Antagonist discrimination of two muscarinic responses elicited by applied agonists and orthodromic stimuli in superior cervical ganglion of rabbit.

Pirenzepine and gallamine selectively and differentially antagonized two muscarinic responses, in the superior cervical ganglion of the rabbit, whether elicited by the muscarinic agonist methacholine or by orthodromic stimulation. Methacholine elicited a biphasic ganglionic response, consisting of hyperpolarizing and depolarizing components that were the agonist-induced equivalents of the slow-inhibitory and slow-excitatory postsynaptic potentials elicited by orthodromic stimulation. Superfusion of ganglia with pirenzepine resulted in a concentration-dependent suppression of depolarization induced by methacholine with no suppressant action on ganglionic hyperpolarization. In contrast, superfusion of ganglia with gallamine resulted in a concentration-dependent suppression of ganglionic hyperpolarization and the slow-inhibitory postsynaptic potential. These effects occurred without appreciable suppression of ganglionic depolarization or the slow-excitatory postsynaptic potential. The action of gallamine was specific for muscarinic hyperpolarization. Hyperpolarizations produced by superfusion with dopamine or norepinephrine were unaffected by gallamine, at concentrations that suppressed the muscarinic slow-inhibitory post-synaptic potential. Incubation with anti-cholinesterases produced a parallel shift, to the right, of concentration-response curves for suppression by gallamine of the slow-inhibitory postsynaptic potential. This was presumably the consequence of an increase in the acetylcholine available for interaction with the muscarinic receptor. The evidence suggests that the ability of gallamine and pirenzepine to suppress selectively the slow-inhibitory and slow-excitatory postsynaptic potentials, as previously demonstrated, is through an action at muscarinic receptors. Furthermore, the data suggest that these pharmacological agents produce their effects by interaction at different muscarinic recognition sites.

Differential and selective antagonism of the slow-inhibitory postsynaptic potential and slow-excitatory postsynaptic potential by gallamine and pirenzepine in the superior cervical ganglion of the rabbit.

Two cholinergic antagonists, gallamine and pirenzepine, agents that have been shown to bind selectively to different subpopulations of the muscarinic receptor, were found to antagonize selectively and differentially the amplitudes of the slow-inhibitory and slow-excitatory postsynaptic potentials in the superior cervical ganglion of the rabbit. Incubation of ganglia with gallamine resulted in a concentration-dependent suppression of the slow-inhibitory postsynaptic potential. The pharmacological action of gallamine was highly specific. At concentrations which reduced the amplitude of the slow-inhibitory postsynaptic potential by as much as 70-90%, there was no reduction of the amplitudes of the muscarinic slow-excitatory postsynaptic potential, the nicotinic fast-excitatory postsynaptic potential, noncholinergic slow-slow-excitatory postsynaptic potential, or post-stimulus hyperpolarizing afterpotentials. The amplitude of the slow-excitatory postsynaptic potential was actually facilitated in the presence of gallamine, presumably as a result of suppression of the overlapping slow-inhibitory postsynaptic potential. In contrast to the action of gallamine, pirenzepine produced a selective suppression of the amplitude of the slow-excitatory postsynaptic potential. Pirenzepine had very little influence on the amplitude of the slow-inhibitory postsynaptic potential at concentrations sufficient to reduce the amplitude of the slow-excitatory postsynaptic potential by as much as 50%, and had no effect on the amplitudes of the nicotinic fast-excitatory postsynaptic potential or noncholinergic slow-slow-excitatory postsynaptic potential. The evidence presented suggests that multiple muscarinic recognition sites, previously identified by studies of the affinities of pharmacological agents for the muscarinic receptor, may actually be involved in synaptic transmission and functionally coupled to cellular effector mechanisms.

Metoclopramide mimics a D-1 type of dopamine action in rabbit superior cervical ganglion.

Metoclopramide (MCP) in a sufficiently high concentration (100 microM) induced a large and persisting potentiation of slow-excitatory postsynaptic potentials (s-epsp) and slow-inhibitory postsynaptic potentials (s-epsp) but depressed in fast epsp. This modulatory action of metoclopramide was markedly suppressed by (+)-butaclamol (7 microM) and, to a lesser extent, by spiroperidol (2.5-4 microM). Metoclopramide also possessed weak anti-acetylcholinesterase activity(I50% = 245 microM; measured by Dr N. Inestrosa), but this was shown not to account for the potentiating actions of metoclopramide. Thus, although metoclopramide is a D-2 antagonist, it appears to mimic the D-1 action of dopamine in modulating the slow psps.

