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Neuromodulation of activity-dependent synaptic enhancement at crayfish neuromuscular junction.

Action potential-evoked transmitter release is enhanced for many seconds after moderate-frequency stimulation (e.g. 15 Hz for 30 s) at the excitor motorneuron synapse of the crayfish dactyl opener muscle. Beginning about 1.5 s after a train, activity-dependent synaptic enhancement (ADSE) is dominated by a process termed augmentation (G.D. Bittner, D.A. Baxter, Synaptic plasticity at crayfish neuromuscular junctions: facilitation and augmentation, Synapse 7 (1991) 235-243'[4]; K.L. Magleby, Short-term changes in synaptic efficacy, in: G.M. Edelman, L.E. Gall, C.W. Maxwell (Eds.), Synaptic Function, John Wiley and Sons, New York, 1987, pp. 21-56; K.L. Magleby; J.E. Zengel, Augmentation: a process that acts to increase transmitter release at the frog neuromuscular junction, J. Physiol. (Lond.) 257 (1976) 449-470) which decays approximately exponentially with a time constant of about 10 s at 16 degrees C, reflecting the removal of Ca2+ which accumulates during the train in presynaptic terminals (K.R. Delaney, D.W. Tank, R.S. Zucker, Serotonin-mediated enhancement of transmission at crayfish neuromuscular junction is independent of changes in calcium, J. Neurosci. 11 (1991) 2631-2643). Serotonin (5-HT, 1 microM) increases evoked and spontaneous transmitter release several-fold (D. Dixon, H.L. Atwood, Crayfish motor nerve terminal's response to serotonin examined by intracellular microelectrode, J. Neurobiol. 16 (1985) 409-424; J. Dudel, Modulation of quantal synaptic release by serotonin and forskolin in crayfish motor nerve terminals, in: Modulation of Synaptic Transmission and Plasticity in Nervous Systems, G. Hertting, H.-C. Spatz (Eds.), Springer-Verlag, Berlin, 1988; S. Glusman, E.A. Kravitz. The action of serotonin on excitatory nerve terminals in lobster nerve-muscle preparations, J. Physiol. (Lond.) 325 (1982) 223-241). We found that ADSE persists about 2-3 times longer after moderate-frequency presynaptic stimulation in the presence of 5-HT. This slowing of the decay of ADSE by 5-HT was not accompanied by significant changes in the initial amplitude of activity-dependent components of enhancement 1.5 s after the train. Measurements of presynaptic [Ca2+] indicated that the time course of Ca2+ removal from the presynaptic terminals after trains was not altered by 5-HT. Changes in presynaptic action potential shape, resting membrane potential or postsynaptic impedance after trains cannot account for slower recovery of ADSE. Axonal injection of EDTA slows the removal of residual Ca2+ and the decay of synaptic augmentation after trains of action potentials (K.R. Delaney, D.W. Tank, A quantitative measure of the dependence of short-term synaptic enhancement on presynaptic residual calcium, J. Neurosci. 14 (1994) 5885-5902), but has little or no effect on the 5-HT-induced persistence of ADSE. This also suggests that the time course of ADSE in the presence of 5-HT is not determined primarily by residual Ca2+ removal kinetics. The slowing of ADSE recovery after trains by 5-HT reverses with washing in 5-HT-free saline along with the 5-HT-mediated enhancement of release.

Action Potentials↗

Local connections between the columns of the periaqueductal gray matter: a case for intrinsic neuromodulation.

Chemical stimulation of the lateral or ventrolateral columns of the midbrain periaqueductal gray matter (PAG) in conscious animals produces opposite responses (viz., defensive behavior and pressor responses from the lateral column vs. quiescence and depressor responses from the ventrolateral column), raising the possibility that the two columns are interconnected. To test this hypothesis, two types of anatomical experiments were performed in rats. First, the anterograde axonal marker Phaseolus vulgaris leuco-agglutinin (PHA-L) was injected into individual PAG columns or adjoining regions which included the Edinger-Westphal, dorsal raphe, and precommissural nuclei. The results shows that each column projects bilaterally to all of the other PAG columns, and also provides local connections within its own column. Furthermore, the Edinger-Westphal and precommissural nuclei project to all four PAG columns, while the dorsal raphe nucleus projects only to the ventrolateral and lateral columns. In a second experiment, we found that cardiovascular-related PAG projection neurons of both the lateral and ventrolateral columns receive an input from the reciprocal PAG column. This was demonstrated by a double tracer neuroanatomical study in which PHA-L was first iontophoretically ejected into either the lateral or ventrolateral PAG columns and then, several days later the retrograde transneuronal viral tracer, pseudorabies virus, was injected into the stellate sympathetic ganglion. Intra-PAG circuits were visualized by a dual immunohistochemical procedure. These results suggest that during the fight-or-flight response when the 'fight' program is activated, inhibition of the 'flight' PAG network may occur and the converse situation may occur during the flight response.

Animals↗

Neuromodulation of memory in the hippocampus by vasopressin.

