Substantia nigra stimulation influences monkey superior colliculus neuronal activity bilaterally

The inhibitory drive arising from the basal ganglia is thought to prevent the occurrence of orienting movements of the eyes, head, and body in monkeys and other mammals. The direct projection from the substantia nigra pars reticulata (SNr) to the superior colliculus (SC) mediates the inhibition. Since the original experiments in the SNr of monkeys the buildup or prelude neuron has been a focus of SC research. However, whether the SNr influences buildup neurons in SC is unknown. Furthermore, a contralateral SNr-SC pathway is evident in many species but remains unexplored in the alert monkey. Here we introduced electrical stimulation of one or both SNr nuclei while recording from SC buildup neurons. Stimulation of the SNr reduced the discharge rate of SC buildup neurons bilaterally. This result is consistent with activation of an inhibitory drive from SNr to SC. The time course of the influence of ipsilateral SNr on the activity of most SC neurons was longer (approximately 73 ms) than the influence of the contralateral SNr (approximately 34 ms). We also found that the variability of saccade onset time and saccade direction was altered with electrical stimulation of the SNr. Taken together our results show that electrical stimulation activates the inhibitory output of the SNr that in turn, reduces the activity of SC buildup neurons in both hemispheres. However, rather than acting as a gate for saccade initiation, the results suggest that the influence of SNr inhibition on visually guided saccades is more subtle, shaping the balance of excitation and inhibition across the SC.     

Modification of saccadic eye movements by GABA-related substances. II. Effects of muscimol in monkey substantia nigra pars reticulata

The preceding study (21) showed that a gamma-aminobutyric acid (GABA) agonist or antagonist injected into the superior colliculus (SC) disrupted saccadic eye movements. The purpose of the present experiments was to determine whether this result was due to altering the inhibitory input to the SC from the substantia nigra pars reticulata (SNr). SNr cells are themselves inhibited by GABA. Injection of muscimol, a GABA agonist, into the SNr should increase the inhibition acting on SNr cells and should reduce the inhibition acting on the SC. If the effects of GABA inhibition in the SC results from terminals originating in the SNr, muscimol in the SNr should act like bicuculline in the SC. Muscimol in the SNr has the same general effect as bicuculline in the SC. The monkey made irrepressible saccades toward the contralateral visual field where cells in the SNr at the injection site had their visual or movement field. During visual fixation saccadic jerks occurred, interspersed with spontaneous saccades, instead of saccades to visual targets or to remembered targets. Saccades to remembered targets were more vulnerable to these saccadic intrusions than were saccades to visual targets. Since muscimol in the SNr acts like bicuculline in the SC, we conclude that a substantial fraction of GABA-mediated inhibitory inputs in the SC originates from the SNr. These experiments, in conjunction with previous experiments, show that the SNr exerts a tonic inhibition on saccade-related cells in SC and that this inhibition is mediated by GABA. The role of the SNr in initiation of saccades to remembered targets is particularly important since these saccades are more severely disrupted by muscimol in the SNr as well as in the SC. We suggest that both of these conclusions about eye movement might apply to skeletal movements as well. First, the basal ganglia contribute to the initiation of movement by a release of the target structure from tonic inhibition. Second, this mechanism is particularly critical of the movements based on stored or remembered signals that are not currently available as incoming sensory inputs.     

Kv3-like potassium channels are required for sustained high-frequency firing in basal ganglia output neurons

