strychnine and 2-amino-4-phosphonobutyric-acid

Sensory systems change their sensitivity based on recent stimuli to adjust their response range to the range of inputs and to predict future sensory input. Here, we report the presence of retinal ganglion cells that have antagonistic plasticity, showing central adaptation and peripheral sensitization. Ganglion cell responses were captured by a spatiotemporal model with independently adapting excitatory and inhibitory subunits, and sensitization requires GABAergic inhibition. Using a simple theory of signal detection, we show that the sensitizing surround conforms to an optimal inference model that continually updates the prior signal probability. This indicates that small receptive field regions have dual functionality--to adapt to the local range of signals but sensitize based upon the probability of the presence of that signal. Within this framework, we show that sensitization predicts the location of a nearby object, revealing prediction as a functional role for adapting inhibition in the nervous system.

Topics: Action Potentials; Adaptation, Physiological; Ambystoma; Aminobutyrates; Animals; Contrast Sensitivity; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; GABA Antagonists; Glycine Agents; Larva; Models, Biological; Neural Inhibition; Photic Stimulation; Picrotoxin; Predictive Value of Tests; Retina; Retinal Ganglion Cells; Signal Detection, Psychological; Strychnine; Visual Fields; Visual Pathways

Nonspiking cells of several sensory systems respond to stimuli with graded changes in neurotransmitter release and possess specialized synaptic ribbons. Here, we show that manipulations to synaptic ribbons caused dramatic effects on mEPSC-like (mlEPSC) amplitude and frequency. Damage to rod-bipolar cell ribbons using fluorophore-assisted light inactivation resulted in the immediate reduction of mlEPSC amplitude and frequency, whereas the first evoked response after damage remained largely intact. The reduction in amplitude could not be recovered by increasing release frequency after ribbon damage. In parallel experiments, we looked at mlEPSCs from cones of hibernating ground squirrels, which exhibit dramatically smaller ribbons than awake animals. Fewer and smaller mlEPSCs were observed postsynaptic to cones from hibernating animals, although depolarized cones were able to generate larger mlEPSCs. Our results indicate that ribbon size may influence mlEPSC frequency and support a role for ribbons in coordinating multivesicular release.

Topics: Alcohol Oxidoreductases; Aminobutyrates; Animals; Biophysics; Co-Repressor Proteins; DNA-Binding Proteins; Dose-Response Relationship, Drug; Electric Stimulation; Excitatory Amino Acid Agonists; Excitatory Postsynaptic Potentials; GABA Antagonists; Glycine Agents; Hibernation; In Vitro Techniques; Mice; Mice, Inbred C57BL; Patch-Clamp Techniques; Phosphinic Acids; Phosphoproteins; Picrotoxin; Pyridines; Receptors, AMPA; Retina; Sciuridae; Strychnine; Synapses; Visual Pathways; Wakefulness

Chronic neuropathic pain remains an unmet clinical problem because it is often resistant to conventional analgesics. Metabotropic glutamate receptors (mGluRs) are involved in nociceptive processing at the spinal level, but their functions in neuropathic pain are not fully known. In this study, we investigated the role of group III mGluRs in the control of spinal excitatory and inhibitory synaptic transmission in a rat model of neuropathic pain induced by L5/L6 spinal nerve ligation. Whole-cell recording of lamina II neurons was performed in spinal cord slices from control and nerve-ligated rats. The baseline amplitude of glutamatergic EPSCs evoked from primary afferents was significantly larger in nerve-injured rats than in control rats. However, the baseline frequency of GABAergic and glycinergic inhibitory postsynaptic currents (IPSCs) was much lower in nerve-injured rats than in control rats. The group III mGluR agonist l(+)-2-amino-4-phosphonbutyric acid (l-AP4) produced a greater inhibition of the amplitude of monosynaptic and polysynaptic evoked EPSCs in nerve-injured rats than in control rats. l-AP4 inhibited the frequency of miniature EPSCs in 66.7% of neurons in control rats but its inhibitory effect was observed in all neurons tested in nerve-injured rats. Furthermore, l-AP4 similarly inhibited the frequency of GABAergic and glycinergic IPSCs in control and nerve-injured rats. Our study suggests that spinal nerve injury augments glutamatergic input from primary afferents but decreases GABAergic and glycinergic input to spinal dorsal horn neurons. Activation of group III mGluRs attenuates glutamatergic input from primary afferents in nerve-injured rats, which could explain the antinociceptive effect of group III mGluR agonists on neuropathic pain.