The involvement of [Arg(8)]vasopressin in memory processes was analyzed in the hippocampal structure, since we have reported that this is one of the main central target structures of the vasopressin-enhancing effect on memory. This structure is functionally differentiated along its dorsoventral axis, and the expression of the vasopressinergic system is dependent upon whether the dorsal or ventral part of the hippocampus is involved. For this reason, the effect of vasopressin injected into hippocampus was evaluated on the basis of the site of injection. We have shown, using a Go-No Go visual discrimination task with mice that both parts of the hippocampus are involved in the effect of endogenous or exogenous vasopressin, but with higher sensitivity for the ventral part. Based on the expression of Fos protein following intracerebroventricular injection of vasopressin in unconditioned or conditioned mice, we confirmed the greater involvement of the ventral hippocampus in the enhancing effect of vasopressin on memory processes. The effect of the peptide seems specific, since only a few of the hippocampal cells that expressed Fos protein in the unconditioned mice did so in the conditioned mice (cells in the dentate gyrus and the CA3 hippocampal field). Moreover, we have shown that in the ventral hippocampus, vasopressin generates different behavioral effects whether treatment is performed at the beginning or in the middle of the learning process, suggesting that the mnemonic context is an important factor for understanding the effect of vasopressin on memory in the ventral hippocampus.

Animals↗

Neuromodulator role of zinc and copper during prolonged ATP applications to P2X4 purinoceptors.

To further elucidate the modulator role of trace metals such as zinc and copper on the activity of nucleotide purinoceptors, the action of these metals was assessed during prolonged ATP applications to rat P2X(4) purinoceptors expressed in Xenopus laevis oocytes. Application of ATP for 3 min resulted in a biphasic effect; a fast transient peak was followed by a slower stable current component with similar pharmacological and biophysical characteristics. The application of 1-300 microM Cu(2+) inhibited both current components to a comparable extent; likewise, Zn(2+) facilitated to a similar degree the transient and the slower stable current components. Carnosine (Car), cysteine (Cys), histidine (His), and the metal chelator, penicillamine, prevented the inhibitory action of Cu(2+); the Zn(2+) facilitation was not prevented by neither Car nor His but by either bathophenantroline or Cys, revealing metal selectivity. While the noncompetitive Cu(2+) inhibition appears to decrease channel conductance, Zn(2+) likely increases ATP affinity independently of the activation state of the purinoceptor. These results strongly support the notion that trace metals modulate the activity of the P2X(4) purinoceptor and could become relevant during continual activity of a P2X(4) purinoceptor-containing synapse.

Adenosine Triphosphate↗

Predictors of success with neuromodulation in lower urinary tract dysfunction: results of trial stimulation in 100 patients.

Chronic lower urinary tract dysfunction can be treated by sacral neuro-stimulation. Clinical parameters for selection of patients for this expensive and invasive treatment modality are not well defined to date. Therefore, before implantation of a permanent stimulator, the effect is tested by temporary implantation of a wire electrode connected to an external stimulator. According to the literature, many patients do not respond during temporary implantation and a mean of 25% of the patients with a permanent stimulator implanted fail to respond as well. To improve patient selection, we attempted to define clinical parameters to predict the outcome of sacral neuro-stimulation in 100 consecutive patients who were tested with temporary sacral stimulation. A total of 34 patients achieved a complete cure on trial stimulation. It appeared that detrusor overactivity and urethral instability responded best but they were not predictors of success. We conclude that neither gender, patient age, history nor diagnosis are predictors of success in sacral neuro-stimulation of lower urinary tract dysfunction.

Adolescent↗

Neuromodulation of hypoglossal motoneurons: cellular and developmental mechanisms.

Hypoglossal motoneurons (HMs) in the caudal brainstem have a respiratory-related activity pattern and contribute to control of upper airway resistance. In this review, we focus primarily on signalling mechanisms utilized by neurotransmitters to enhance HM excitability. In particular, we consider: (1) the membrane depolarization induced by a number of different putative transmitters [thyrotropin-releasing hormone (TRH), serotonin (5-HT), norepinephrine (NE)]; and (2) the inhibition of a calcium-dependent spike after hyperpolarization (AHP) by 5-HT and its effect on firing behavior. Potential functional consequences on HM behavior of these different neurotransmitter effects is discussed. In addition, we describe postnatal changes in transmitter effects and suggest potential cellular mechanisms to explain those developmental changes. Most of the data discussed are derived from in vitro electrophysiological recordings performed in preparations from neonatal and adult rats.

Animals↗

Neuromodulators and hypoxic hypothermia in the rat.

This study was designed to assess if opioids or adenosine are involved in the hypometabolism induced by hypoxia in the rat. Accordingly, antagonists such as naloxone (NLX) for opioids or theophylline (THEO) for adenosine were injected into conscious adult rats acutely exposed to either ambient hypoxia (AHx, FIO2: 12%) at ambient temperatures of 26 or 9 degrees C, or to CO hypoxia (COHx, FICO = 0.05%) at an ambient temperature (Ta) of 9 degrees C. Oxygen consumption, ventilation, colonic temperature and shivering were recorded. The results show that with NLX, the degree of hypoxic hypometabolism was reduced with AHx at 26 degrees C and slightly decreased with COHx at 9 degrees C. With THEO, hypoxic hypometabolism was slightly reduced with AHx and COHx at 9 degrees C. The ventilatory response to AHx and COHx was not consistently affected by either NLX or THEO. It is concluded that adenosine and opioids play a minor role, in mediating AHx or COHx hypothermia, especially during cold exposure.

Adenosine↗