Digital Variance Angiography in Lower-Limb Angiography with Metal Implants.

PURPOSE: The presence of metal implants may reduce angiographic image quality due to automated beam adjustments. Digital variance angiography (DVA) is reported to be superior to digital subtraction angiography (DSA) with increased contrast-to-noise ratio (CNR) and better image quality. The aim of the study was to evaluate whether DVA could counterbalance the image quality impairment of lower-limb angiographies with metal implants. MATERIALS AND METHODS: From November 2019 to January 2020, 85 raw lower-limb iodine contrast angiograms of 12 patients with metal implants were processed retrospectively with DVA analyses. For objective comparison, CNR of DSA and DVA images was calculated and the ratio CNRDVA/CNRDSA was determined. Visual image quality was evaluated in a paired comparison and by a five-grade Likert scale by three experienced radiologists. RESULTS: The CNR was calculated and compared in 1252 regions of interest in 37 image pairs containing metal implants. The median ratio of CNRDVA/CNRDSA was 1.84 with an interquartile range of 1.35-2.32. Paired comparison resulted in 84.5% in favour of DVA with an interrater agreement of 83.2% (Fleiss κ 0.454, p < 0.001). The overall image quality scores for DSA and DVA were 3.64 ± 0.08 and 4.43 ± 0.06, respectively (p < 0.001, Wilcoxon signed-rank test) with consistently higher individual ratings for DVA. CONCLUSION: Our small-sample pilot study shows that DVA provides significantly improved image quality in lower-limb angiography with metal implants, compared to DSA imaging. The improved CNR suggest that this approach could reduce radiation exposure for lower-limb angiography with metal implants. LEVEL OF EVIDENCE: Level 4, case studies.

Role of presynaptic nicotinic acetylcholine receptors in the regulation of gastrointestinal motility.

Presynaptic nicotinic acetylcholine receptors (nAChRs) located on cholinergic terminals facilitate the release of acetylcholine (ACh), thereby constituting a fail-safe mechanism at strategic locations, such as the neuromuscular junction, where reliable transmission is vital. Accumulating data indicate that myenteric neurons in the enteric nervous system possess not only somatodendritic nAChRs, which mediate cholinergic transmission between neurons, but also presynaptic nAChRs. Functional evidence shows that these receptors mediate a positive feedback with respect to ACh release from myenteric motoneurons, and might therefore play an important role in the regulation of gastrointestinal motility. These presynaptic nAChRs were found to be more sensitive to nicotinic ligands than somatodendritic nAChRs and could therefore be primary targets of exogenous compounds, such as nicotine. This interaction might provide a neurochemical basis for the effect of smoking on gastrointestinal motility. Another important human pharmacological implication is based on our recent observation that monoamine uptake inhibitor-type antidepressant drugs are able to inhibit presynaptic nAChRs in the enteric nervous system. The disruption of the nAChR-mediated positive feedback modulation by antidepressants might explain the frequent occurrence of constipation, a common side effect, attributed to these drugs. Clarification of the role of presynaptic nAChRs in feedback mechanisms in the enteric nervous system might be instrumental in the development of new drugs affecting gastrointestinal motility.

Nicotinic acetylcholine receptor antagonistic property of the selective dopamine uptake inhibitor, GBR-12909 in rat hippocampal slices.

Previously we found that inhibitors of noradrenaline (NA) and/or 5-HT reuptake are able to inhibit neuronal nicotinic acetylcholine receptors (nAChRs) in the CNS most probably by a channel blocker-type mechanism. The aim of our study was to clarify whether selective dopamine uptake inhibitors also possess this property, therefore we investigated the effect of GBR-12909 on the nicotine-evoked release of [3H]NA from rat hippocampal slices. GBR-12909, similar to selective NA and 5-HT uptake blockers, inhibited the nicotine-evoked release with an IC50 of 2.32 microM. The ability of monoamine uptake blockers to inhibit nicotine-evoked [3H]NA release (IC50) and NA reuptake (Ki) showed no correlation, indicating that the NA uptake system is not involved in the inhibition of the response to nicotine. Previously we have shown in whole cell patch clamp experiments, that GBR-12909, depending on the stimulation pattern, inhibits Na+-currents with an IC50 in the 6-35 microM concentration range [Mike A, Karoly R, Vizi ES, Kiss JP (2003) Inhibitory effect of the DA uptake blocker GBR-12909 on sodium channels of hippocampal neurons. Neuroreport 14:1945-1949]. To study whether the inhibition of Na+-channels is involved in the action of GBR-12909 on the nicotine-evoked [(3)H]NA release, we compared the effect of GBR-12909 and the Na(+)-channel blocker tetrodotoxin (TTX) on the electrical stimulation- and nicotine-evoked response. TTX prevented the release of [3H]NA induced by both types of stimulation, whereas GBR-12909 inhibited only the nicotine-induced response, indicating that under our experimental conditions the target of GBR-12909 is not the Na+-channel. These data indicate that the selective DA uptake inhibitor GBR-12909 is able to inhibit nAChRs, that is, the nAChR antagonistic property of monoamine uptake inhibitors is independent of their selectivity. The fact that monoamine uptake inhibitors with different chemical structure and selectivity are able to inhibit nAChRs may reveal some common properties of nicotinic receptors and monoamine uptake carriers.

