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J T Williams

Publications and source records attributed to J T Williams.

At least 127 records · Page 7Linked to original sources
PubMed1990

Ion conductances affected by 5-HT receptor subtypes in mammalian neurons.

5-Hydroxytryptamine (5-HT) has both excitatory and inhibitory actions in the CNS and PNS. The development of new 5-HT ligands has led to the expansion of 5-HT receptor subtypes into three categories: 5-HT1, 5-HT2 and 5-HT3. Each category has further subdivisions. The literature concerning the biochemical basis of this division has been reviewed recently. While this approach has elucidated many of the pharmacological properties of 5-HT receptors, it has not addressed the question of how 5-HT modulates cell excitability. Physiological studies have confirmed the existence of a multiplicity of 5-HT receptors that act through a variety of ionic mechanisms. The purpose of this review is to summarize what is known of the ionic mechanisms associated with the activation of identified mammalian 5-HT receptor subtypes, as well as some effects of 5-HT where the receptor could not be defined.

Animals↗
PubMed1990

Serotonin-mediated inhibitory postsynaptic potential in guinea-pig prepositus hypoglossi and feedback inhibition by serotonin.

1. Intracellular recordings were made from neurones of the nucleus prepositus hypoglossi (PH) in slices of guinea-pig brain. Focal stimulation evoked an inhibitory postsynaptic potential (IPSP) that was typically 10-25 mV in amplitude and 1 s in duration. The IPSP reversal potential showed a Nernstian dependence on the external potassium concentration ([K+]o). 2. Spiperone blocked the IPSP with an IC50 of 40 nM, while ketanserin and (-)sulpiride had no effect. Cocaine (1 microM) prolonged the IPSP half-duration by 157%, and increased the amplitude by 28%. 3. 5-Hydroxytryptamine (5-HT, serotonin) hyperpolarized PH cells with an EC50 of 8.5 microM in control, and 135 nM in cocaine (10 microM). 8-Hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) also hyperpolarized PH cells with an EC50 of 16 nM, although the maximal effect was only 81% of the maximum 5-HT hyperpolarization. Spiperone produced a parallel, right shift of the 5-HT concentration-response curve; Schild analysis gave a Kd of 10 nM. Application of 5-HT to neurones voltage-clamped near their resting potential (about -55 mV) caused an outward current and an increase in membrane conductance. 4. The amplitude of the IPSP was reversibly decreased by non-hyperpolarizing concentrations of 5-HT and by the 5-HT1 receptor agonists 1-(m-trifluoromethylphenyl)piperazine (TFMPP) and 1-(3-chlorophenyl)piperazine (mCPP). The IC50 values for the latter two compounds were 50 nM and 1.5 microM, respectively; the maximal effect was a 90% inhibition. Neither compound affected the membrane potential nor changed the hyperpolarization induced by 5-HT. Quipizine competitively antagonized TFMPP with an estimated Kd of 165 nM. 5. When trains of stimuli were applied, an inhibition of the IPSP was observed following the first stimulus. At a frequency of 1 Hz, the inhibition was approximately 75%. This frequency-dependent 'run-down' of the IPSP was markedly attenuated by pre-treatment with TFMPP (1 microM). 6. It is concluded that the IPSP in PH cells is caused by 5-HT acting on 5-HT1A receptors to activate a potassium conductance. The release of 5-HT can be inhibited by activation of a presynaptic 5-HT1D receptor. This presynaptic receptor appears to be at least partly responsible for the run-down phenomenon, and may be involved in the physiological regulation of 5-HT synaptic transmission.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1990

Opioid actions on single nucleus raphe magnus neurons from rat and guinea-pig in vitro.