The GABA projection neurons in the substantial nigra pars reticulata (SNr) are key output neurons of the basal ganglia motor control circuit. These neurons fire sustained high-frequency, short-duration spikes that provide a tonic inhibition to their targets and are critical to movement control. We hypothesized that a robust voltage-activated K(+) conductance that activates quickly and resists inactivation is essential to the remarkable fast-spiking capability in these neurons. Semi-quantitative RT-PCR (qRT-PCR) analysis on laser capture-microdissected nigral neurons indicated that mRNAs for Kv3.1 and Kv3.4, two key subunits for forming high activation threshold, fast-activating, slow-inactivating, 1 mM tetraethylammonium (TEA)-sensitive, fast delayed rectifier (I(DR-fast)) type Kv channels, are more abundant in fast-spiking SNr GABA neurons than in slow-spiking nigral dopamine neurons. Nucleated patch clamp recordings showed that SNr GABA neurons have a strong Kv3-like I(DR-fast) current sensitive to 1 mM TEA that activates quickly at depolarized membrane potentials and is resistant to inactivation. I(DR-fast) is smaller in nigral dopamine neurons. Pharmacological blockade of I(DR-fast) by 1 mM TEA impaired the high-frequency firing capability in SNr GABA neurons. Taken together, these results indicate that Kv3-like channels mediating fast-activating, inactivation-resistant I(DR-fast) current are critical to the sustained high-frequency firing in SNr GABA projection neurons and hence movement control.     

Inhibitory effects of acetylcholine on neurones in the feline nucleus reticularis thalami.

1. Short iontophoretic pulses of acetylcholine (ACh) inhibited almost every spontaneously active cell encountered in the nucleus reticularis thalami of cats anaesthetized with a mixture of halothane, nitrous oxide and oxygen. On 200 cells the mean current needed to eject an effective inhibitory dose of ACh was 67 +/- 2 nA. When the ACh-evoked inhibition was mimicked by gamma-aminobutyric acid (GABA) or glycine on the same cell, the current required to release ACh was found to be approximately twice as great as that required to release an equally effective dose of GABA or glycine. 2. ACh inhibitions developed with a latency which was very much shorter than that for ACh excitation in cells of the ventrobasal complex. The latency of the ACh-evoked inhibition was as rapid as the onset and offset of the excitation of the same cells glutamate and their inhibition by GABA or glycine. 3. The firing pattern of ACh-inhibited neurones in the nucleus reticularis was characterized by periods of prolonged, high frequency bursts, and their mean firing frequency was 22 Hz. Raster dot displays and interspike interval histograms showed that whereas ACh suppressed the spikes that occurred between bursts much more readily than those that occurred during bursts, all spikes were equally sensitive to the depressant action of GABA and glycine. Large doses of ACh provoked or exaggerated burst activity. 4. ACh-evoked inhibition was extremely sensitive to blockade by short iontophoretic applications of atropine, which had no effect on the inhibitions evoked on the same cell equipotent doses of GABA or glycine. The ACh-evoked inhibitions were also antagonized by dihydro-beta-erythroidine released with slightly larger currents. When tested on the same cell, small iontophoretic applications of picrotoxin and bicuculline methoiodide blocked the inhibition evoked by GABA but had no effect on that evoked by ACh. Iontophoretic strychnine only rarely affected the inhibition evoked by ACh, while readily blocking the inhibition evoked on the same cell by an equipotent dose of glycine. In two cats, intravenous strychnine (1-2 mg/kg) had no effect on the ACh-evoked inhibition, while greatly reducing the sensitivity of the cell under study to glycine. 5. Only four out of forty-eight ACh-inhibted cells tested were inhibited by iontophoretic applications of either guanosine or adenosine 3':5'-phosphate. 6. Cells of the nucleus reticularis have been shown to have an inhibitory action on the thalamic relay cells, which are excited by ACh. It is suggested that the presence of both ACh excited and inhibited cells in different nuclei of the thalamus could be of considerable functional significance in gating sensory transmission through the thalamus.     