Topics: Aminobutyrates; Animals; Biophysical Phenomena; Disease Models, Animal; Dose-Response Relationship, Drug; Electric Stimulation; Excitatory Amino Acid Agonists; Excitatory Postsynaptic Potentials; Glycine Agents; Hyperalgesia; In Vitro Techniques; Inhibitory Postsynaptic Potentials; Male; Neuralgia; Patch-Clamp Techniques; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Spinal Nerves; Strychnine; Synaptic Transmission

Retinal bipolar cells can be divided into on and off types based on the polarity of their response to light. Bipolar activity is further shaped by inhibitory inputs, characterized here by the events that occur immediately after the onset of a light step: 1) in most off bipolar cells, excitatory current decreased, whereas inhibitory current increased. These currents reinforced each other, enhancing the light response. 2) In about half of the on cone bipolar cells, the excitatory current increased, whereas inhibitory current decreased, also reinforcing the light response. Both of these reinforcing interactions were mediated by glycinergic inhibition. 3) In the remaining on cone bipolar cells, excitation and inhibition both increased, but inhibition was delayed so that these cells responded transiently. 4) Finally, in rod bipolar cells, excitation and inhibition both increased so that inhibition suppressed excitation, reducing the light response at all time scales. The suppressive inhibition seen in on cone and rod bipolar cells was mediated by GABA. Thus morphologically diverse bipolar cells receive only four main types of inhibitory input, and the majority of "inhibitory" inputs actually serve to enhance excitation.

Topics: Aminobutyrates; Animals; Axons; Electrophysiology; Feedback; GABA Antagonists; gamma-Aminobutyric Acid; Glycine; Glycine Agents; Image Processing, Computer-Assisted; In Vitro Techniques; Patch-Clamp Techniques; Phosphinic Acids; Photic Stimulation; Pyridines; Rabbits; Receptors, GABA; Retina; Retinal Bipolar Cells; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells; Strychnine

Electroretinograms (ERGs) were recorded from the giant danio (Danio aequipinnatus) to study glutamatergic input mechanisms onto bipolar cells. Glutamate analogs were applied to determine which receptor types mediate synaptic transmission from rods and cones to on and off bipolar cells. Picrotoxin, strychnine, and tetrodotoxin were used to isolate the effects of the glutamate analogs to the photoreceptor-bipolar cell synapse. Under photopic conditions, the group III metabotropic glutamate receptor (mGluR) antagonist (RS)-alpha-cyclopropyl-4-phosphonophenylglycine (CPPG) only slightly reduced the b-wave, whereas the excitatory amino acid transporter (EAAT) blocker dl-threo-beta-benzyl-oxyaspartate (TBOA) removed most of it. Complete elimination of the b-wave required both antagonists. The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX) blocked the d-wave. Under scotopic conditions, rod and cone inputs onto on bipolar cells were studied by comparing the sensitivities of the b-wave to photopically matched green and red stimuli. The b-wave was >1 log unit more sensitive to the green than to the red stimulus under control conditions. In CPPG or l-AP4 (l-(+)-2-amino-4-phosphonobutyric acid, a group III mGluR agonist), the sensitivity of the b-wave to the green stimulus was dramatically reduced and the b-waves elicited by the 2 stimuli became nearly matched. The d-wave elicited by dim green stimuli, which presumably could be detected only by the rods, was eliminated by NBQX.. 1) cone signals onto on bipolar cells involve mainly EAATs but also mGluRs (presumably mGluR6) to a lesser extent; 2) rods signal onto on bipolars by mainly mGluR6; 3) off bipolar cells receive signals from both photoreceptor types by AMPA/kainate receptors.