1. Intracellular recordings were made from neurons of the nucleus raphe magnus (NRM) from rat (n = 128) and guinea-pig (n = 115). Two types of cells were found in each, primary (103 in rat, 27 in guinea-pig) and secondary cells (25 in rat, 88 in guinea-pig). 2. Primary cells had input resistances of 186 +/- 9 M omega (n = 9) in rat and 255 +/- 50 M omega (n = 11) in guinea-pig. The action potential in each was about 1.5 ms in duration. Synaptic potentials were evoked by focal electrical stimulation and consisted of both gamma-aminobutyric acid (GABA) and excitatory amino acid components. 3. Morphine, [Met5]enkephalin (ME) and [D-Ala2,N-Me-Phe4, Gly5-ol]enkephalin (DAMGO) depressed the amplitude of the GABA-mediated synaptic potential by a maximum of 50-65% and had little effect on the excitatory amino acid-mediated synaptic potential. There was no effect of these opioids on the resting membrane potential or input resistance of primary cells in rat or guinea-pig. 4. Secondary cells had short duration action potentials (less than 1 ms) and an input resistance of 354 +/- 47 M omega in rat (n = 6) and 290 +/- 40 M omega in guinea-pig (n = 15). The synaptic potential observed in the cells of this group was mediated by activation of only excitatory amino acid receptors. 5. ME hyperpolarized and/or abolished the spontaneous firing in sixteen out of twenty-four neurons in the secondary group from rat and eight out of eighty-four neurons from guinea-pig. ME induced an outward current at -60 mV that reversed polarity at potentials more negative than -92 +/- 3 mV in rat (n = 6) and -98 +/- 2 mV in guinea-pig (n = 18). The reversal potential of the opioid current was shifted to less negative potentials when the external potassium concentration was increased, as predicted by the Nernst equation. 6. The morphology of the two types of cells were distinguishable in that primary cells were oval (29 x 18 microns in rat; 36 x 19 microns in guinea-pig) with two to four thick tapering dendrites that branched within 50 microns of the cell body. Secondary cells were generally round or oval (about 24 x 13 microns in rat; 27 x 17 microns in guinea-pig) with two to five thin non-tapering dendrites.(ABSTRACT TRUNCATED AT 400 WORDS)

2-Amino-5-phosphonovalerate↗
PubMed1989

Serotonin augments the cationic current Ih in central neurons.

Serotonin (5-HT) induced a slow depolarization when superfused onto neurons of the rat brainstem nucleus prepositus hypoglossi (PH) in vitro. The depolarization was associated with a decrease in cell input resistance. In voltage clamp, 5-HT caused an inward current that activated at approximately -50 mV and was present only at potentials negative to this. With hyperpolarizing voltage-clamp steps, PH neurons exhibited a slow inward current relaxation. The properties of this conductance were consistent with the cationic, nonselective current, Ih. Bath-applied 5-HT augmented Ih. Extracellular CsCl blocked both Ih and the inward current produced by 5-HT. In addition, forskolin, isobutylmethylxanthine, and 8-bromo-cAMP mimicked the inward current seen with 5-HT. The 5-HT1 agonist 5-carboxamidotryptamine produced a similar inward current. We conclude that 5-HT excites PH neurons by augmenting Ih, probably through receptor-mediated stimulation of adenylate cyclase. As Ih is found in many types of neurons, this mechanism may be a common mode of regulating cell excitability.

1-Methyl-3-isobutylxanthine↗
PubMed1989

GABA- and glutamate-mediated synaptic potentials in rat dorsal raphe neurons in vitro.

1. Synaptic potentials were recorded with intracellular electrodes from rat dorsal raphe neurons in a slice preparation. 2. Synaptic potentials were evoked by applying electrical pulses to bipolar stimulating electrodes positioned immediately dorsal to the raphe nucleus; these arose after a latency of 0.5-5 ms and had a duration of 20-200 ms. 3. The synaptic potential was biphasic (at the resting potential) when the recording electrodes contained potassium citrate; a depolarization was followed by a hyperpolarization. The hyperpolarization reversed in polarity at -70 mV and was blocked by bicuculline. 4. The depolarizing synaptic potential was reduced to 50-90% of control by kynurenate (1-2 mM) or 6-cyano-2,3-dihydroxy-7-nitro-quinoxaline (CNQX) (10 microM) and increased in amplitude and duration by magnesium-free solution. 5. In magnesium-free solutions (with CNQX), the depolarizing synaptic potential was blocked by DL-2-amino-5-phosphonovaleric acid (APV, 50 microM). APV also blocked depolarization caused by adding N-methyl-D-aspartate (NMDA) to the superfusion solution. 6. The results indicate that raphe neurons display two synaptic potentials having a duration of 150-200 ms: one that is mediated by GABA and a second that is due to an excitatory amino acid. The component mediated by an excitatory amino acid involves, in part, a receptor of the NMDA type.