Opposite functions of histamine H1 and H2 receptors and H3 receptor in substantia nigra pars reticulata

The substantia nigra pars reticulata (SNr) is a key basal ganglia output nucleus. Inhibitory outputs from SNr are encoded in spike frequency and pattern of the inhibitory SNr projection neurons. SNr output intensity and pattern are often abnormal in movement disorders of basal ganglia origin. In Parkinson's disease, histamine innervation and histamine H3 receptor expression in SNr may be increased. However, the functional consequences of these alterations are not known. In this study, whole cell patch-clamp recordings were used to elucidate the function of different histamine receptors in SNr. Histamine increased SNr inhibitory projection neuron firing frequency and thus inhibitory output. This effect was mediated by activation of histamine H1 and H2 receptors that induced inward currents and depolarization. In contrast, histamine H3 receptor activation hyperpolarized and inhibited SNr inhibitory projection neurons, thus decreasing the intensity of basal ganglia output. By the hyperpolarization, H3 receptor activation also increased the irregularity of the interspike intervals or changed the pattern of SNr inhibitory neuron firing. H3 receptor-mediated effects were normally dominated by those mediated by H1 and H2 receptors. Furthermore, endogenously released histamine provided a tonic, H1 and H2 receptor-mediated excitation that helped keep SNr inhibitory projection neurons sufficiently depolarized and spiking regularly. These results suggest that H1 and H2 receptors and H3 receptor exert opposite effects on SNr inhibitory projection neurons. Functional balance of these different histamine receptors may contribute to the proper intensity and pattern of basal ganglia output and, as a consequence, exert important effects on motor control.     

Molecular and functional differences in voltage-activated sodium currents between GABA projection neurons and dopamine neurons in the substantia nigra

GABA projection neurons (GABA neurons) in the substantia nigra pars reticulata (SNr) and dopamine projection neurons (DA neurons) in substantia nigra pars compacta (SNc) have strikingly different firing properties. SNc DA neurons fire low-frequency, long-duration spikes, whereas SNr GABA neurons fire high-frequency, short-duration spikes. Since voltage-activated sodium (Na(V)) channels are critical to spike generation, the different firing properties raise the possibility that, compared with DA neurons, Na(V) channels in SNr GABA neurons have higher density, faster kinetics, and less cumulative inactivation. Our quantitative RT-PCR analysis on immunohistochemically identified nigral neurons indicated that mRNAs for pore-forming Na(V)1.1 and Na(V)1.6 subunits and regulatory Na(V)β1 and Na(v)β4 subunits are more abundant in SNr GABA neurons than SNc DA neurons. These α-subunits and β-subunits are key subunits for forming Na(V) channels conducting the transient Na(V) current (I(NaT)), persistent Na current (I(NaP)), and resurgent Na current (I(NaR)). Nucleated patch-clamp recordings showed that I(NaT) had a higher density, a steeper voltage-dependent activation, and a faster deactivation in SNr GABA neurons than in SNc DA neurons. I(NaT) also recovered more quickly from inactivation and had less cumulative inactivation in SNr GABA neurons than in SNc DA neurons. Furthermore, compared with nigral DA neurons, SNr GABA neurons had a larger I(NaR) and I(NaP). Blockade of I(NaP) induced a larger hyperpolarization in SNr GABA neurons than in SNc DA neurons. Taken together, these results indicate that Na(V) channels expressed in fast-spiking SNr GABA neurons and slow-spiking SNc DA neurons are tailored to support their different spiking capabilities.     

Striatal, pallidal, and pars reticulata evoked inhibition of nigrostriatal dopaminergic neurons is mediated by GABA(A) receptors in vivo