The mechanism of activity-dependent sodium channel inhibition by the antidepressants fluoxetine and desipramine.

The effect of monoamine uptake inhibitor-type antidepressants on sodium channels of hippocampal neurons was investigated. Members of the tricyclic group of antidepressants are known to modify multiple targets, including sodium channels, whereas selective serotonin-reuptake inhibitors (SSRIs) are regarded as highly selective compounds, and their effect on sodium channels was not investigated in detail. In this study, a representative member of each group was chosen: the tricyclic antidepressant desipramine and the SSRI fluoxetine. The drugs were roughly equipotent use-dependent inhibitors of sodium channels, with IC(50) values approximately 100 microM at -150 mV holding potential, and approximately 1 microM at -60 mV. We suggest that therapeutic concentrations of antidepressants affect neuronal information processing partly by direct, activity-dependent inhibition of sodium channels. As for the mechanism of inhibition, use-dependent inhibition by antidepressants was believed to be due to a preferential affinity to the fast-inactivated state. Using a voltage and perfusion protocol by which relative affinities to fast-versus slow-inactivated states could be assessed, we challenged this view and found that the affinity of both drugs to slowinactivated state(s) was higher. We propose a different mechanism of action for these antidepressants, in which slow rather than fast inactivation plays the dominant role. This mechanism is similar but not equivalent with the novel mechanism of usedependent sodium channel inhibition previously described by our group (Neuroscience 125:1019-1028, 2004; Neuroreport 14:1945-1949, 2003). Our results suggest that different drugs can produce use-dependent sodium channel inhibition by different mechanisms.

A novel modulatory mechanism of sodium currents: frequency-dependence without state-dependent binding.

We have previously found that the dopamine uptake inhibitor 1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (GBR 12909) inhibits neuronal sodium channels. The inhibition was profoundly dependent on the voltage protocol, suggesting that the effect is determined by the activity pattern of individual neurons. Our present study was aimed to understand more thoroughly the mechanism of this inhibition. The effect of GBR 12909 on sodium currents was investigated using whole-cell patch clamp recordings on cultured hippocampal neurons. Repetitive trains of depolarizations revealed two distinct components of inhibition: a frequency-dependent, transient and a frequency-independent, sustained component. Frequency-dependent inhibition can reflect dynamic equilibrium of binding or gating. In order to decide which is the dominant mechanism in the case of GBR 12909, we studied the rates of association and dissociation. We found an unexpectedly fast rate of association (tau=819.2 ms) to resting ion channels kept at hyperpolarized membrane potential (-150 mV), while the rate of dissociation was too slow to explain recovery between trains of stimulation (tau=248 s). These data suggest that frequency-dependent inhibition cannot be explained by binding and unbinding, but rather it is due to conformational transitions of the liganded channel, which can only be explained if ligand binding is assumed to enhance slow inactivation. We studied, therefore, the rate of slow inactivation in the presence of different concentrations of GBR 12909. We have found that GBR 12909 accelerates slow inactivation substantially (time constants more than hundredfold lower at concentrations above 10 microM), causing the time range of slow inactivation to overlap with the time range of fast inactivation. Slow inactivation can even be the dominant process, especially during subthreshold depolarizations in the presence of >10 microM of GBR 12909. This mechanism of inhibition could provide a selective inhibition of neurons not only with high frequency bursting activity but also with moderately depolarized membrane potential.

