fg-9041 and 2-hydroxysaclofen

Anatomic and physiologic studies in the rat have shown projections from the hippocampal formation (HF) and mediodorsal (MD) thalamic nucleus to the medial prefrontal cortex (mPFC). The authors used multi-barrel iontophoresis to: confirm the neurotransmitter used in the projection from HF to mPFC; investigate the role of GABAergic inhibition in the regulation of this projection; and examine the functional convergence of projections from HF and MD onto single mPFC neurons. During HF stimulation, nine cells (6%) showed excitation followed by prolonged inhibition, 39 cells (26%) showed prolonged inhibition alone and 100 cells (68%) showed no clear response. In a further 12 cells that showed no predrug excitation to HF stimulation (representing 16% of the cells in this category), iontophoresis of the GABAA antagonist bicuculline methiodide (BMI) revealed excitatory responses. A total of six mPFC cells (38% of the cells showing excitatory responses to HF stimulation) showed convergent excitation to HF and MD thalamic (or adjacent paratenial nucleus) stimulation. Five out of eight (63%) of the predrug or BMI-revealed excitatory responses of mPFC neurons to HF stimulation were selectively decreased after AMPA antagonist iontophoresis (either CNQX or DNQX). These data confirm that the HF projection to prefrontal cortex is, at least in part, glutamatergic; suggest that the responses of mPFC neurons to activity in this HF pathway are regulated by GABAergic inhibition; and indicate that projections from HF and MD converge onto single mPFC neurons.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Action Potentials; Animals; Baclofen; Bicuculline; Brain Mapping; Electric Stimulation; Electrophysiology; GABA-A Receptor Antagonists; GABA-B Receptor Antagonists; gamma-Aminobutyric Acid; Glutamic Acid; Limbic System; Male; Neurons; Organophosphorus Compounds; Piperazines; Prefrontal Cortex; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Thalamus

1. Activity-dependent depression (fading) of polysynaptic inhibition and the effects of this disinhibition on signal transmission were studied in the dentate gyrus of the rat hippocampal slice with the use of intracellular and extracellular recordings. 2. Polysynaptic inhibitory postsynaptic potentials/currents (IPSP/Cs) were evoked in dentate granule cells by stimulation of mossy fibers in stratum lucidum of area CA3b/c. These mossy fiber-evoked IPSP/Cs consisted of an early GABAA receptor-mediated component (IPSP/CA) and a late GABAB receptor-mediated component (IPSP/CB). 3. When paired stimuli were delivered 200 ms apart under voltage clamp, the amplitude of the IPSCA and IPSCB evoked by the second stimulus was reduced by 37.0 +/- 4.0 and 61.6 +/- 7.8% (mean +/- SE), respectively. Paired-pulse depression of both IPSCA and IPSCB was greatest at interstimulus intervals of 100-400 ms with a maximal effect when stimuli were delivered 200 ms apart. 4. (+/-) Baclofen, a GABAB receptor agonist, suppressed both components of the mossy fiber-evoked IPSP in a concentration-dependent fashion. At a concentration that only partially suppressed the initial IPSP, baclofen occluded paired-pulse depression of IPSPA. In addition, paired-pulse depression of IPSPA was blocked in a concentration-dependent fashion by 2-hydroxy-saclofen (10-400 microM), a GABAB receptor antagonist. 5. The contribution of the IPSPB conductance increase to paired-pulse depression of IPSPA was evaluated. Paired-pulse depression of IPSPA was significantly greater than was the depression of the response to a current pulse delivered 200 ms after the mossy fiber stimulus. In addition, injection of granule cells with GTP gamma S, a nonhydrolyzable guanosine triphosphate (GTP) analogue, occluded both IPSPB as well as the effects of baclofen on the granule cell membrane by activating G proteins but did not reduce paired-pulse depression of IPSPA or suppression of IPSPA by baclofen. Finally, examination of the first and second IPSCA evoked by paired stimuli 200 ms apart revealed no significant differences in response kinetics. Taken together, these results indicate that postsynaptic GABAB receptors on the granule cells are not responsible for paired-pulse depression of IPSPA. 6. Monosynaptic IPSPs were evoked by direct stimulation of inhibitory neurons in the inner molecular layer of the dentate gyrus during pharmacological blockade of excitatory transmission with D(-)-2-amino-5-phosphonovaleric acid (

Topics: 2-Amino-5-phosphonovalerate; Animals; Baclofen; Culture Techniques; GABA-A Receptor Antagonists; Hippocampus; Male; Membrane Potentials; Nerve Fibers; Neural Inhibition; Organophosphorus Compounds; Picrotoxin; Quinoxalines; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, GABA-A; Synaptic Transmission; Theta Rhythm

Long-term potentiation of synpatic transmission (LTP) of the perforant path--dentate gyrus synapse is induced by 5 Hz, theta-like stimulation patterns. Such stimuli induce plasticity that is most likely driven by a decrease in synaptic inhibition (disinhibition) mediated by GABAB autoreceptors. In the present study, we demonstrate that LTP induced in this manner is completely antagonized by ethanol. In order to determine the site of ethanol inhibition of LTP induced by theta-like stimulation, we combined slice patch recordings with pharmacologic isolation of the individual glutamatergic and GABAergic synaptic currents. The present experiments revealed that ethanol inhibited NMDA receptor-mediated synaptic currents without potentiation of GABAA currents or attenuation of GABAB-mediated fading of GABAA synaptic currents. These observations with ethanol contrasted with the actions of the water-soluble benzodiazepine midazolam, which strongly potentiated GABAA synaptic currents, reversed the effect of GABAB-mediated fading of GABAA synaptic currents, and therefore blocked the resulting NMDA synaptic currents. These data indicate that the effects of ethanol on long-term changes in synaptic strength in the rat hippocampal formation are due primarily to an action at the NMDA receptor-channel complex.