Topics: Aminobutyrates; Anesthetics, Local; Animals; Aspartic Acid; Cyclopentanes; Dose-Response Relationship, Radiation; Drug Interactions; Electroretinography; Excitatory Amino Acid Agonists; GABA Antagonists; Glycine; Glycine Agents; Neurons; Photic Stimulation; Picrotoxin; Quinoxalines; Receptors, Metabotropic Glutamate; Retina; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells; Strychnine; Synaptic Transmission; Tetrodotoxin; Visual Pathways; Zebrafish

In the dark, light signals are conventionally routed through the following circuit: rods synapse onto rod bipolar (RB) cells, which in turn contact AII amacrine cells. AII cells segregate the light signal into the on and off pathways by making electrical synapses with on cone bipolar (CB) cells and glycinergic inhibitory chemical synapses with off CB cells. These bipolar cells synapse onto their respective ganglion cells, which transfer on and off signals to the visual centers of the brain. Two alternative pathways have recently been postulated for the signal transfer in scotopic conditions: 1) electrical coupling between rods and cones, and 2) a circuit independent of cone photoreceptors, implying direct contacts between rods and off CB cells. Anatomical evidence supports the existence of both these circuits. To investigate the contribution of these alternative pathways to scotopic vision in the mammalian retina, we have performed patch-clamp recordings from ganglion cells in the dark-adapted retina of the rabbit, mouse, and rat. Approximately one-half of the ganglion cells in the rabbit retina received off signals through a circuit that was independent of RB cells. This was shown by their persistence in the presence of the glutamate agonist 2-amino-4-phosphonobutyric acid (APB), which blocks rod-->RB cell signaling. Consistent with this result, strychnine, a glycine receptor antagonist, was unable to abolish these off responses. In addition, we were able to show that some off cone bipolar dendrites terminate at rod spherules and make potential contacts. In the mouse retina, however, there seems to be a very low proportion of off signals carried by an APB-resistant pathway. No ganglion cells in the rat retina displayed APB- and strychnine-resistant responses. Our data support signaling through flat contacts between rods and off CB cells as the alternative route, but suggest that the significance of this pathway differs between species.

Topics: Aminobutyrates; Animals; Cats; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Glycine Agents; Immunohistochemistry; In Vitro Techniques; Light; Membrane Potentials; Mice; Models, Neurological; Neurons; Patch-Clamp Techniques; Photic Stimulation; Rats; Retina; Species Specificity; Strychnine; Visual Pathways

Previous studies have demonstrated that microinjection of the putative group III metabotropic glutamate receptor (mGluR) agonist, l(+)-2-amino-4-phosphonobutyric acid (L-AP4), into the nucleus tractus solitarius (NTS) produces depressor and sympathoinhibitory responses. These responses are significantly attenuated by a group III mGluR antagonist and may involve ionotropic glutamatergic transmission. Alternatively, a previous report in vitro suggests that preparations of L-AP4 may nonspecifically activate NMDA channels due to glycine contamination (Contractor A, Gereau RW, Green T, and Heinemann SF. Proc Natl Acad Sci USA 95: 8969-8974, 1998). Therefore, the present study tested whether responses to L-AP4 specifically require the N-methyl-D-aspartate (NMDA) receptor and whether they are due to actions at the glycine site on the NMDA channel. To test these possibilities in vivo, we performed unilateral microinjections of L-AP4, glycine, and selective antagonists into the NTS of urethane-anesthetized rats. L-AP4 (10 mM, 30 nl) produced sympathoinhibitory responses that were abolished by the NMDA receptor antagonist 2-amino-5-phosphonovaleric acid (AP-5, 10 mM) but were unaffected by the non-NMDA antagonist 6-nitro-7-sulfamobenzoquinoxaline-2,3-dione (NBQX, 2 mM). Microinjection of glycine (0.02-20 mM) failed to mimic sympathoinhibitory responses to L-AP4, even in the presence of the inhibitory glycine antagonist, strychnine (3 mM). Strychnine blocked pressor and sympathoexcitatory actions of glycine (20 mM) but failed to reveal a sympathoinhibitory component due to presumed activation of NMDA receptors. The results of these experiments suggest that responses to L-AP4 require NMDA receptors and are independent of non-NMDA receptors. Furthermore, although it is possible that glycine contamination or other nonspecific actions are responsible for the sympathoinhibitory actions of L-AP4, our data and data in the literature argue against this possibility. Thus we conclude that responses to L-AP4 in the NTS are mediated by an interaction between group III mGluRs and NMDA receptors. Finally, we also caution that nonselective actions of L-AP4 should be considered in future studies.