Functional neurochemical evidence for the presence of presynaptic nicotinic acetylcholine receptors at the terminal region of myenteric motoneurons: a study with epibatidine.

The aim of this study was to verify the presence of presynaptic nicotinic acetylcholine receptors (nAChRs) at the terminals of myenteric motoneurons using a potent and highly selective nicotinic agonist, epibatidine. We examined contraction, and release of [3H]ACh on a guinea-pig longitudinal muscle strip preparation. First, we compared the ability of epibatidine and nicotine to induce isometric contraction and found epibatidine (EC50 = 23.1 nM) to be 300-fold more potent than nicotine (EC50 = 7.09 microM). The release and contraction induced by 30 nM epibatidine were inhibited by the nicotinic antagonist mecamylamine (3 microM) and the Na(+)-channel blocker TTX (1 microM), indicating that the effects are mediated via nAChRs and are fully dependent on the propagation of action potentials. Atropine (0.1 microM) significantly increased the [3H]ACh release but could not block contraction suggesting that a substantial part of the response develops via a noncholinergic mechanism. Epibatidine at a higher concentration (300 nM) induced contraction, which was only partly (45%) inhibited by TTX (1 microM). The TTX-resistant contraction, however, was completely blocked by mecamylamine (3 microM). Our data provide functional neurochemical evidence for the existence of presynaptic nAChRs at myenteric motoneuron terminals and suggest that these receptors can be activated only/by a higher concentration of agonists.

Differential effect of nicotinic agonists on the [3H]norepinephrine release from rat hippocampal slices.

The aim of this study was to investigate the mechanisms involved in the effect of nicotinic agonists on the [3H]norepinephrine ([3H]NE) release from rat hippocampal slices. The stimulatory effect of nicotine, cytisine, epibatidine and anatoxin-A was completely blocked by the nicotinic antagonist mecamylamine (10 microM). In contrast, the effect of dimethylphenylpiperazinium (DMPP) was only partially inhibited by mecamylamine but was completely blocked by the NE uptake inhibitor desipramine (DMI, 10 microM). Finally, the effect of lobeline was not affected by mecamylamine and was only partially blocked by DMI. Our data indicate that the majority of nicotinic agonists increase the release of [3H]NE exclusively via stimulation of nicotinic acetylcholine receptors (nAChRs). DMPP, in addition to the stimulation of nAChRs, also evokes a carrier-mediated release. Lobeline has no stimulatory effect on nAChRs, induces a carrier-mediated release and has a further action of unidentified mechanism. Our results suggest that special caution is required for the interpretation of data, when DMPP or lobeline are used as nicotinic agonists.

Analysis of high intracellular [Na+]-induced release of [3H]noradrenaline in rat hippocampal slices.

Our aim was to investigate the mechanisms involved in the high intracellular sodium-induced transmitter release in the CNS through the characterisation of the veratridine-evoked (40 microM) noradrenaline release from rat hippocampal slices. The response to veratridine was completely inhibited by tetrodotoxin (1 microM), indicating that the effect is due to the activation of sodium channels. Omission of Ca2+ from the superfusion fluid inhibited the veratridine-evoked release by 72%, showing that the majority of release results from external Ca2+-dependent exocytosis. The residual Ca2+-independent release was not blocked by the intracellular Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N,N-tetraacetic acid acetoxymethyl ester (100 microM) suggesting that intracellular Ca2+ stores are not involved in this component of veratridine effect. The noradrenaline uptake blockers, desipramine (10 microM) and nisoxetine (10 microM), inhibited the external Ca2+-independent release by 50 and 46%, respectively, indicating that the release partly originates from the reversal of transporters (carrier-mediated release). In contrast to uptake blockers, lowering the temperature, another possibility to inhibit transporter function, completely inhibited the effect of veratridine in the absence of Ca2+. Further experiments revealed that low temperature (20 and 12 degrees C) reduces the veratridine-induced increase of intracellular sodium concentration ([Na+]i) in rat cortical synaptosomes (68 and 78% inhibition, respectively). The clinical relevance of our data is that during ischemia a massive release of transmitters occurs mainly due to the elevation of [Na+]i, which contributes to the development of ischemic brain injury. Our results show that low temperature may be a better therapeutic approach to the treatment of ischemia because it has a dual action on this process. Firstly, it inhibits the function of uptake transporters and hence reduces the carrier-mediated outflow of transmitters. Secondly, it inhibits the sodium influx and therefore prevents the unwanted elevation of [Na+]i. Our data also suggest that veratridine stimulation can be a suitable model for ischemic conditions.