Dopaminergic neurons express both GABA(A) and GABA(B) receptors and GABAergic inputs play a significant role in the afferent modulation of these neurons. Electrical stimulation of GABAergic pathways originating in neostriatum, globus pallidus or substantia nigra pars reticulata produces inhibition of dopaminergic neurons in vivo. Despite a number of prior studies, the identity of the GABAergic receptor subtype(s) mediating the inhibition evoked by electrical stimulation of neostriatum, globus pallidus, or the axon collaterals of the projection neurons from substantia nigra pars reticulata in vivo remain uncertain. Single-unit extracellular recordings were obtained from substantia nigra dopaminergic neurons in urethane anesthetized rats. The effects of local pressure application of the selective GABA(A) antagonists, bicuculline and picrotoxin, and the GABA(B) antagonists, saclofen and CGP-55845A, on the inhibition of dopaminergic neurons elicited by single-pulse electrical stimulation of striatum, globus pallidus, and the thalamic axon terminals of the substantia nigra pars reticulata projection neurons were recorded in vivo. Striatal, pallidal, and thalamic induced inhibition of dopaminergic neurons was always attenuated or completely abolished by local application of the GABA(A) antagonists. In contrast, the GABA(B) antagonists, saclofen or CGP-55845A, did not block or attenuate the stimulus-induced inhibition and at times even increased the magnitude and/or duration of the evoked inhibition. Train stimulation of globus pallidus and striatum also produced an inhibition of firing in dopaminergic neurons of longer duration. However this inhibition was largely insensitive to either GABA(A) or GABA(B) antagonists although the GABA(A) antagonists consistently blocked the early portion of the inhibitory period indicating the presence of a GABA(A) component. These data demonstrate that dopaminergic neurons of the substantia nigra pars compacta are inhibited by electrical stimulation of striatum, globus pallidus, and the projection neurons of substantia nigra pars reticulata in vivo. This inhibition appears to be mediated via the GABA(A) receptor subtype, and all three GABAergic afferents studied appear to possess inhibitory presynaptic GABA(B) autoreceptors that are active under physiological conditions in vivo.     

Evidence for inhibitory amino acid receptors on guinea pig medial vestibular nucleus neurons in vitro

There is little evidence to indicate the identity of the inhibitory receptors which mediate inhibitory interaction between the two medial vestibular nuclei ('brainstem commissural inhibition'). In the present study we tested the hypothesis that medial vestibular nucleus (MVN) neurons have gamma-aminobutyric acid (GABA) or glycine receptors by recording from single MVN neurons in isolated guinea pig MVN slices maintained in vitro while superfusing with GABA (10(-8) M) and the non-competitive GABAA antagonist picrotoxin (10(-6) M or 2 x 10(-6) M), or glycine (10(-6) M) and the competitive glycine antagonist strychnine (10(-6) M). Forty-four % (16/36) of the neurons tested with GABA showed a decrease in firing; in 7 out of 8 cases in which a decrease in firing occurred, the addition of the antagonist picrotoxin completely blocked the effect of the GABA alone. Fifty % (7/14) of the neurons tested with glycine showed a decrease in firing; in 4 out of 6 cases where a decrease occurred, the addition of the antagonist strychnine completely blocked the effect of the glycine alone. In one case only did a cell respond both to GABA and glycine (8 neurons tested with both). These results are consistent with the hypothesis that some MVN neurons have GABA or glycine receptors (but in most cases not both), which may mediate brainstem commissural inhibition.     

Responses of rat substantia nigra pars reticulata units to cortical stimulation.

In order to study the function of multiple pathways between the sensorimotor cortex (Cx) and the substantia nigra pars reticulata (SNr), responses of SNr units to stimulation of the Cx were studied in anesthetized rats. Most of the units (229 of 236) exhibited repetitive firing with fairly short, regular intervals. The other 7 units displayed long duration spikes, irregular firing intervals and slow spontaneous firing. Stimulation of the Cx usually resulted in a short latency excitation and occasionally a long latency inhibition in both types of units. When strong stimulation was applied, multiple excitatory and inhibitory responses alternating each other with about a 25 ms interval were observed. SNr units responded with different patterns and latencies to stimulation of different sites of the sensorimotor Cx. The results indicate that signals derived from the sensorimotor Cx reach the SNr via multiple pathways and converge on many SNr neurons.     