Animals↗
PubMed1989

5-HT-mediated synaptic potentials in the dorsal raphe nucleus: interactions with excitatory amino acid and GABA neurotransmission.

1. Intracellular recordings from neurons within dorsal raphe nucleus in slices from rat brain were used to study an inhibitory postsynaptic potential (IPSP) evoked by electrical stimulation. 2. The IPSP was observed in approximately 70% of neurons, had a latency to onset of 40-65 ms, reached a peak in 350-400 ms, had a total duration of 1-2 s, and reversed polarity at the potassium equilibrium potential. 3. This IPSP was blocked by spiperone (1 microM) and prolonged by fluoxetine (300 nM-30 microM) suggesting that it was mediated by 5-hydroxytryptamine (5-HT). 4. Superfusion with gamma-aminobutyric acid (GABA) and excitatory amino acid receptor antagonists were used to block "fast" synaptic potentials that preceded the IPSP such that it could be studied in isolation. Blockade of the GABA-mediated synaptic potentials increased the amplitude of the IPSP by 1.3-fold. The amplitude of the IPSP was reduced by 30% after blockade of the excitatory amino acid-mediated synaptic potential. 5. The results indicate that the IPSP recorded in dorsal raphe neurons was caused by 5-HT released at least in part from indirect (synaptically induced) excitation of 5-HT-containing cells within the slice.

Animals↗
PubMed1989

Relationship between two nontraditional procedures for assessing speech-sound discrimination.

Test of speech-sound discrimination are used by special educators, reading specialists and speech-language pathologists in assessing children's ability to differentiate between speech sounds occurring in standard English. Such tests are important in determining if speech-sound articulation errors are caused by difficulty in making such differentiations. However, during the past 10 years, these tests have been criticized on the basis of their reliability and validity. The purpose of this study was to examine the use of two alternative methods of assessing speech-sound discrimination with a school-aged population to determine if they elicited responses in a similar manner.

Child↗
PubMed1989

Serotonin agonists inhibit synaptic potentials in the rat locus ceruleus in vitro via 5-hydroxytryptamine1A and 5-hydroxytryptamine1B receptors.

Intracellular recordings were made from rat locus ceruleus neurons in the slice preparation in vitro. Depolarizing synaptic potentials (DSP)2 elicited by electrical stimulation were typically 10 to 15 mV in amplitude and 200 msec in duration. Superfusion with 5-hydroxytryptamine (5-HT, serotonin) or the 5-HT1 receptor agonist 5-carboxamidotryptamine (5-CT), produced an inhibition of the DSP. The maximal inhibition was 55 +/- 2% (mean +/- S.E.M.). The EC50 for 5-CT was 60 nM, whereas for 5-HT it was 12 microM. Cocaine (10 microM) shifted the 5-HT concentration-response curve to the left and the EC50 to 320 nM. 8-Hydroxy-2-(di-n-propylamino)tetralin, a selective 5-HT1A receptor ligand, also inhibited the DSP, but only produced about 65% of the maximal 5-CT or 5-HT response (EC50 = 50 nM). A relatively selective 5-HT1B ligand (65-fold 5-HT1B greater than 5-HT1A), 1-(m-trifluoromethyl-phenyl)-piperazine, acted as a full agonist (EC50 = 110 nM). None of these compounds had any effects on the membrane properties of the cell at the doses tested. The response to 8-hydroxy-2-(di-n-propylamino) tetralin was antagonized by pretreatment with the 5-HT1A antagonist spiperone (1 microM). The estimated KD for spiperone was 16 nM. At this same concentration, however, there was no effect on the 5-CT-induced inhibition. The antagonist 4-(3-ter-butyl-amino-2-hydroxy-propoxyl)-indol-2-carbonic acid isopropyl ester (LM 21-009, 100 nM) was found to be a partial agonist producing a 26 +/- 4% inhibition of the DSP.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1989

DTG and (+)-3-PPP inhibit a ligand-activated hyperpolarization in mammalian neurons.