Differential effects of the muscarinic M2 antagonists, AF-DX 116 and gallamine, on single neurons of rabbit sympathetic ganglia.

Intracellular recording techniques were used to compare the effects of the M2 muscarinic antagonists, AF-DX 116 and gallamine, on membrane potential (Vm), input resistance (Ri), responses induced by methacholine, muscarinic slow postsynaptic potentials and action potentials in the superior cervical ganglion of the rabbit. Gallamine or AF-DX 116 antagonized methacholine-induced or synaptically-evoked muscarinic hyperpolarization, without having significant effect on depolarization induced by methacholine or synaptically. The drug AF-DX 116 reduced evoked muscarinic hyperpolarizing potentials, without significant change in Vm or Ri, recorded in the absence of muscarinic stimulation. In contrast to AF-DX 116, gallamine elicited a concentration-dependent depolarization of the membrane, with a corresponding increase in Ri, when tested in the absence of muscarinic stimulation. These effects of gallamine were accompanied by an increase in duration and decrease in the slope of the descending phase of the action potential. Blockade by gallamine of evoked hyperpolarization was independent of membrane depolarization and readily occurred when gallamine-induced depolarization was prevented by clamping Vm at its pre-gallamine level. The effects of gallamine were maintained during its presence and reversed upon washing with gallamine-free physiological solution. These results indicate that AF-DX 116 and gallamine have a specificity for antagonism of muscarinic responses, mediated by receptors of the M2 type in the superior cervical ganglion. However, gallamine, while an effective antagonist of M2 responses, also has the ability to modify the electrical characteristics of ganglion cells and thus may modify ganglionic transmission by mechanisms other than antagonism of receptors.

Neuropeptide Y receptor agonists: multiple effects on spontaneous activity in the paraventricular hypothalamus.

In vitro rat hypothalamic slices were used to examine the ability of neuropeptide Y (NPY), and the putative Y1 and Y2 receptor agonists [Pro34]NPY and [C2]NPY, to modify spontaneous single-neuron discharge in the paraventricular nucleus (PVN). NPY and [Pro34]NPY, at high concentrations (1500 nM), decreased discharge rates. At intermediate concentrations (150 nM) these peptides produced multiple effects, including increases, decreases, and biphasic changes. At lower concentrations (0.15-15 nM), they typically increased discharge rates. In contrast, [C2]NPY, at all concentrations (1.5-1500 nM), predominantly increased discharge rates. Thus, these NPY subtype agonists have multiple effects on discharge rate, which may be due to actions on multiple NPY receptor subtypes.

GABAergic suppression prevents the appearance and subsequent fatigue of an NMDA receptor-mediated potential in neocortex.

We have investigated the regulation of an N-methyl-D-aspartate (NMDA) receptor-mediated synaptic potential by gamma-aminobutyric acid (GABA)-mediated inhibition using extracellular and whole-cell voltage clamp recordings in rat auditory cortex in vitro. Single afferent stimulus pulses at low intensity elicited a slow extracellular negativity (Component C) that was mediated by NMDA receptors. At higher intensities, Component C was suppressed by recruitment of GABAergic inhibition. To understand the actions of GABAergic inhibition on Component C, we determined the effects of: (i) paired-pulse stimulation, which depresses GABAergic inhibition; (ii) pharmacological antagonism of GABA receptors; and (iii) afferent stimulation in slices from neonatal rats prior to the development of cortical inhibition. The results indicate that GABAergic inhibition prevents Component C from occurring, thereby preventing its reduction upon repeated stimulation. Whole-cell voltage clamp recordings were used to test the hypothesis that GABAergic suppression occurred by way of membrane hyperpolarization. At hyperpolarized holding potentials no NMDA receptor-mediated synaptic current was elicited, even with paired-pulse stimulation. At depolarized holding potentials a significant NMDA synaptic current was elicited despite the presence of GABAergic synaptic currents. We conclude that membrane hyperpolarization by GABAergic inhibition prevents the appearance and subsequent fatigue of an NMDA receptor-mediated synaptic potential. Reduction of inhibition can act as a 'switch' to fully release the NMDA potential as frequently as once every 10-20 s.