Topics: 2-Amino-5-phosphonovalerate; Aminobutyrates; Animals; Cardiovascular System; Excitatory Amino Acid Agonists; Glycine; Glycine Agents; Male; Microinjections; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Solitary Nucleus; Strychnine

1. Whole-cell patch recording and puff pipette techniques were used to identify glutamate receptor mechanisms on bipolar cell (BC) dendrites in the zebrafish retinal slice. Recorded neurons were stained with Lucifer Yellow, to correlate glutamate responses with BC morphology. 2. BC axon terminals (ATs) consisted of swellings or varicosities along the axon, as well as at its end. AT stratification patterns identified three regions in the inner plexiform layer (IPL): a thick sublamina a, with three bands of ATs, a narrow terminal-free zone in the mid-IPL, and a thin sublamina b, with two bands of ATs. BCs occurred with ATs restricted to sublamina a(Group a), sublamina b(Group b) or with ATs in both sublaminae (Group a/b). 3. OFF-BCs belonged to Group a or Group a/b. These cells responded to glutamate or kainate with a CNQX-sensitive conductance increase. Reversal potential (Erev) ranged from -0.6 to +18 mV. Bipolar cells stimulated sequentially with both kainate and glutamate revealed a population of glutamate-insensitive, kainate-sensitive cells in addition to cells sensitive to both agonists. 4. ON-BCs responded to glutamate via one of three mechanisms: (a) a conductance decrease with Erev approximately 0 mV, mimicked by L-(+)-2-amino-4-phosphonobutyric acid (APB) or trans-1-amino-1, 3-cyclopentanedicarboxylic acid (trans-ACPD), (b) a glutamate-gated chloride conductance increase (IGlu-like) characterized by Erev >= ECl (where ECl is the chloride equilibrium potential) and partial blockade by extracellular Li+/Na+ substitution or (c) the activation of both APB and chloride mechanisms simultaneously to produce a response with outward currents at all holding potentials. APB-like responses were found only among BCs in Group b, with a single AT ramifying deep within sublamina b; whereas, cells expressing IGlu-like currents had one or more ATs, and occurred within Groups b or a/b. 5. Multistratified cells (Group a/b) were common and occurred with either ON- or OFF-BC physiology. OFF-BCs typically had one or more ATs in sublamina a and only one AT in sublamina b. In contrast, multistratified ON-BCs had one or more ATs in sublamina b and a single AT ramifying deep in sublamina a. Multistratified ON-BCs expressed the IGlu-like mechanism only. 6. Visual processing in the zebrafish retina involves at least 13 BC types. Some of these BCs have ATs in both the ON- and OFF-sublaminae, suggesting a significant role for ON- and OFF-inputs throughout the IPL.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Aminobutyrates; Animals; Axons; Chlorides; Cycloleucine; Dendrites; Excitatory Amino Acid Antagonists; Fluorescent Dyes; Glutamic Acid; In Vitro Techniques; Isoquinolines; Kainic Acid; Neurons; Picrotoxin; Retina; Strychnine; Zebrafish

The electroretinogram (ERG) was recorded from the Xenopus retina, to examine the effects of glycine and strychnine on these responses and to determine the origins of these changes. Glycine at concentrations between 0.1 and 10 mM reduced the b- and d-waves of the ERG in a dose-dependent manner, while strychnine increased their amplitude. 2-Amino-4-phosphonobutyric acid (APB) reduced the b-wave and blocked the effect of glycine, but not strychnine, on the d-wave. When the d-wave had first been blocked by kynurenic acid (KYN) or reduced by (+/-)cis-2,3-piperidine dicarboxylic acid (PDA) the b-wave was enhanced by glycine, but not by strychnine. N-methyl-DL-aspartate (NMDLA), which alters responses in the proximal retina only, blocked the effects of glycine and strychnine on the ERG. This suggests that the glycinergic effects on the ERG are at least partly mediated by processes in the proximal retina. The results further support the suggestion that inhibitory neurotransmitters in the proximal retina may modulate both the b- and d-waves of the Xenopus ERG.

Topics: Aminobutyrates; Animals; Dose-Response Relationship, Drug; Electroretinography; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Glycine; Glycine Agents; In Vitro Techniques; Kynurenic Acid; N-Methylaspartate; Photic Stimulation; Pipecolic Acids; Retina; Strychnine; Xenopus laevis

Perfusion with the ON channel blocker 2-amino-4-phosphonobutyrate (APB) of dark adapted frog eyecups not only abolished the ganglion cells' (GC) ON responses and the ERG b-wave, but markedly potentiated the OFF responses of ON-OFF and phasic OFF-GCs and the d-wave amplitude of simultaneously recorded local ERG. Glycinergic blockade by strychnine prevented this potentiating effect in 31 out of 69 GCs, but did not change it at all in the other cells. At the same time the d-wave potentiation was preserved during the glycinergic blockade in all eyecups. The results indicate that glycinergic transmission is involved in the inhibition exerted from ON upon OFF channel in some but not all frog retinal GCs.