Baclofen attenuates harmaline induced tremors in rats

Because activation of D2 dopamine receptors inhibits gamma-aminobutyric acid (GABA) release from intrapallidal nerve terminals, we measured the effects of modifiers of dopamine D2 receptors on the firing rate of single neurons in the globus pallidus (GP) of the anesthetized rat. The predominant effect of intrapallidal administration of the selective D2 agonist quinpirole was an increase in the rate of spontaneous firing while the D2 blocker sulpiride caused a decrease. The spontaneous firing of GP neurons is inhibited by stimulation of the GABAergic striatopallidal projection. We therefore measured the effects of modifiers of D2 receptors on striatal inhibition of GP neurons and found that intrapallidal quinpirole blocked the inhibitory effects of striatal stimulation while sulpiride enhanced them. These experiments show that both the spontaneous rate of firing of pallidal neurons and its modification by striatopallidal inputs is controlled by intrapallidal dopamine D2 receptors. In addition, taken together with other findings in the literature, our results suggest that activation of dopamine D2 receptors within the globus pallidus leads to inhibition of GABA release from presynaptic terminals.     

The membrane effects, and sensitivity to strychnine, of neural inhibition of the Mauthner cell, and its inhibition by glycine and GABA

1. Anionic conductance changes in Mauthner neurones of goldfish were measured during synaptically evoked inhibition and inhibition caused by iontophoretic application of the putative inhibitory transmitters glycine and gamma-aminobutyric acid (GABA).2. The effects of either amino acid were indistinguishable from those of the neural inhibitory transmitter(s). The membrane permeability during the neural or drug response was increased to Br(-), Cl(-), I(-), SCN(-), NO(3) (-), ClO(3) (-), and formate (HCOO(-)), but not to HCO(3) (-), BrO(3) (-), IO(3) (-), SO(4) (-), HPO(4) (-), H(2)PO(4) (-), acetate and citrate.3. Strychnine was injected intramuscularly, iontophoretically, or applied topically to the exposed brain in order to compare quantitatively its ability to prevent inhibition evoked by synaptic activation and by pharmacological means. Inhibitions were measured by the increase in membrane conductance.4. Strychnine, at concentrations just adequate to block completely the late collateral inhibition (LCI) and crossed VIII nerve inhibition, had little effect on the pharmacological inhibition caused by glycine, and sometimes there was no detectable effect at all. In one experiment even a local iontophoretic application of strychnine in a sufficient dose to diffuse over the cell and block the LCI almost completely, merely halved the effect of a small dose of glycine applied to the same localized region of the membrane.5. Higher concentrations of strychnine than those necessary to block synaptically evoked inhibition would reduce the effect of glycine but not that of GABA. The evidence indicated that any apparent effect of strychnine upon GABA could be explained by displacement of the GABA-containing iontophoretic pipette.6. The glycine-blocking action of iontophoretic pulses of strychnine was of relatively very slow onset and long duration compared to the effects of pulses of glycine and GABA.7. These findings can be interpreted as either (1) strychnine has a presynaptic action, preventing the release of inhibitory neurotransmitter, in addition to its less potent post-synaptic one in blocking pharmacological inhibition, or (2) strychnine acts entirely post-synaptically, but the physiological transmitter action differs from that of glycine and GABA in being considerably more sensitive to strychnine antagonism. In either case, the use of strychnine as evidence for the claim that glycine is an inhibitory neurotransmitter at the Mauthner cell is questionable.     

Bicuculline and thalamic inhibition

Summary A study was made of the effects of electrophoretically administered bicuculline on the recurrent inhibition of thalamo-cortical relay neurones of the ventrobasal complex and the dorsal lateral geniculate nucleus of decerebrate and anaesthetised cats (pentobarbitone sodium). Electrophoretically administered glycine, GABA and taurine depressed the firing of thalamic neurones. GABA was usually the most potent depressant, glycine the least. The effects of GABA and taurine were blocked by bicuculline, those of taurine and glycine were blocked by strychnine. The inhibition of the firing of lateral geniculate neurones by electrical stimulation of the visual cortex was reduced by bicuculline but not by strychnine. The inhibition of these cells following an optic nerve volley, and the inhibition of ventrobasal neurones by stimulation of the primary somatosensory cortex, were also reduced by bicuculline.These findings suggest that intrathalamic inhibitory neurones release GABA as a transmitter at synapses on thalamo-cortical relay neurones. There is insufficient evidence to assess the significance of glycine and taurine as inhibitory transmitters in these thalamic nuclei.     