Basal forebrain stimulation modifies auditory cortex responsiveness by an action at muscarinic receptors.

We have hypothesized that auditory cortex plasticity involves modification of thalamocortical transmission by basal forebrain (BF) cholinergic neurons, and that this action may involve muscarinic receptors. In a first test of this hypothesis, we report that BF stimulation can suppress or facilitate, depending on the intensity of stimulation, auditory cortical responses elicited by thalamic stimulation. BF-mediated facilitation is antagonized by atropine, implicating muscarinic receptors. These data suggest that BF cholinergic neurons functionally modify auditory cortex by regulating thalamocortical transmission.

Modulation of slow postsynaptic potentials by dopamine, in rabbit sympathetic ganglion.

(1) Temporary exposure of rabbit's superior cervical ganglion (SCG) to dopamine (DA), in the presence of an inhibitor of catechol-o-methyltransferase (COMT) is consistently followed by a potentiation of the slow (s)-EPSP and s-IPSP, lasting for some hours. The fast (f)-EPSP is not significantly increased, but it is better maintained than in control ganglia. (2) Exposure to the COMT-inhibitor U-0521 alone induces less but substantial potentiations of both s-PSPs. This effect is explained as due to protection of DA released intraganglionically at rest. (3) This evidence suggests that COMT may significantly limit the access of catecholamines to postsynaptic receptors, for at least certain types of neuron-to-neuron synaptic actions. (4) The potentiation of both s-PSPs, whether induced by DA in the presence of U-0521 or by U-0521 alone, is depressed by DA-1 antagonists that have been found to depress DA-stimulation of adenyl cyclase in rabbit SCG; these are spiroperidol, butaclamol and, to a lesser extent, bromocriptine. The specific 'DA-2' antagonists metoclopramide and sulpiride, and the alpha-adrenergic antagonist dihydroergotamine, did not depress potentiation. (5) Potentiation of s-EPSP is viewed as identical in nature to the previously discovered DA-modulatory enhancement of direct muscarinic depolarizing actions (by acetylcholine or its agonists). Potentiation of s-IPSP may be due to a similar DA-modulation of other muscarinic response(s) involved in mediating the s-IPSP. The consistency and comparative ease with which these DA-modulatory effects can be induced, under presently described experimental conditions, should facilitate future study of this mode of synaptic action.

Effect of inhibitors of protein synthesis on dopamine modulation of the slow-EPSP in rabbit superior cervical ganglion.

The protein synthesis inhibitors, anisomycin and cycloheximide, were tested for their ability to prevent dopamine-induced long-term enhancement of the slow-EPSP in rabbit superior cervical ganglion. Exposure of ganglia to either inhibitor of protein synthesis, at a concentration that suppressed [3H]leucine incorporation into ganglionic protein by at least 95%, had no effect on the development of dopamine-induced enhancement of the slow-EPSP. Incubation of ganglia with dopamine, without an inhibitor of protein synthesis, was without effect on [3H]leucine incorporation into ganglionic protein. It is concluded that synthesis of new protein is not required for the development of long-term enhancement of the slow-EPSP induced by dopamine.

Modulation by dopamine of population responses and cell membrane properties of hippocampal CA1 neurons in vitro.

Dopamine (DA) was applied to rat hippocampal slices maintained in vitro. Extracellular and intracellular recording techniques were used to study the effect of DA on population responses, membrane potentials, and membrane responses to hyperpolarizing current pulses in CA1 pyramidal cells. Temporary exposure of hippocampal slices to DA has a dual effect. The initial action of DA is to produce a suppression of the extra-cellularly recorded population responses. In individual neurons, this initial effect is seen as a membrane hyperpolarization accompanied by a decrease in the amplitude of responses to hyperpolarizing current pulses. The frequency of occurrence of spontaneous depolarizations and spikes is reduced. The early action of DA is followed by a profound potentiation of the population responses that can last for hours. This long-lasting potentiation of the population response, induced by DA, is depressed by spiroperidol, a DA antagonist. In individual neurons, the late effect of DA is a long-lasting membrane depolarization associated with an increase in the amplitude of responses to hyperpolarizing current pulses. During this late phase, spontaneous activity is increased, as are single cell responses to stimulation of afferents. The evidence presented here indicates that DA is able to induce a long-lasting modification of the excitability of CA1 hippocampal neurons. This modulation of excitability by DA may be similar in nature to previously described DA-modulatory actions in the peripheral nervous system.