Nitric oxide: a novel link between synaptic and nonsynaptic transmission.

Accumulating evidence indicates that nitric oxide (NO) inhibits the function of monoamine transporters. Because the production of NO by neuronal NO synthase (nNOS) is closely related to the activation of NMDA receptors, the level of NO around nNOS-containing synapses reflects the activity of glutamate-mediated neurotransmission. Glutamate participates mainly in synaptic interactions, but with the help of NO, the strength of excitatory input might be nonsynaptically signaled to the surrounding monoaminergic neurons, which can adapt to the changes without receiving glutamatergic input and without synthesizing glutamate receptors. Thus, the effect of NO on transporters represents a new form of interneuronal communication, a nonsynaptic interaction without receptors.

Opposite role of alpha2- and beta-adrenoceptors in the modulation of interleukin-10 production in endotoxaemic mice.

Our aim was to investigate the role of adrenoceptors in the modulation of in vivo interleukin-10 (IL-10) production in lipopolysaccharide (LPS)-treated mice. The effect of different adrenergic drugs on plasma concentration of IL-10 was measured by ELISA 90 min after LPS injection. Our results confirmed the involvement of beta-adrenoceptors since the beta-agonist isoproterenol significantly increased the IL-10 production in response to LPS stimulation, whereas the beta-antagonists propranolol decreased it. In contrast, the alpha2-agonists UK-14304, clonidine and xylazine significantly decreased the IL-10 plasma level, whereas the alpha2-antagonists CH-38083, prazosine and WB-4101 increased it. Our results provide the first in vivo evidence that, in addition to beta-adrenoceptors; alpha-adrenoceptors play also a very important role in the regulation of IL-10 production under endotoxaemic conditions.

Role of nitric oxide in the regulation of monoaminergic neurotransmission.

Data accumulated in the last decade indicate that nitric oxide (NO) participates in the regulation of neurotransmission in the central nervous system. Due to its physicochemical properties, NO is an ideal mediator of nonsynaptic interactions. The importance of monoaminergic systems in the function of the brain is clearly shown by the number of severe neuropsychiatric diseases (e.g. depression, Parkinson's disease) caused by the impairment of monoaminergic neurotransmission. Because of their neuroanatomical characteristic, monoaminergic systems participate mainly in nonsynaptic interactions. Since NO is a potential nonsynaptic modulator, it may have an important role in the regulation of monoaminergic systems. The aim of the present review is to survey the literature on the effect of NO on dopaminergic, noradrenergic and serotonergic neurotransmission. The potential mechanisms of action are summarized. Since there is no agreement in the literature on the nature of the effect of NO exerted on monoaminergic neurotransmission, and there are contradictory data concerning the mechanisms involved, the possible reasons for this unusual inconsistency are also discussed.

Differential involvement of sympathetic nervous system and immune system in the modulation of TNF-alpha production by alpha2- and beta-adrenoceptors in mice.

In the present study, the regulation of tumor necrosis factor-alpha (TNF-alpha) production by alpha2- and beta-adrenoceptors located on noradrenergic nerve terminals and on macrophages was studied in endotoxaemic mice. We found that reduction of the sympathetic outflow by reserpine dramatically increased the lipopolysaccharide (LPS)-induced TNF-alpha production, demonstrating that the release of endogenous noradrenaline (NA), controlled by presynaptic alpha2-adrenoceptors, was a determinant factor in this model. By using alpha2- and beta-adrenergic drugs (clonidine, CH-38083, isoproterenol, propranolol) we provided the first in vivo evidence that, beside the dominance of neuronal alpha2- and macrophage beta-adrenoceptors, the alpha2-adrenoceptors on macrophages were also involved in the modulation of LPS-induced TNF-alpha production. Since adrenergic drugs are widely used in the clinical practice, our findings may have therapeutical implications.

Contribution of differently localized alpha 2- and beta-adrenoceptors in the modulation of TNF-alpha and IL-10 production in endotoxemic mice.