Beta-alanine induced ion channels in the membrane of cultured spinal cord neurons

beta-Alanine (beta-ALa) is a structural analog of the putative inhibitory transmitters gamma-aminobutyric acid (GABA) and glycine. beta-ALa itself depresses firing in cultured mouse spinal cord (SC) neurons, by selectively increasing membrane conductance to chloride ions. Patch clamp recordings now reveal that beta-ALa-sensitive chloride channels in SC cells can open to at least 5 conductance states, 4 of which are very similar to states seen when GABA or glycine is applied to these cells. However, a large, 80 pS conductance state is activated at detectable frequency only in the presence of beta-ALa itself.     

Involvement of GABA in medullary raphe-evoked modulation of neuronal activity in the periaqueductal grey matter in the rat

Experiments were carried out in urethane-anaesthetised rats to investigate whether GABA is involved in mediating inhibition of neuronal activity in the dorsal half of the periaqueductal grey matter (PAG) after stimulation of the serotonin-containing projection to the PAG from nucleus raphe obscurus (NRO). Multibarrelled micropipettes were used to make recordings from 42 neurones in the dorsal half of the PAG. Most (n = 36) cells were quiescent. Their firing rate was therefore raised to 10-16 Hz by continuous iontophoretic application of DL-homocysteic acid (DLH) in order to facilitate the study of inhibitory events. Iontophoretic application of GABA (0-10 nA) silenced every neurone tested (n = 42), and the effect was blocked by the GABAA antagonist bicuculline (BIC, 10-20 nA; 15/15 cells). BIC also produced an increase in ongoing activity in 14 of 15 cells, indicating the presence of inhibitory GABAergic tone. Iontophoretically applied serotonin (5-HT; 10-70 nA) also inhibited ongoing activity in 9 of 11 cells. The effect of 5-HT was not blocked by BIC. In six of seven cells, microinjection of 100-200 nl DLH into NRO produced a 72.3 +/- 9.4% decrease in neuronal firing rate which was maximal 112 +/- 18 s after the start of the injection and lasted for a total of 313 +/- 63 s. In five of six cells, the raphe-evoked inhibition was blocked by BIC. It is suggested that activation of the serotonergic projection to the PAG from NRO engages GABA-containing interneurones within the PAG which mediate the inhibitory effects of raphe stimulation.     

The effectiveness of bicuculline as an antagonist of GABA and visually evoked inhibition in the cat''s striate cortex.

1. The iontophoretic application of the alkaloid bicuculline to neurones in area 17 of the cat's visual cortex effectively antagonized the inhibitory action of iontophoretically applied GABA in fifty-four out of sixty-two neurones examined. It had little or no effect on the inhibitory action of iontophoretically applied glycine. 2. At the stage that the iontophoretic application of bicuculline blocked the inhibitory action of GABA it also reduced or blocked visually evoked inhibitory influences acting on forty-three of the fifty-four cells. This effect on visually evoked inhibition was not reproduced by simply raising the neural spontaneous activity with iontophoretically applied glutamate. 3. For those seven neurones where the iontophoresis of bicuculline failed to block the inhibitory action of iontophoretically applied GABA it also failed to produce any change in visually evoked inhibition. 4. In all cases where a visually evoked inhibition of a cells resting discharge was reduced by the iontophoretic application of bicuculline, the inhibitory response was replaced by an excitatory response. The application of bicuculline also revealed excitatory responses to certain of the visual stimuli that previously appeared to exert neither inhibitory nor excitatory effects on a cell, and often where cells normally exhibited small excitatory responses it produced large increases in the magnitude of the evoked response. 5. These results indicate that the normal responses of the neurones examined in the present work, to the particular visual stimuli used, reflect an interaction between simultaneously evoked excitatory and inhibitory inputs. It is suggested that the iontophoretic application of bicuculline by blocking or reducing the inhibitory input moves the balance between the inputs in favour of the excitatory input. 6. The present results support the view that GABA is an inhibitory transmitter in the visual cortex.     