The effects of three compounds with high affinity for the haloperidol-sensitive alpha-binding site were studied with intracellular recordings in the vitro neuronal preparations of the rat locus ceruleus, rat dorsal raphe and the guinea pig submucous plexus. Both (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [(+)-3-PPP] and 1,3-di-o-tolylguanidine (DTG) inhibited the hyperpolarization induced by a ligand-activated potassium conductance. In the locus ceruleus, (+)-3-PPP and DTG produced a maximal 40 to 45% inhibition of the [Met5]enkephalin hyperpolarization, and had EC50 values of 6.6 and 2.2 microM, respectively. In the submucous plexus, the two compounds had a similar action on the alpha-2 adrenoceptor agonist UK14304 hyperpolarization, producing a maximal 50% inhibition with EC50 values of 140 and 32 nM, respectively. In addition, DTG inhibited the alpha-2-mediated inhibitory postsynaptic potential in both preparations. In contrast, (+)-3-PPP increased and prolonged the inhibitory postsynaptic potential. This action is qualitatively similar to the actions of cocaine on locus ceruleus and submucous plexus neurons. Haloperidol (1-10 microM) shared none of these actions. It is concluded that DTG and (+)-3-PPP are inhibitors of the opiate and alpha-2-mediated hyperpolarization at a postreceptor site, possibly the potassium channel. In addition, (+)-3-PPP, but not DTG, inhibits norepinephrine reuptake. None of these effects appear to be related to the sigma -binding site, because haloperidol acted as neither an agonist nor an antagonist.

Animals↗
PubMed1989

Electrical coupling synchronizes subthreshold activity in locus coeruleus neurons in vitro from neonatal rats.

Locus coeruleus neurons in brain slices prepared from neonatal rats have rhythmic oscillations in membrane potential at frequencies ranging from 0.3 to 3 Hz. Recordings from pairs of neurons separated by 50-300 microns showed that this oscillatory activity was synchronized at ages less than 24 d. Slices cut from rats 24-27 d old showed rhythmic activity which was only partially synchronous between cell pairs, but full synchrony could be restored by superfusion with tetraethylammonium (2 mM) and/or barium (2 mM). No synchronous rhythmic activity was observed between neurons in slices from rats 40 d old, even in the presence of tetraethylammonium and barium. In those cells in which rhythmic potential oscillations were synchronous, action potentials occurring in one cell were not observed in the second cell. Electrotonic coupling was directly demonstrated between 41% of neurons (12 of 29 pairs) in slices from rats less than 10 d old but not in tissue from older rats (4 pairs). The input resistance of neurons from neonatal rats (less than 15 d old) was about half (81 M omega) that measured under identical conditions from neurons from adult rats (213 M omega). The electrotonic potential in cells from rats less than 15 d old was best fit by a double exponential, whereas that from adults was best fit by a single exponential. The results demonstrate that significant electrical coupling occurs among locus coeruleus neurons from neonatal rats; this appears to decline with age. The coupling serves as a low-pass filter and causes the synchronized occurrence of membrane potential oscillations. Such a rhythmic background activity within the entire nucleus may be important for the widespread trophic role of the noradrenergic neurons during development.

Animals↗
PubMed1989

Differential actions of cocaine and amphetamine on dorsal raphe neurons in vitro.