Evidence is presented that the immune response to endotoxemia is under tonic control of the sympathetic nervous system. Adrenergic agents may influence the immune response both directly through alpha- and beta-adrenergic receptors expressed by immunologically competent cells and indirectly via alteration of the endogenous NA level by influencing the activity of release-regulating presynaptic alpha 2-adrenoceptors located on the sympathetic nerve terminals. In the immunomodulatory effect of NA/adrenergic drugs, their action on beta-adrenoceptors was dominant, but the considerable role of alpha-adrenoceptors on macrophages was also demonstrated. According to our findings, regulation of the ascending wing of the inflammatory response, that is, TNF-alpha production, is more sensitive to the adrenoceptor effect, whereas modulation of its deregulation by IL-10 production also involves some other determining factors.

Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices.

The aim of our study was to investigate the effect of different monoamine uptake blockers on the nicotine-evoked release of [3H]noradrenaline ([3H]NA) from rat hippocampal slices. We found that desipramine (DMI), nisoxetine, cocaine, citalopram, and nomifensine inhibit the nicotine-evoked release of [3H]NA with an IC50 of 0.36, 0.59, 0.81, 0.93, and 1.84 microM, respectively. These IC50 values showed no correlation with the inhibitory effect (Ki) of monoamine uptake blockers on the neuronal NA transporter (r = 0.17, slope = 0.02), indicating that the NA uptake system is not involved in the process. In whole-cell patch clamp experiments neither drug blocked Na+ currents at 1 microM in sympathetic neurons from rat superior cervical ganglia, and only DMI produced a pronounced inhibition (52% decrease) at 10 microM. Comparison of the effect of DMI and tetrodotoxin (TTX) on the electrical stimulation- and nicotine-evoked release of [3H]NA showed that DMI, in contrast to TTX, inhibits only the nicotine-induced response, indicating that the target of DMI is not the Na+ channel. Our data suggest that monoamine uptake blockers with different chemical structure and selectivity are able to inhibit the nicotinic acetylcholine receptors in the CNS. Because these compounds are widely used in the therapy of depressed patients, our findings may have great importance in the evaluation of their clinical effects.

A possible role of nitric oxide in the regulation of dopamine transporter function in the striatum.

Brain microdialysis and high-performance liquid chromatography with electrochemical detection were used to study the effect of the nitric oxide synthase inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME) on striatal dopamine (DA) release in the anesthetized rat. Systemic administration of L-NAME (10 mg/kg, i.p.) significantly decreased the resting release of DA. The peak effect (23% decrease) was reached 45 min after injection. The inactive enantiomer D-NAME (10 mg/kg, i.p.) or the vehicle (saline, 5 ml/kg i.p.) had no effect on the striatal DA level. Neither treatment altered significantly the concentration of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). To investigate the possible involvement of the DA uptake system L-NAME was injected also in the presence of the DA uptake inhibitor nomifensine. Local application of nomifensine (10 microM in the dialysate medium) increased the extracellular concentration of DA to about eight-fold of the basal value and stabilized it at this higher level. Under these conditions L-NAME (10 mg/kg, i.p.) was not able to alter the striatal DA level. Neither nomifensine nor L-NAME caused any change in the level of DOPAC and HVA. Our data suggest that endogenously produced nitric oxide may influence the activity of the DA transporter which effect may have special importance in the regulation of extracellular transmitter concentration in the striatum.

Analysis of deprenyl metabolites in the rat brain using HPLC-ES-MS.

Methylamphetamine and amphetamine, the two major metabolites of deprenyl in the rat brain were analyzed using HPLC method combined with electrospray-mass spectrometer. (-)-Deprenyl and (+)-deprenyl were orally administered to rats either in a single dose of 10 mg/kg, or three times a week for three weeks. The metabolites were determined in four different parts of the rat brain, such as in the frontal cortex, corpus striatum, hippocampus, and hypophysis. The ratio of methylamphetamine to amphetamine was also compared after (-)-deprenyl and (+)-deprenyl treatments.

Effect of neostigmine on the hippocampal noradrenaline release: role of cholinergic receptors.

The effect of the cholinesterase inhibitor neostigmine on hippocampal noradrenaline (NA) release was studied using in vivo microdialysis. Local application of neostigmine significantly increased the release of NA. The effect was potentiated by coperfusion of the nicotinic antagonist mecamylamine but was completely blocked by the muscarinic antagonist atropine. The neostigmine-evoked NA release was not affected by the M2-selective muscarinic antagonist gallamine but was completely blocked by the M1-selective muscarinic antagonist pirenzepine. While muscarinic antagonists had no effect on the resting release of NA, mecamylamine increased it. Our data indicate that acetylcholine can stimulate the hippocampal NA release via M1 muscarinic receptors and that a population of nicotinic receptors mediate inhibitory tone on hippocampal NA release. The fact that neostigmine is able to enhance both cholinergic and noradrenergic neurotransmission may help to understand the beneficial effect of cholinesterase inhibitors in Alzheimer's disease.