Neuronal interactions in the substantia nigra pars reticulata through axon collaterals of the projection neurons

Summary Substantia nigra pars reticulata (SNr) neurons, antidromically activated following stimulation of the dorsal thalamus and/or superior colliculus were intracellularly stained with HRP. Light microscopic analysis revealed that the labeled SNr neurons have axon collaterals arborizing within SNr. Axon collaterals of SNr neurons partially overlapped with the dendritic fields of their parent cells and also extended beyond the parent dendritic fields. The labeled axon terminals did not closely appose the parent cell processes, suggesting that the collaterals most likely terminate on neurons other than the parent cell.Electrical stimulation of either the thalamus or the superior colliculus induced monosynaptic and polysynaptic IPSPs in SNr cells. The polysynaptic IPSPs evoked from thalamic stimulation disappeared following hemitransection of the brain just rostral to the thalamus while the monosynaptic IPSPs remained the same. Since there are no known afferents from either thalamus or superior colliculus to SNr, we consider that these monosynaptic IPSPs are due to activation of the recurrent collaterals of SNr projection cells. The results of this study indicate that projection neurons of SNr also have an inhibitory role within the SNr.Supported by USPHS NIH Grant NS 14866 to S.T. Kitai and F32 NS 06249 to J.P. Donoghue. Foundation Simone el Cino del Duca, Paris, France, furnished travel funds to J.M. Deniau     

Inhibitory nigral influence on tectospinal neurons,a possible implication of basal ganglia in orienting behavior

Summary We have established in previous electrophysiological studies that the substantia nigra pars reticulata (SNr) exerts a potent inhibitory influence on cells located in the intermediate and deep tectal strata. The present study demonstrates that, in the rat, the tectospinal neurons constitute one of the cellular populations of the tectum on which the SN exerts its influence.Tectospinal neurons were identified using the antidromic activation method. Following SNr stimulation 17/37 (45%) of these cells showed a shortlatency (1.5–2 ms) short-duration (7–15 ms) inhibition. This effect was revealed by a blockade of spontaneous and peripherally evoked discharges. Moreover, in some cases the nigral inhibition delayed the antidromic invasion of the somato-dendritic portion of the neuron. Tectospinal neurons have been considered as one of the neuronal substrate by which the superior colliculus (SC) can promote head orienting movements. The evidence that the SNr influences the responsiveness of these cells to their peripheral sensory inputs suggests that the basal ganglia and in particular the SNr are involved in the integrative sensorimotor processes underlying head orienting movements.This work was supported by DGRST Grant 83 C 0336     

Change in mechanical receptive field properties induced by GABAA receptor activation in the trigeminal spinal nucleus caudalis neurons in rats