Pharmacological properties and monoaminergic mediation of the slow IPSP, in mammalian sympathetic ganglion.

Phenoxybenzamine can selectively eliminate the s-IPSP, in the presence of anti-cholinesterases that enhance s-IPSP and s-EPSP; and the alpha 2-antagonist, yohimbine, can partially but consistently depress s-IPSP selectively. The results provide positive pharmacological support for the monoaminergic nature of the transmitter for s-IPSP in mammalian sympathetic ganglia and argue against suggestions that the s-IPSP is a direct hyperpolarizing response to acetylcholine.

Tetanic stimulation and metabotropic glutamate receptor agonists modify synaptic responses and protein kinase activity in rat auditory cortex.

We investigated whether tetanic-stimulation and activation of metabotropic glutamate receptors (mGluRs) can modify field-synaptic-potentials and protein kinase activity in rat auditory cortex, specifically protein kinase A (PKA) and protein kinase C (PKC). Tetanic stimulation (50 Hz, 1 s) increases PKA and PKC activity only if the CNQX-sensitive field-EPSP (f-EPSP) is also potentiated. If the f-EPSP is unchanged, then PKA and PKC activity remains unchanged. Tetanic stimulation decreases a bicuculline-sensitive field-IPSP (f-IPSP), and this occurs whether the f-EPSP is potentiated or not. Potentiation of the f-EPSP is blocked by antagonists of mGluRs (MCPG) and PKC (calphostin-C, tamoxifen), suggesting that the potentiation of the f-EPSP is dependent on mGluRs and PKC. PKC antagonists block the rise in PKC and PKA activity, which suggests that these may be coupled. In contrast, ACPD (agonist at mGluRs) decreases both the f-EPSP and the f-IPSP, but increases PKC and PKA activity. Quisqualate (group I mGluR agonist), decreases the f-IPSP, and increases PKA activity, suggesting that the increase in PKA activity is a result of activation of group I mGluRs. Additionally, the increase in PKC and PKA activity appears to be independent of the decrease of the f-EPSP and f-IPSP, because PKC antagonists block the increase in PKC and PKA activity levels but do not block ACPD's effect on the f-EPSP or f-IPSP. These data suggest that group I mGluRs are involved in potentiating the f-EPSP by a PKC and possibly PKA dependent mechanism which is separate from the mechanism that decreases the f-EPSP and f-IPSP.

Argiotoxin-636 blocks excitatory synaptic transmission in rat hippocampal CA1 pyramidal neurons.

Argiotoxin 636, (AR636), a synaptic antagonist from orb weaver spider venom, is shown to produce reversible blockade of excitatory transmission in CA1 pyramidal neurons of the in vitro rat hippocampus. Microtopical application of AR636 (5-50 nM) resulted in a concentration-dependent suppression of the amplitude of the dendritic field EPSP recorded from stratum radiatum, and the amplitude of the population spike recorded from stratum pyramidale in response to stimulation of the Schaffer collaterals. The maximum effect of AR636 occurred at about 15-25 min. These effects were reversible after washing with toxin-free physiological solution with the rate of recovery having an inverse relationship to the concentration of AR636. In contrast to the effects observed with orthodromic stimulation, the amplitude of the antidromic spike was not affected by exposure to AR636. The temporal pattern of GABAergic paired-pulse inhibition was unaffected by exposure to AR636. Neuronal discharge elicited by pressure ejection of L-glutamate was abolished by AR636, whereas, responses to L-aspartate were not significantly affected. These data suggest that AR636 functions as a selective antagonist of glutamate-mediated synaptic transmission in rat hippocampus.

Muscarinic reduction of GABAergic synaptic potentials results in disinhibition of the AMPA/kainate-mediated EPSP in auditory cortex.