Neurochemistry and pharmacology of the major hippocampal transmitter systems: synaptic and nonsynaptic interactions.

Hippocampus plays a crucial role in important brain functions (e.g. memory, learning) thus in the past two decades this brain region became a major objective of neuroscience research. During this period large number of anatomical, neurochemical and electrophysiological data have been accumulated. While excellent reviews have been published on the anatomy and electrophysiology of hippocampal formation, the neurochemistry of this area has not been thoroughly surveyed. Therefore the aim of this review is to summarize the neurochemical and pharmacological data on the release of the major neurotransmitters found in the hippocampal region: glutamate (GLU), gamma-amino butyric acid (GABA), acetylcholine (ACh), noradrenaline (NA) and serotonin (5-HT). In addition, this review analyzes the synaptic and nonsynaptic interactions between hippocampal neuronal elements and overviews how auto- and heteroreceptors are involved in the presynaptic modulation of transmitter release. The presented data clearly show that transmitters released from axon terminals without synaptic contact play an important role in the fine tuning of communication between neurons within a neuronal circuit.

Nicotinic acetylcholine receptor antagonist effect of fluoxetine in rat hippocampal slices.

We compared the effect of mecamylamine and fluoxetine on the hippocampal noradrenaline (NA) release evoked by nicotine in vitro. Nicotine (100 microM) increased the basal release of [3H]NA from rat hippocampal slices. This effect was blocked by the potent nicotinic antagonist mecamylamine in a dose-dependent manner (IC50 = 0.19 microM). The selective serotonin reuptake inhibitor (SSRI) fluoxetine also antagonised the response to nicotine in a dose-dependent manner with a similar strength (IC50 = 0.57 microM). Our data indicate that fluoxetine has nicotinic acetylcholine receptor antagonist effect in the central nervous system. The possible clinical significance of this finding is discussed.

Dual effect of DMPP on the resting release of noradrenaline from rat hippocampal slices.

The effect of the nicotinic receptor agonist dimethylphenylpiperazinium iodide (DMPP) on the resting release of [3H]noradrenaline from superfused hippocampal slices was studied in rat. Continuous administration of DMPP at a concentration range of 1-100 microM increased the [3H]noradrenaline release in a dose-dependent manner. The response to DMPP was characterized by an immediate steep increase (peak response) followed by a sudden decline to a lower level that was constant with time (tall response) and still was significantly higher than the spontaneous release. Further analysis revealed that the release of noradrenaline in response to DMPP consists of two components. While nicotinic receptor antagonists (mecamylamine 10 microM, pancuronium 10 microM, pipecuronium 10 microM), the nonselective Ca-antagonist Cd2+ (125 microM) and tetrodotoxin (TTX, 1 microM) completely abolished the peak response (phase I), they had no effect on the tall response (phase II). Ca(2+)-free medium containing 1 mM EGTA also blocked phase I but in contrast with other drugs enhanced phase II. The release during phase I is subject to presynaptic feedback modulation, since the alpha 2-adrenoceptor agonist xylazine (3 microM) inhibited the DMPP-evoked stimulation of [3H]noradrenaline release, that inhibition was antagonized by a selective alpha 2-adrenoceptor antagonist, (+/-)-[7,8-(methylenedioxy)-14-alpha-hydroxyalloberbane hydrochloride [(+/-)-CH-38083] (2 microM). (+/-)-CH-38083 (2 microM) alone significantly enhanced the DMPP-evoked increase of [3H]noradrenaline release. Phase II was not effected by alpha 2-adrenergic drugs. Whereas the noradrenaline uptake blockers despramine (DMI, 1-10 microM), nisoxetine (1-10 microM), and nomifensine (10 microM) inhibited both phases, nomifensine at a concentration of 1 microM selectively blocked only phase II. Our data indicate that DMPP has a dual effect on the hippocampal noradrenaline release: phase I is a transient, nicotinic receptor-mediated exocytotic release, and phase II is a maintained, carrier-mediated process.