Intracellular recordings of membrane potential were made from neurons in nucleus dorsal raphe in the rat brain slice. Cocaine (300 nM-30 microM) caused a concentration-dependent hyperpolarization of the membrane potential, with a maximum effect of 13.3 +/- 2.2 mV (N = 6) and an EC50 of 4.2 microM. This action was antagonized by spiperone (1 microM), suggesting that the hyperpolarization was mediated indirectly through endogenous 5-hydroxytryptamine (5-HT). Cocaine (300 nM) increased the time constant for decay (tau 2) of the 5-HT inhibitory postsynaptic potential (IPSP) from 432 +/- 57 msec to 708 +/- 81 msec (N = 14); 10 microM increased tau 2 by about 9-fold. Amphetamine (100 nM-10 microM) caused a depolarization that was antagonized by prazosin (100 nM). In slices taken from reserpine-treated animals (5 mg/kg, 12 hr), the 5-HT-mediated IPSP, the noradrenaline-mediated slow excitatory postsynaptic potential and the amphetamine-induced depolarization were absent. These results indicate that the amphetamine-induced depolarization resulted from the release of endogenous noradrenaline. In the presence of prazosin (100 nM), amphetamine caused a hyperpolarization at a threshold concentration of 10 microM, had an EC50 of 26 microM and a maximum effect of 10 +/- 0.9 mV (N = 8). This hyperpolarization as well as the cocaine-induced hyperpolarization were not reduced by prior treatment with reserpine. Amphetamine (10 microM) caused a 2.2-fold increase in the time constant of decay of the IPSP with no change in the amplitude.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamine↗
PubMed1988

Pertussis toxin pretreatment discriminates between pre- and postsynaptic actions of baclofen in rat dorsal raphe nucleus in vitro.

Intracellular recordings were made from rat dorsal raphe neurons in vitro. Baclofen (30 microM) and 5-carboxamidotryptamine (5-CT, 300 nM to 1 microM) hyperpolarized these neurons by 10 and 13 mV, respectively. Depolarizing synaptic potentials (DSPs) were evoked by single shocks: baclofen reduced the amplitude of the DSP by 81%, but 5-CT reduced it by only 23%. The somatic response to iontophoretically applied glutamate pulses was reduced by 12% by baclofen, and 23% by 5-CT. In slices from rats pretreated with intracerebroventricular pertussis toxin (PTX), the ability of baclofen to reduce the DSP was almost unchanged, although the hyperpolarizing action of baclofen, and both actions of 5-CT were virtually eliminated. We conclude that it is possible to distinguish the pre- and postsynaptic actions of baclofen with PTX, and that the actions of 5-CT are both blocked.

Animals↗
PubMed1988

Synaptic potentials in rat locus coeruleus neurones.

1. Intracellular recordings were made from locus coeruleus neurones in a slice of tissue cut from the rat pons. A depolarizing postsynaptic potential (PSP) followed electrical stimulation of the slice surface; the latency was 1-3 ms and the duration was 50-200 ms. 2. The reversal potential of the PSP (estimated by extrapolation from potentials between -60 and -90 mV) was -27 mV when the recording electrodes contained potassium chloride, and -36 mV when electrodes contained potassium acetate or methylsulphate. 3. Kynurenic acid depressed the PSP amplitude by up to 60%. The residual PSP reversed polarity at -50 mV (extrapolated, potassium chloride in electrodes) or -70 mV (observed, potassium methylsulphate in electrodes): it was blocked by bicuculline (10 microM). 4. Exogenously applied gamma-aminobutyric acid (GABA) depolarized cells when the recording electrode contained potassium chloride (reversal potential was -45 mV) and hyperpolarized cells when the recording electrode contained potassium methylsulphate (reversal potential was -70 mV). 5. In the presence of bicuculline, the residual PSP was blocked by kynurenic acid, whereas DL-2-amino-5-phosphonovaleric acid (2-APV) reduced its amplitude to 80% of control. 6. Exogenously applied glutamate, quisqualate and N-methyl-D-aspartate (NMDA) all caused a membrane depolarization (or an inward current under voltage clamp) which reversed polarity at about 0 mV. These effects were blocked by kynurenic acid (500 microM); 2-APV (50 microM) selectively blocked the effect of NMDA. 7. The results indicate that the PSP evoked by focal stimulation within the nucleus locus coeruleus results from an excitatory amino acid acting predominantly at non-NMDA receptors, and from GABA acting at GABAA receptors.

2-Amino-5-phosphonovalerate↗
PubMed1988

Inward rectification of resting and opiate-activated potassium currents in rat locus coeruleus neurons.