Topics: Aminobutyrates; Animals; Electroretinography; gamma-Aminobutyric Acid; Glycine; Rana ridibunda; Receptors, Glycine; Retinal Ganglion Cells; Strychnine

Current understanding suggests that mammalian rod photoreceptors connect only to an ON-type bipolar cell. This rod-specific bipolar cell excites the All amacrine cell, which makes connections to cone-specific bipolar cells of both ON and OFF type; these, in turn, synapse with ganglion cells. Recent work on rabbit retina has shown that rod signals can also reach ganglion cells without passing through the rod bipolar cell. This route was thought to be provided by electrical gap junctions, through which rods signal directly to cones and thence to cone bipolar cells. Here, we show that the mouse retina also provides a rod pathway bypassing the rod bipolar cell, suggesting that this is a common feature in mammals. However, this alternative pathway does not require cone photoreceptors; it is perfectly intact in a transgenic mouse whose retina lacks cones. Instead, the results can be explained if rods connect directly to OFF bipolar cells.

Topics: Aminobutyrates; Animals; Darkness; Excitatory Amino Acid Agonists; Eye Proteins; Female; Humans; In Vitro Techniques; Light; Mammals; Mice; Mice, Inbred C57BL; Mice, Transgenic; Models, Biological; Photic Stimulation; Rabbits; Retinal Cone Photoreceptor Cells; Retinal Ganglion Cells; Retinal Pigments; Retinal Rod Photoreceptor Cells; Rod Opsins; Signal Transduction; Strychnine; Synapses

Superfusion with 200 microM 2-amino-4-phosphonobutyrate (APB) of dark and chromatically adapted frog eyecups caused marked potentiation of the ERG OFF-response (d-wave). Blockade of the glycinergic synapses by strychnine did not change this effect at all. Blockade of the GABAergic synapses by picrotoxin slightly diminished the effect of APB in chromatically-adapted eyes with isolated cones' activity, and did not change it in dark-adapted eyes. The results indicate that the action of APB on ERG OFF-response does not depend significantly on GABAergic and glycinergic neurotransmission in frog retina.

Topics: Adaptation, Ocular; Aminobutyrates; Animals; Color; Dark Adaptation; gamma-Aminobutyric Acid; Glycine; In Vitro Techniques; Picrotoxin; Rana ridibunda; Retina; Strychnine; Synapses; Synaptic Transmission; Time Factors

All-amacrine cells are crucial interneurons in the rod pathway of the mammalian retina. They receive input synapses from rod bipolar cells and make electrical output synapses into the ON-pathway and glycinergic chemical synapses into the OFF-pathway. Whole-cell currents from more than 50 voltage-clamped All-amacrine cells were recorded in a slice preparation of the rat retina. The recorded cells were identified by intracellular staining with Lucifer yellow. Spike-like potentials could be elicited upon depolarization by current injection. A voltage-activated, fast, TTX-sensitive, inward Na+ current was identified. A prominent outward K+ current could be suppressed by tetraethylammonium. GABA as well as glycine activated Cl- channels, which could be blocked by bicuculline and strychnine, respectively. Four agonists of excitatory amino acid receptors--kainate (KA), AMPA, 2-amino-4-phosphonobutyrate (APB), and NMDA--were tested. Inward currents at holding potentials of VH = -70 mV were found by application of KA and AMPA but not by application of APB and NMDA. These currents could be blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). ACh did not evoke any current responses.

Topics: 4-Aminopyridine; 6-Cyano-7-nitroquinoxaline-2,3-dione; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Aminobutyrates; Animals; Cobalt; Electrophysiology; gamma-Aminobutyric Acid; Glutamates; Glutamic Acid; Glycine; Ibotenic Acid; In Vitro Techniques; Ion Channel Gating; Ion Channels; Kainic Acid; Membrane Potentials; N-Methylaspartate; Potassium Channels; Quinoxalines; Rats; Receptors, Amino Acid; Retina; Retinal Ganglion Cells; Sodium Channels; Strychnine; Synapses; Tetraethylammonium; Tetraethylammonium Compounds; Tetrodotoxin

