properties.

A novel GABA(A) alpha 5 receptor inhibitor with therapeutic potential.

Novel 2,3-benzodiazepine and related isoquinoline derivatives, substituted at position 1 with a 2-benzothiophenyl moiety, were synthesized to produce compounds that potently inhibited the action of GABA on heterologously expressed GABAA receptors containing the alpha 5 subunit (GABAA α5), with no apparent affinity for the benzodiazepine site. Substitutions of the benzothiophene moiety at position 4 led to compounds with drug-like properties that were putative inhibitors of extra-synaptic GABAA α5 receptors and had substantial blood-brain barrier permeability. Initial characterization in vivo showed that 8-methyl-5-[4-(trifluoromethyl)-1-benzothiophen-2-yl]-1,9-dihydro-2H-[1,3]oxazolo[4,5-h][2,3]benzodiazepin-2-one was devoid of sedative, pro-convulsive or motor side-effects, and enhanced the performance of rats in the object recognition test.

Astrocytic adenosine kinase regulates basal synaptic adenosine levels and seizure activity but not activity-dependent adenosine release in the hippocampus.

Adenosine is an endogenous inhibitor of excitatory synaptic transmission with potent anticonvulsant properties in the mammalian brain. Given adenosine's important role in modulating synaptic transmission, several mechanisms exist to regulate its extracellular availability. One of these is the intracellular enzyme adenosine kinase (ADK), which phosphorylates adenosine to AMP.

Synthesis, conformation and biological evaluation of the enantiomers of 3-fluoro-gamma-aminobutyric acid ((R)- and (S)-3F-GABA): an analogue of the neurotransmitter GABA.

Gamma-aminobutyric acid or GABA (1) is one of the major inhibitory amino acid neurotransmitters of the central nervous system. This article describes the first synthesis of both the (R)- and (S)- enantiomers of 3-fluoro-GABA (2, 3F-GABA). DFT calculations were carried out in a continuum solvent model (PCM-B3LYP) to estimate the preferred conformations of 3F-GABA in aqueous solution.

Endogenous adenosine modulates epileptiform activity in rat hippocampus in a receptor subtype-dependent manner.

The purine nucleoside adenosine is released during seizure activity and exerts an anticonvulsant influence through inhibition of glutamate release and hyperpolarization of neurons via adenosine A(1) receptors. However, activation of adenosine A(2A) and A(3) receptors may counteract the inhibitory effects of A(1) receptors. We have therefore examined the extent to which endogenous adenosine released during seizure activity activates the different adenosine receptor subtypes and the implications for seizure activity in the rat hippocampus in vitro.

Plasticity of purine release during cerebral ischemia: clinical implications?

Adenosine is a powerful modulator of neuronal function in the mammalian central nervous system. During a variety of insults to the brain, adenosine is released in large quantities and exerts a neuroprotective influence largely via the A(1) receptor, which inhibits glutamate release and neuronal activity. Using novel enzyme-based adenosine sensors, which allow high spatial and temporal resolution recordings of adenosine release in real time, we have investigated the release of adenosine during hypoxia/ischemia in the in vitro hippocampus.