fg-9041 and saclofen

A fundamental issue in understanding activity-dependent long-term plasticity of neuronal networks is the interplay between excitatory and inhibitory synaptic drives in the network. Using dual whole-cell recordings in cultured hippocampal neurons, we examined synaptic changes occurring as a result of a transient activation of NMDA receptors in the network. This enhanced transient activation led to a long-lasting increase in synchrony of spontaneous activity of neurons in the network. Simultaneous long-term potentiation of excitatory synaptic strength and a pronounced long-term depression of inhibitory synaptic currents (LTDi) were produced, which were independent of changes in postsynaptic potential and Ca2+ concentrations. Surprisingly, miniature inhibitory synaptic currents were not changed by the conditioning, whereas both frequency and amplitudes of miniature EPSCs were enhanced. LTDi was mediated by activation of a presynaptic GABAB receptor, because it was blocked by saclofen and CGP55845 [(2S)-3-{[(15)-1-(3, 4-dichlorophenyl)ethyl]amino-2-hydroxypropyl)(phenylmethyl)phosphinic acid]. The cAMP antagonist Rp-adenosine 3 ', 5 ' -cyclic monophosphothioate abolished all measured effects of NMDA-dependent conditioning, whereas a nitric oxide synthase inhibitor was ineffective. Finally, network-induced plasticity was not occluded by a previous spike-timing-induced plasticity, indicating that the two types of plasticity may not share the same mechanism. These results demonstrate that network plasticity involves opposite affects on inhibitory and excitatory neurotransmission.

Topics: 2-Amino-5-phosphonovalerate; Animals; Baclofen; Calcium; Cells, Cultured; Colforsin; Cyclic AMP; Evoked Potentials; Hippocampus; Long-Term Potentiation; Long-Term Synaptic Depression; Neuronal Plasticity; Neurons; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Patch-Clamp Techniques; Phosphinic Acids; Propanolamines; Quinoxalines; Rats; Receptors, GABA-B; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission; Tetrodotoxin; Thionucleotides; Time Factors

The present study was done to determine if estrogen interacts with excitatory and/or inhibitory amino acid neurotransmitters to alter neuronal excitability within the parabrachial nucleus (PBN) and modulate autonomic tone. First, the role of estrogen in modulating autonomic tone was investigated in male rats anesthetized with Inactin (100 mg/kg). Animals were instrumented to record blood pressure, heart rate, vagal parasympathetic and renal sympathetic nerve activities as well as baroreflex sensitivity. Direct, bilateral injection of 17beta-estradiol (0.5 microM; 200 nl/side) into the PBN resulted in a significant decrease in blood pressure (17+/-4 mmHg), sympathetic tone (20+/-5%) and heart rate (22+/-5 beats/min) while increasing parasympathetic tone (34+/-4%) 30 min post-injection. These estrogen-induced effects were completely blocked by the co-injection of estrogen with the estrogen receptor antagonist, ICI 182,780 (20 microM; 200 nl/side). Co-injection of the NMDA receptor antagonist, (+/-)-3-(2-carboxypiperazine-4-yl) propyl-1-phosphonic acid (CPP; 10 microM; 200 nl/side), with estradiol resulted in complete blockade of the estrogen-induced decrease in heart rate and increase in parasympathetic tone only. Co-injection of estradiol with the GABA(A) receptor antagonist, (+)-bicuculline (0.1 microM; 200 nl/side), resulted in complete blockade of the estrogen-induced decrease in blood pressure and sympathetic nerve activity only. These results suggest that estrogen acts on estrogen receptors on neurons in the PBN to modulate GABA(A)-receptor mediated inhibitory neurotransmission to alter sympathetic tone and blood pressure and on neurons in a separate, parallel pathway to modulate NMDA-receptor mediated neurotransmission to alter parasympathetic tone and heart rate.

Topics: Animals; Autonomic Nervous System; Baclofen; Baroreflex; Bicuculline; Blood Pressure; Cardiotonic Agents; Dose-Response Relationship, Drug; Drug Interactions; Estradiol; Estrogen Antagonists; Estrogens; Excitatory Amino Acid Antagonists; Fulvestrant; GABA Antagonists; Heart Rate; Male; Membrane Potentials; Phenylephrine; Piperazines; Pons; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate; Time Factors