Electrophysiological studies on benzodiazepine antagonists.

The actions of the benzodiazepine (BDZ) antagonists 3-hydroxymethyl-beta-carboline (3-HMC), Ro 14-7437 and Ro 15-1788 were tested on single cell activity of rat hypothalamic neurons in tissue cultures and on membrane properties of CA1 hippocampal pyramidal neurons in transverse slices. In addition, we examined the interactions of some of these agents with inhibitions elicited by gamma-aminobutyric acid (GABA) as well as the ability of Ro 14-7437 to reverse the GABA-enhancing action of the BDZ agonist flurazepam. BDZ antagonists did not alter patterns of spontaneous activity of hypothalamic neurons and did not affect resting membrane potential or membrane conductance in CA1 pyramidal cells. Ro 14-7437 either partially or totally reversed the potentiation by flurazepam of GABA-elicited depression of hypothalamic neuronal activity. Small and inconsistent actions on GABA-mediated inhibitions of hypothalamic neurons were noted. Electrically-elicited inhibitions of hypothalamic neurons were either not altered or slightly reduced. In the hippocampal slice, the frequency of spontaneous IPSPs, the amplitude of stratum-radiatum evoked IPSPs and the conductance increase caused by stratum-radiatum stimulation were either not altered or slightly reduced. These findings demonstrate that non-convulsant BDZ antagonists block the action of BDZ agonists in facilitating GABA and further that the presence of a BDZ agonist is not required for these GABA-mediated events to occur. However, these experiments do not exclude a modulatory role for an endogenous BDZ agonist on GABA-mediated events.

Highly efficient synthesis of 1-thioglycosides in solution and solid phase using iminophosphorane bases.

Disaccharides of 1-thioglycosides, an important class of glycomimics, can be synthesized by direct S-alkylation in exceptionally high yields when iminophosphorane bases are employed. The reaction conditions employed appear to be general and stereospecific. Axial and equatorial 4-triflates and primary tosylates of alkyl pyranosides provided excellent yields of thio-disaccharides without substantial elimination products. The iminophosphorane bases also proved to be useful in solid support-bound couplings of thioglycosides though with lower efficiency.

Histamine modulates local inhibition in the rat hippocampal slice.

1. These experiments investigated the action of histamine on local inhibition in the CA1 region of the in vitro hippocampal slice preparation using a paired-pulse paradigm. 2. We observed that histamine produced a concentration-dependent and reversible attenuation of paired-pulse inhibition. This effect was reduced by the H2 receptor antagonist, cimetidine, and mimicked by the H2 receptor agonist, impromidine. 3. We also observed that histamine produced concentration-dependent effects on the amplitude of the population spike that could be correlated with alterations in the field excitatory postsynaptic potential (EPSP) amplitude and input fiber volley. High concentrations of histamine produced a reduction in the amplitude of the population spike which was always accompanied by a reduction in the EPSP and fiber volley amplitude. 4. These results suggest that histamine, through the occupancy of H2 receptors, acts to modulate the efficacy of the local synaptic circuitry which is involved in producing paired-pulse inhibition in the hippocampus.

Differences in the responses of raphe nuclei to repetitive somatosensory stimulation.

The responses of single units in raphe (R.) nuclei dorsalis, magnus, pallidus, and obscurus to repetitive stimulation of peripheral nerves were studied in the chloralose-anesthetized cat. Low-intensity electrical stimuli (1.5T) which activated the large-diameter fibers were applied to the common peroneal and lateral gastrocnemius nerves at 0.25, 0.5, 1 and 2 Hz. Responses evoked at each frequently were compared with the control response evoked at 0.1 Hz. All units isolated demonstrated response decrements during periods of stimulation greater than or equal to 0.5 Hz. The long-term effects of repetitive stimulation, however, varied among the four nuclei. After 150 stimulus presentations at 0.5, 1, or 2 Hz, sensory responsiveness decreased in R. dorsalis but was enhanced in caudal R. obscurus units. Changes in the responsiveness of the other two nuclei were not significantly different from control. Responses to twin pulses indicated that R. neurons are not well suited to relay rapid, repetitive stimuli. The functional significance of these observations has implications for the role of the raphe in habituation and in the modulation of sensory traffic to higher centers. Raphe responses are also contrasted to the known responses of reticular formation neurons to repetitive stimulation.

Electrophysiological actions of histamine.

This paper reviews data which illustrate that histamine has prominent actions on the electrophysiology of mammalian central neurons. Extracellular recordings reveal that this amine can either excite or depress neuronal activity in different regions of the brain. The excitations are associated with activation of H1 histamine receptors, whereas depressions are associated with occupancy of H2 receptors. Intracellular experiments have revealed multiple actions of histamine on membrane potential and conductance as well as on amplitude and frequency of postsynaptic potentials. In addition, we present preliminary data from rat cerebral cortex and hippocampal slices which suggest a modulatory role for histamine on gamma-aminobutyric acid mediated neurotransmission in the areas of the brain.