The purpose of the present study was to characterize the effect of a local GABAergic inhibitory mechanism on the mechanical receptive field properties of trigeminal spinal nucleus caudalis (SpVc) neurons by iontophoretic application of a gamma-aminobutyric acidA (GABA(A))-antagonist and -agonist. A total of 24 SpVc neurons that responded to orofacial mechanical stimulation were extracellularly recorded by means of multibarrel microelectrodes in urethane-anesthetized rats. The GABA(A) antagonist bicuculline (30 nA, 5 min) enhanced the activities of SpVc neurons (20/24) induced by both touch/pressure and pinch stimuli and also lowered the mechanical stimulation threshold (touch/pressure). Spontaneous discharges in these neurons (20/24) were significantly increased after bicuculline application. Eighteen out of 24 SpVc neurons showed signs of expansion of the receptive field size after iontophoretic application of bicuculline. These changes showed a current-dependent manner and were reversed in approximately 15-20 min. Iontophoretic application of the GABA(A) agonist muscimol induced a current-related inhibition of neuronal activity elicited by touch/pressure and pinch stimuli as well as a decrease in the size of receptive fields. The facilitation of evoked responses and receptive field expansion of SpVc neuron induced by bicuculline application were blocked by coapplication of muscimol (50 nA, 5 min). These results suggest that a local mechanism acting via GABA(A) receptors normally exerts a tonic inhibition of mechanoreceptive transmission in the trigeminal spinal nucleus neurons and this effect may limit responsiveness and size of receptive fields.     

GABAB receptor-mediated tonic inhibition of noradrenergic A7 neurons in the rat

Noradrenergic (NAergic) A7 neurons that project axonal terminals to the dorsal horn of the spinal cord to modulate nociceptive signaling are suggested to receive tonic inhibition from local GABAergic interneurons, which are under the regulation of descending analgesic pathways. In support of this argument, we presently report GABA(B) receptor (GABA(B)R)-mediated tonic inhibition of NAergic A7 neurons. Bath application of baclofen induced an outward current (I(Bac)) in NAergic A7 neurons that was blocked by CGP 54626, a GABA(B)R blocker. The I(Bac) was reversed at about -99 mV, displayed inward rectification, and was blocked by Ba(2+) or Tertipian-Q, showing it was mediated by G protein-activated inward-rectifying K(+) (GIRK) channels. Single-cell RT-PCR results suggested that GIRK1/3 heterotetramers might dominate functional GIRK channels in NAergic A7 neurons. Under conditions in which GABA(A) and glycine receptors were blocked, bath application of GABA inhibited the spontaneous firing of NAergic A7 neurons in a dose-dependent manner. Interestingly, CGP 54626 application not only blocked the effect of GABA but also increased the firing rate to 126.9% of the control level, showing that GABA(B)Rs were constitutively active at an ambient GABA concentration of 2.8 μM and inhibited NAergic A7 neurons. GABA(B)Rs were also found at presynaptic excitatory and inhibitory axonal terminals in the A7 area. Pharmacological activation of these GABA(B)Rs inhibited the release of neurotransmitters. No physiological role was found for GABA(B)Rs on excitatory terminals, whereas those on the inhibitory terminals were found to exert autoregulatory control of GABA release.     

Inhibitory actions of a novel endogenous tripeptide,methyionyl-tyrosyl-lysine,on proprioceptive neurons in the lumbar spinal cord of the cat

The actions of a tripeptide, methionyl-tyrosyl-lysine (Met-Tyr-Lys), isolated from spinal cord and dorsal root ganglia have been investigated by iontophoretic application to single neurones in the spinal cord of the cat. Met-Tyr-Lys inhibited a group of neurons located mainly in laminae V and VI of the lumbar dorsal horn: excitation was never observed. The inhibition was rapid in onset and was not mimicked by the action of the constituent amino acids. Neurons inhibited by Met-Tyr-Lys received proprioceptive inputs as shown by their excitation or inhibition from stimulation of deep receptors and by their responses to leg or foot movement. Bicuculline and strychnine separately, at doses which antagonized responses to γ-aminobutyric acid and glycine, respectively, had no or little effect both on responses to Met-Tyr-Lys and on the inhibition evoked in the same neurons by low-intensity (1.5–4T) stimulation of the tibial or common peroneal nerves.Thus receptors for Met-Tyr-Lys are different from those for glycine or γ-aminobutyrate. In addition it is possible that there is a component of the inhibition evoked by peripheral nerve stimulation which is not mediated by either glycine or γ-aminobutyrate. Met-Tyr-Lys may have an inhibitory role in relation to proprioception.