Intracellular recordings were made from rat locus coeruleus neurons in vitro, and membrane currents were measured at potentials from -50 to -130 mV. In the absence of any applied agonists, the slope conductance of the cells increased 3-fold when the cell was hyperpolarized from -60 to -120 mV. This conductance increase was complete within 5 msec of the onset of a hyperpolarizing command and was subsequently independent of time for several seconds. The conductance increase was blocked by cesium chloride (1-2 mM), rubidium chloride (1-2 mM), or barium chloride (1-100 microM). The membrane potential range over which the conductance increased was centered at the potassium equilibrium potential (EK; extracellular potassium concentration, 2.5-10.5 mM): the current/voltage (I/V) relation of the cell could be well described by supposing that there were 2 potassium conductances, one voltage independent (G1) and the other (inward rectifier, Gir) activated according to the expression Gir = Gir,max/(1 + exp[(V - EK)/k]), where k ranged from 15 mV in 2.5 mM potassium to 6 mV in 10.5 mM potassium. The additional membrane potassium conductance that developed when agonists at mu-opioid and alpha 2-adrenoceptors were applied also became larger with membrane hyperpolarization, and this voltage dependence was also reduced or blocked by rubidium, cesium, and barium; in the presence of these agonists the current also reached its final value within 5 msec. However, the conductance increased by the agonists (Gag) was not well expressed by simply increasing the values of G1 and Gir,max. It was best described by a potassium conductance that increased according to Gag,max/(1 + exp[(V - Vm)/k]), where Vm (the potential at which the conductance was half-maximum) was close to the resting potential of the cell.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenergic alpha-Agonists↗
PubMed1988

Voltage- and ligand-activated inwardly rectifying currents in dorsal raphe neurons in vitro.

Intracellular recordings were made from neurons in rat dorsal raphe in the slice preparation maintained at 37 degrees C. The single-electrode voltage-clamp method was used to measure membrane currents at potentials more negative than rest (-60 mV). Three types of inward rectification were observed: 2 in the absence of any drugs and the third induced by 5-HT 1 and GABA-B receptor agonists. In the absence of any drugs, an inward current activated over 1-2 sec when the membrane potential was stepped to potentials more negative than -70 mV. This current was blocked by cesium (2 mM) and resembles IQ or IH. A second inward current (IIR) occurred at membrane potentials near the potassium equilibrium potential (EK). This inward current activated within the settling time of the clamp and was abolished by both barium (10-100 microM) and cesium (2 mM). 5-HT 1 agonists activated a potassium conductance that hyperpolarized the cells at rest. This potassium conductance was about 2 nS at -60 mV and increased linearly with membrane hyperpolarization to about 4 nS at -120 mV. Baclofen activated a potassium conductance identical in amplitude and voltage dependence to that induced by 5-HT 1 agonists. Both the baclofen- and 5-HT-induced currents were nearly abolished in animals pretreated with pertussis toxin. The results indicate that a common potassium conductance is increased by 5-HT acting on 5-HT 1 receptors and baclofen acting on GABA-B receptors. This potassium conductance rectifies inwardly and is distinct from the Q-current. The ligand-activated potassium conductance also differs from the other form of inward rectification (IIR) in its voltage dependence and sensitivity to pertussis toxin.

Animals↗
PubMed1988

Susceptibility of the pre-parturient ewe to infection with Trichostrongylus vitrinus and Ostertagia circumcincta.

During two successive years, groups of pregnant ewes and non-pregnant worm-free sheep were given anthelmintic, challenged one week later with 10,000 infective larvae of either Trichostrongylus vitrinus or Ostertagia circumcincta and killed two, four and six weeks after challenge. All of the ewes were killed within three days of their predicted lambing date. There was no annual variation in the response of the ewes to infection with either species. Compared to adult naive animals, ewes expressed resistance to infection with T vitrinus at all times, with significantly lower worm burdens composed largely of inhibited third stage larvae. Ewes challenged with O circumcincta were fully as susceptible as naive animals with regard to the size and stage of development of their worm populations. Mechanisms regulating the numbers of adult O circumcincta were operative in the adult naive animals but not in the ewes.

Animals↗