The directional selectivity of amacrine and ganglion cells was studied using conventional intracellular recording techniques and drug application in the superfused retina-eyecup preparation of the tiger salamander. Baclofen, a GABAB receptor agonist, enhanced normal directional responses in some directionally selective third-order neurons. In about 30% of the cells that were not normally directional, baclofen induced direction-selective responses. This effect was particularly marked when 2-amino-4-phosphonobutyrate (APB) was used to isolate the OFF pathway. Comparisons of the effects of APB and baclofen on induced directional cells indicate that directional information in the ON and OFF channels is often handled separately and frequently is not aligned. This tends to obscure the observation of directionality as seen from the soma. Application of picrotoxin blocked both normal directional selectivity and baclofen-induced directional selectivity in some cells. Superfusion of picrotoxin and strychnine together blocked directionality in almost all cells. In both normal and induced directionality, the null direction response varied from cell to cell between a small depolarization, no voltage response, or a hyperpolarization. Injection of positive current often revealed "silent" inhibition. Some induced direction-selective cells did not show any evidence of inhibition in the null direction. The similarities in the response to baclofen, the influence of GABA and glycine antagonists, and the characteristics of the null-direction responses suggest that both normal and induced directionality originate from the same sources or mechanisms. Baclofen also induced orientation selectivity, but this was rarely observed.

Topics: Ambystoma; Aminobutyrates; Animals; Baclofen; Electric Stimulation; Electrophysiology; Evoked Potentials; In Vitro Techniques; Neurons; Photic Stimulation; Picrotoxin; Receptors, GABA-A; Retina; Strychnine

Previous studies have reported that the surround responses of retinal ganglion cells weaken or disappear upon dark adaptation. The mechanism(s) by which this occurs is largely unknown, although changes in activity of retinal dopaminergic neurons have been implicated. In the light-adapted rabbit retina, the surround ON responses of OFF-center ganglion cells have been shown to be markedly reduced or abolished by a dopamine antagonist. This effect of a dopamine antagonist was recently shown to be reversed by the glycine antagonist strychnine and by compounds that elevate intracellular cAMP levels. The present study was conducted to determine whether strychnine and cAMP-elevating compounds could bring out the surround ON responses in OFF-center ganglion cells that are diminished upon dark adaptation. Extracellular recordings of OFF-center brisk ganglion cells were made from isolated, superfused retinal preparations. During the course of dark adaptation, the surround ON responses of many cells decreased markedly. Application of low micromolar concentrations of strychnine to the bathing solution brought out the surround ON responses in both brisk-transient and brisk-sustained OFF-center ganglion cells. The center OFF responses of these cells, on the other hand, were not enhanced by strychnine. Of the cAMP-elevating compounds tested, 8-(4-chlorophenylthio) cyclic AMP was the most effective in bringing out the surround ON responses in dark-adapted OFF-center ganglion cells. The effects of bath application of this cAMP analog were very similar to those of strychnine. The findings from this study suggest that under dark-adapted conditions glycinergic neurons inhibit the surround component of OFF-center ganglion cells. The release of glycine from these neurons is suggested to be regulated by a cAMP-dependent mechanism.

Topics: Aminobutyrates; Animals; Cyclic AMP; Dark Adaptation; Dopamine; Electrophysiology; Glycine; Photic Stimulation; Rabbits; Receptors, Glycine; Receptors, Neurotransmitter; Retina; Retinal Ganglion Cells; Strychnine; Thionucleotides