Topics: Animals; Baclofen; Electrophysiology; Ethanol; gamma-Aminobutyric Acid; Glutamine; Granulocytes; Hippocampus; Male; Midazolam; Neuronal Plasticity; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Synapses

Lethargic (lh/lh) mice, which function as an animal model of absence seizures, have spontaneous seizures that have behavioral and electrographic features and anticonvulsant sensitivity similar to those of human absence seizures. Antagonists of the gamma-aminobutyric acidB (GABAB) receptor suppressed these seizures in lethargic mice, whereas agonists of GABAB receptors exacerbated them. Furthermore, GABAB receptor binding and synaptically evoked GABAB receptor-mediated inhibition of N-methyl-D-aspartate responses were selectively increased in lh/lh mice. Therefore, enhanced GABAB receptor-mediated synaptic responses may underlie absence seizures in lh/lh mice, and GABAB receptor antagonists hold promise as anticonvulsants for absence seizures.

Topics: Animals; Anticonvulsants; Baclofen; Disease Models, Animal; Dose-Response Relationship, Drug; Electroencephalography; Electrophysiology; Epilepsy, Absence; Hippocampus; In Vitro Techniques; Mice; Mice, Inbred Strains; Organophosphorus Compounds; Picrotoxin; Quinoxalines; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate

GABA receptor regulation of NMDA-receptor-mediated synaptic responses was studied in area CA1 of the rat hippocampus using extracellular and intracellular recording techniques. Picrotoxin (PTX) was used to suppress GABAA inhibition and 6,7-dinitroquinoxaline-2,3-dione (DNQX) was used to suppress non-NMDA receptor-mediated responses. In this manner, we were able to avoid the complicating factors caused by potentials induced by other excitatory and inhibitory amino acid receptors. Under these conditions, large NMDA-receptor-mediated EPSPs were observed. When paired stimuli were given at interstimulus intervals from 100 to 400 msec, powerful inhibition of the second response was observed. This inhibition was reversed by the GABAB antagonists phaclofen and 2-hydroxy-saclofen; it was also depressed by removal of Mg2+ from the bath. Examination of non-NMDA receptor-mediated synaptic responses (determined in the presence of D-2-amino-5-phosphonovalerate and PTX) showed no such inhibition, thereby supporting the hypothesis that GABAB inhibition of NMDA EPSPs is postsynaptic. This difference in paired-pulse inhibition of NMDA and non-NMDA EPSPs leads us to conclude that there was no evidence of GABAB-mediated presynaptic inhibition of excitatory transmitter release. Intracellular recordings in the presence of DNQX and PTX revealed a phaclofen-sensitive late IPSP that correlated in time with the period of inhibition of NMDA responses. Taken together, these data suggest that paired-pulse-inhibition of NMDA responses is produced by a GABAB-receptor-mediated hyperpolarization of the postsynaptic membrane, causing an enhanced block of the NMDA channels by Mg2+. Regulation of NMDA-mediated synaptic responses by GABAB receptors constitutes a powerful mechanism for control of a major excitatory system in hippocampal pyramidal cells.

Topics: Animals; Baclofen; Electric Stimulation; Evoked Potentials; Hippocampus; In Vitro Techniques; Male; N-Methylaspartate; Picrotoxin; Pyramidal Tracts; Quinoxalines; Rats; Rats, Inbred Strains; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate; Synapses; Synaptic Transmission

The effects of baclofen microinjected into the nucleus tractus solitarii (NTS) on blood pressure, heart rate and baroreflex bradycardia were studied in urethane-anesthetized rats. Baclofen caused dose-dependent pressor and tachycardic effects and inhibited the reflex bradycardia elicited by i.v. phenylephrine. The effects of baclofen were inhibited by similarly administered GABAB receptor antagonists, phaclofen and 2-OH-saclofen, or the non-NMDA glutamate receptor antagonist, DNQX, or by pretreatment of rats with intracisternally administered pertussis toxin. DNQX and pertussis toxin, but not the NMDA antagonist, MK-801, also inhibited baroreflex bradycardia. Intra-NTS injections of glutamate caused hypotension and bradycardia, which were potentiated by baclofen, and were not affected by either DNQX or MK-801 or by pretreatment with pertussis toxin. These findings indicate that the cardiovascular effects of stimulation of GABAB receptors in the NTS are due, at least in part, to inhibition of the depressor baroreflex response. Inhibition of the release and/or postsynaptic action of an excitatory amino acid transmitter other than glutamate is the most likely mechanism.

Topics: Anesthesia; Animals; Baclofen; Blood Pressure; Dizocilpine Maleate; Dose-Response Relationship, Drug; Heart Rate; Hemodynamics; Male; Medulla Oblongata; Microinjections; Pertussis Toxin; Pressoreceptors; Quinoxalines; Rats; Rats, Inbred Strains; Receptors, GABA-A; Urethane; Virulence Factors, Bordetella