The present study is concerned with the ability of muscarinic actions of acetylcholine (ACh) to modulate glutamate and gamma-aminobutyric acid (GABA)-mediated synaptic transmission in the in vitro rat auditory cortex. Whole-cell patch clamp recordings were obtained from layer II-III pyramidal neurons, and the fast-EPSP (AMPA/kainate), fast-IPSP (GABA(A)), and slow-IPSP (GABA(B)), were elicited following a stimulus to deep gray/white matter. Acetyl-beta-methylcholine (MCh), a muscarinic receptor agonist, applied by either superfusion or iontophoresis, produced an atropine-sensitive increase or decrease in the amplitude of the fast-EPSP. The effect of MCh could be predicted by the response of the fast-EPSP to paired-pulse stimulation (i.e. a conditioning pulse followed 300 ms later by a test pulse). The fast-EPSP was decreased in amplitude by MCh in cases where the test-EPSP was suppressed in the pre-MCh condition, and increased in amplitude when the test-EPSP was facilitated. The fast- and slow-IPSPs were always reduced by MCh. In several experiments, the strength of synaptic inhibition was systematically modified by varying stimulus intensity. When the fast-EPSP was elicited in the absence of IPSPs, it was decreased in amplitude by MCh. However, when the fast-EPSP was elicited in conjunction with large IPSPs it was increased in amplitude during MCh. Because the magnitude of the fast-EPSP is influenced by the degree of temporal overlap with IPSPs, it was hypothesized that enhancement of the fast-EPSP was the result of disinhibition produced as a consequence of muscarinic reduction of GABAergic IPSPs. This view was supported by the finding that MCh could reduce the amplitude of pharmacologically isolated GABAergic IPSPs (i.e. elicited in the absence of glutamatergic transmission). Our results suggest that ACh at muscarinic receptors can modify fast glutamatergic neurotransmission differently as a function of strength of inhibition, to suppress that produced by 'weak' inputs and enhance that produced by 'strong' inputs.

Responses of opossum and rat hippocampal CA1 cells to paired stimulus volleys.

Short-term synaptic plasticity was studied in the in vitro hippocampus of the North American opossum (Didelphis virginiana) and rat (Rattus norvegicus). Conditioning and test stimulus pulses were delivered to fibers in stratum radiatum, and intracellular and extracellular recordings were obtained from area CA1 pyramidal cells. In rat, the amplitude of the population spike in response to the second (test) of two stimulus impulses is suppressed at short inter-pulse-intervals (IPI's). In opossum, the amplitude of the test population spike is facilitated at comparable IPI's. Facilitation of the test population spike in rat occurs only when the test stimulus is separated from the first stimulus (conditioning) by a longer IPI. Peak values of facilitation do not significantly differ between species. Intracellular responses, elicited by stimulus pulses that were subthreshold for spike production, indicate that the amplitude of test EPSP's recorded from opossum pyramidal cells are facilitated at IPI's that result in suppression of test EPSP's in rat pyramidal cells.

Synaptic potentials and effects of amino acid antagonists in the auditory cortex.

Neurons of in vitro guinea pig and rat auditory cortex receive a complex synaptic pattern of afferent information. As many as four synaptic responses to a single-stimulus pulse to the gray or white matter can occur; an early-EPSP followed, sequentially, by an early-IPSP, late-EPSP, and late-IPSP. Paired pulse stimulation and pharmacological studies show that the early-IPSP can modify information transmission that occurs by way of the early-EPSP. Each of these four synaptic responses differed in estimated reversal potential, and each was differentially sensitive to antagonism by pharmacological agents. DNQX (6,7-dinitroquinoxaline-2,3-dione), a quisqualate/kainate receptor antagonist, blocked the early-EPSP, and the late-EPSP was blocked by the NMDA receptor antagonist APV (D-2-amino-5-phosphonovalerate). The early-IPSP was blocked by the GABA-a receptor antagonist bicuculline, and the late-IPSP by the GABA-b receptor antagonists 2-OH saclofen or phaclofen. Presentation of stimulus trains, even at relatively low intensities, could produce a long-lasting APV-sensitive membrane depolarization. Also discussed is the possible role of these synaptic potentials in auditory cortical function and plasticity.

Mesencephalic multiple-unit activity during acquisition of conditioned pupillary dilation.

Multiple-unit recordings were obtained from the interstitial nucleus of Cajal, nucleus of Darkschewitsch and the superior colliculus of the cat during acquisition of classically conditioned pupillary dilation. Multiple-unit responses in all regions were enhanced by conditioning procedures. However, only the acquisition functions for the accessory oculomotor nuclei, i.e., interstitial nucleus of Cajal and nucleus of Darkschewitsch, were significantly correlated with the acquisition of conditioned pupillary dilation. These results were discussed in relation to the mechanism of autonomic control of conditioned pupillary dilation. It was concluded that inhibition of parasympathetic pupillomotor efferents via the accessory oculomotor nuclei may play a role in the acquisition of conditioned pupillary dilation.