Rat pups exhibit transient "developmental dyskinesias," such as tremor and myoclonus, that are analogous to motor immaturities of the human neonate. Myoclonic jerks in the neonatal rat may reflect a developmental imbalance of excitatory and inhibitory neurotransmission. To test this hypothesis, spontaneous myoclonic jerks of naive rat pups (n = 200) were characterized behaviorally and pharmacologically. The frequency of myoclonus was high (154 +/- 14 jerks/30 min) in the first week. The distribution of jerks included limbs (47%) (27% in forelimbs and 20% in hindlimbs), tail (30%), trunk (12%), and head (11%). Myoclonus constituted the predominant neonatal adventitious movement (81%). Myoclonic jerks were variable in intensity, focal and multi-focal more often than generalized, and occurred when nonrespiratory movements were infrequent or absent, suggesting sleep. Myoclonic frequency significantly diminished after the second week; therefore, drug effects were studied in the first 7 days. Systemic injection of the novel noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 blocked neonatal myoclonus in a dose-dependent manner (ID50 = 0.67 mg/kg; r = 0.93). The nonselective excitatory amino acid (EAA) receptor antagonist kynurenic acid was ineffective. The EAA antagonist AP4 (1 and 10 mg/kg) also reduced myoclonic jerks, but other drugs, such as the selective glycine antagonist Iso-THAO (1 and 10 mg/kg), strychnine (0.5 mg/kg), clonazepam, and diazepam (1 mg/kg), were ineffective blockers. The putative agonists quisqualic acid (1-50 mg/kg) and NMDA (1-10 mg/kg) altered myoclonus only at behaviorally toxic doses. These data suggest that EAA receptors participate in developmental myoclonus of the neonatal rat and that development myoclonus may be a useful quantitative model of functional maturity of excitatory/inhibitory synapses. The efficacy of MK-801 also should be evaluated in drug- and lesion-induced myoclonus. Recognition of the high frequency and state dependence of spontaneous myoclonic jerks in neonatal rats may be important to neonatal antiepileptic drug studies.

Topics: Aminobutyrates; Analysis of Variance; Animals; Animals, Newborn; Anticonvulsants; Clonazepam; Diazepam; Dizocilpine Maleate; Dose-Response Relationship, Drug; Female; Isoxazoles; Kynurenic Acid; Male; Myoclonus; N-Methylaspartate; Quisqualic Acid; Rats; Receptors, N-Methyl-D-Aspartate; Strychnine

1. In the intact cat eye, the responses of ganglion cells to light stimulation were recorded extracellularly and the actions of iontophoretically applied 2-amino-4-phosphonobutyrate (APB), a potent agonist at ON-bipolars, and of strychnine, a glycine antagonist, were investigated. 2. Under light-adapted conditions, the activity of ON-center ganglion cells is decreased by APB but is increased by strychnine. APB and strychnine act independently of one another. 3. The activity of light-adapted OFF-center ganglion cells is increased by APB and by strychnine. The light response remains clearly modulated. Strychnine blocks the action of simultaneously applied APB. The results are in agreement with the action of a push-pull mechanism, according to which ON-cone-bipolars provide a glycinergic input into OFF-center ganglion cells. 4. Under dark-adapted conditions, APB blocks the light responses of both ON-center and OFF-center ganglion cells. The discharge rate of ON-center ganglion cells is completely suppressed; OFF-center ganglion cells show a high maintained discharge. 5. Strychnine blocks the scotopic light response of OFF-center ganglion cells and blocks the action of simultaneously applied APB. The light response of ON-center ganglion cells is hardly affected by strychnine. 6. The effects of strychnine on OFF-center ganglion cells are in agreement with the hypothesis that the glycinergic AII amacrine cells modulate the activity of the scotopic OFF-channel. 7. Intravitreally applied APB abolished the scotopic b-wave of the electroretinogram at concentrations of 100 microM. 8. Our data suggest that as in rabbit (10) the rod bipolars in cat retina are depolarizing (ON) bipolar cells.

Topics: Aminobutyrates; Animals; Cats; Dark Adaptation; Drug Interactions; Iontophoresis; Photic Stimulation; Photoreceptor Cells; Retinal Ganglion Cells; Strychnine; Visual Pathways

Incubation of cat retinas with 3H-glycine in vitro, followed by horizontal sectioning and autoradiography, showed labeling of 10-12% of bipolar cells and 45% of amacrine cells. To ascertain the effects of glycine-accumulating bipolar and amacrine cells on the response properties of retinal ganglion cells, in vivo iontophoretic studies were performed in the cat eye. Glycine inhibited all ganglion cells, and this action was blocked by strychnine. Aminophosphonobutyric acid (APB) suppressed ON-ganglion cells, but activated OFF-ganglion cells. The influence of APB upon OFF-ganglion cells could be completely blocked by strychnine. In the mudpuppy, APB suppressed ON-bipolar cells without affecting OFF-bipolar cells and without direct effects on other retinal neurons (Slaughter and Miller, 1981, 1985). If APB has the same mode of action in the cat retina, the present results suggest a glycinergic inhibitory input of the ON-channel upon OFF-ganglion cells.

Topics: Aminobutyrates; Animals; Autoradiography; Bicuculline; Cats; Electrophysiology; Glycine; Histocytochemistry; Iontophoresis; Models, Neurological; Retina; Retinal Ganglion Cells; Strychnine