Facilitation of an NMDA receptor-mediated EPSP by paired-pulse stimulation in rat neocortex via depression of GABAergic IPSPs.

1. Tight seal, whole-cell recordings from auditory cortex in vivo and in vitro were obtained to investigate modification of N-methyl-D-aspartate (NMDA) receptor-mediated synaptic activity by paired-pulse afferent stimulation. 2. In recordings from urethane-anaesthetized rats (at 37 degrees C), or from cortical slices maintained in vitro (32 degrees C), afferent stimulation elicited a monosynaptic early EPSP and polysynaptic early and late IPSPs. In addition, a late EPSP could be elicited when the stimulus was preceded by an identical priming stimulus (interval approximately 200 ms). The late EPSP was attenuated by the NMDA receptor antagonist DL-2-amino-5-phosphonovalerate (APV, 50 microM). 3. Bath application of the gamma-aminobutyric acid-B (GABAB) receptor antagonist 3-amino-2-(4-chlorophenyl)-2-hydroxy-propylsulphonic acid (2-OH-saclofen; 50 microM) attenuated the late IPSP and clearly revealed a late EPSP. However, 2-OH-saclofen had lesser effects on the second late EPSP elicited during paired-pulse stimulation. Membrane depolarization in 2-OH-saclofen increased the magnitude of the early IPSP, which suppressed the late EPSP once again. Since pharmacological blockade of EPSPs revealed paired-pulse depression of monosynaptically elicited early and late IPSPs, these data indicate that (1) both early and late IPSPs were capable of suppressing the late EPSP, and (2) these effects were reduced during paired-pulse stimulation. 4. Pharmacological isolation of the late EPSP allowed testing of the direct effect of paired-pulse stimulation. Application of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 20 microM), picrotoxin (10 microM) and 2-OH-saclofen (50 microM) isolated the late EPSP (onset, 3 ms; peak latency, 28 ms; peak amplitude, 7 mV; duration, 240 ms), which grew in magnitude with membrane depolarization and was largely (> 90%) blocked by APV. Paired-pulse stimulation depressed the isolated late EPSP by 30%. 5. Thus, apparent paired-pulse facilitation of the late EPSP is attributable to release from GABAergic inhibition, and not to direct facilitation. Facilitation of the late EPSP is a functional consequence of IPSP depression. The results indicate the importance of inhibition in regulating synaptic activity mediated by NMDA receptors.

Nucleus basalis stimulation facilitates thalamocortical synaptic transmission in the rat auditory cortex.

Nucleus basalis (NB) neurons are a primary source of neocortical acetylcholine (ACh) and likely contribute to mechanisms of neocortical activation. However, the functions of neocortical activation and its cholinergic component remain unclear. To identify functional consequences of NB activity, we have studied the effects of NB stimulation on thalamocortical transmission. Here we report that tetanic NB stimulation facilitated field potentials, single neuron discharges, and monosynaptic excitatory postsynaptic potentials (EPSPs) elicited in middle to deep cortical layers of the rat auditory cortex following stimulation of the auditory thalamus (medial geniculate, MG). NB stimulation produced a twofold increase in the slope and amplitude of the evoked short-latency (onset 3.0 +/- 0.13 ms, peak 6.3 +/- 0.21 ms), negative-polarity cortical field potential and increased the probability and synchrony of MG-evoked unit discharge, without altering the preceding fiber volley. Intracortical application of atropine blocked the NB-mediated facilitation of field potentials, indicating action of ACh at cortical muscarinic receptors. Intracellular recordings revealed that the short-latency cortical field potential coincided with a short-latency EPSP (onset 3.3 +/- 0.20 ms, peak 5.6 +/- 0.47 ms). NB stimulation decreased the onset and peak latencies of the EPSP by about 20% and increased its amplitude by 26%. NB stimulation also produced slow membrane depolarization and sometimes reduced a long-lasting IPSP that followed the EPSP. The combined effects of NB stimulation served to increase cortical excitability and facilitate the ability of the EPSP to elicit action potentials. Taken together, these data indicate that NB cholinergic neurons can modify neocortical functions by facilitating thalamocortical synaptic transmission.