Norepinephrine Uptake Inhibitor Research Articles

Effects of acute and chronic administration of MCI-225, a new selective noradrenaline reuptake inhibitor with 5-HT3 receptor blocking action, on extracellular noradrenaline levels in the hypothalamus of stressed rats.

In the present study, we investigated the effects of acute and chronic systemic administration of MCI-225 (4-(2-fluorophenyl)-6-methyl-2-(1-piperazinyl)thieno[2,3-d]pyrimidine monohydrate hydrochloride), a newly-developed selective noradrenaline (NA) reuptake inhibitor with 5-HT3-receptor-blocking action, on extracellular NA levels in the hypothalamus of stressed and non-stressed rats by utilizing intracerebral microdialysis. Acute administration of MCI-225 (3 and 10 mg/kg, p.o.) significantly and dose-dependently increased extracellular NA levels in the hypothalamus in non-stressed rats. Footshock for 20 min also significantly increased NA levels in the hypothalamus of both groups of rats pretreated with vehicle and MCI-225. Although chronic administration of MCI-225 (3 or 10 mg/kg, p.o. for 14 days) did not alter the basal extracellular NA levels in the hypothalamus, the stress-induced increases in extracellular NA levels were significantly lower in rats chronically treated with MCI-225 (10 mg/kg) than those of rats pretreated with vehicle for the same period. The increase in extracellular NA levels induced by MCI-225 challenge (3 or 10 mg/kg, p.o.) were not different between rats chronically treated with MCI-225 or vehicle. These results suggest that MCI-225 enhances extracellular NA levels in the hypothalamus in both non-stressed and stressed rats by inhibiting NA uptake and that chronic systemic administration of MCI-225 did not alter basal extracellular NA levels, but reduced the increase in NA release caused by footshock stress. These data suggest the possibility that MCI-225 might possess anxiolytic and/or antidepressant properties.

Effects of Acute and Chronic Administration of MCI-225, a New Selective Noradrenaline Reuptake Inhibitor With 5-HT3 Receptor Blocking Action, on Extracellular Noradrenaline Levels in the Hypothalamus of Stressed Rats

ABSTRACT In the present study, we investigated the effects of acute and chronic systemic administration of MCI-225 (4-(2-fluorophenyl)-6-methyl-2-(1-piperazinyl)thieno[2,3-d]pyrimidine monohydrate hydrochloride), a newly-developed selective noradrenaline (NA) reuptake inhibitor with 5-HT3-receptor-blocking action, on extracellular NA levels in the hypothalamus of stressed and non-stressed rats by utilizing intracerebral microdialysis. Acute administration of MCI-225 (3 and 10 mg/kg, p.o.) significantly and dose-dependently increased extracellular NA levels in the hypothalamus in non-stressed rats. Footshock for 20 min also significantly increased NA levels in the hypothalamus of both groups of rats pretreated with vehicle and MCI-225. Although chronic administration of MCI-225 (3 or 10 mg/kg, p.o. for 14 days) did not alter the basal extracellular NA levels in the hypothalamus, the stress-induced increases in extracellular NA levels were significantly lower in rats chronically treated with MCI-225 (10 mg/kg) than those of rats pretreated with vehicle for the same period. The increase in extracellular NA levels induced by MCI-225 challenge (3 or 10 mg/kg, p.o.) were not different between rats chronically treated with MCI-225 or vehicle. These results suggest that MCI-225 enhances extracellular NA levels in the hypothalamus in both non-stressed and stressed rats by inhibiting NA uptake and that chronic systemic administration of MCI-225 did not alter basal extracellular NA levels, but reduced the increase in NA release caused by footshock stress. These data suggest the possibility that MCI-225 might possess anxiolytic and/or antidepressant properties.

Neuropharmacology of venlafaxine.

Venlafaxine (Effexor) is an effective antidepressant and has also been approved for the treatment of generalized anxiety disorder. Venlafaxine was initially characterized as an inhibitor of both serotonin (5HT) and norepinephrine (NE) uptake and was therefore termed a "dual uptake inhibitor." This chapter reviews data from both in vitro and in vivo studies regarding its effects on 5HT and NE neurotransmission. In addition, the effects of venlafaxine on other systems that may play a role in its therapeutic efficacy effects are described. The data indicate that venlafaxine is a relatively weak inhibitor of NE transport in vitro. In vivo studies indicate that venlafaxine selectively inhibits 5HT uptake at low therapeutic doses and inhibits both 5HT and NE uptake at higher therapeutic doses. This chapter concludes with a discussion of the effects of venlafaxine on various aspects of physiology.

An antidepressant-induced decrease in the responsiveness of hippocampal neurons to group I metabotropic glutamate receptor activation

Imipramine, a serotonin and noradrenaline uptake inhibitor, is the prototypical tricyclic antidepressant. The effects of imipramine on neuronal responsiveness to the group I glutamate metabotropic (mGlu) receptor agonist ( RS)-3,5-dihydroxyphenylglycine (DHPG) were studied ex vivo, in the CA1 area of rat hippocampus, using extracellular and intracellular recording. DHPG increased the population spike amplitude, depolarized CA1 cells and decreased the slow afterhyperpolarization. Imipramine (20 μM) administered acutely in vitro did not change the effect of DHPG on population spikes. Repeated treatment with imipramine (10 mg/kg, twice daily, for 14 days) significantly attenuated the enhancing effect of DHPG (2.5 and 5 μM) on population spikes, as well as the DHPG-induced depolarization and the decrease in the slow afterhyperpolarization. Repeated treatment with imipramine had no effect on passive or active membrane properties of CA1 pyramidal cells. The results of the time-course experiment demonstrated that the imipramine-induced decrease in the responsiveness of CA1 cells to DHPG was apparent after a 7-day treatment; there was a further decrease after 14 days of treatment to a level which was not changed by longer (21-day) administration of imipramine. The attenuation of neuronal responsiveness to DHPG induced by a 14-day treatment was still detectable 7 days after imipramine withdrawal. It is concluded that repeated treatment with imipramine induces a decrease in the responsiveness of rat CA1 hippocampal neurons to group I mGlu receptor activation with a time course which correlates with the delayed onset of the therapeutic effect of antidepressants in humans. This suggests that alterations in mGlu receptors may contribute to antidepressant efficacy.

Modulation of the Extracellular 5-Hydroxytryptamine Brain Concentrations by the Serotonin and Noradrenaline Reuptake Inhibitor, Milnacipran: Microdialysis Studies in Rats

We examined the effects of the administration of milnacipran, a dual inhibitor of serotonin (5-hydroxy-tryptamine, 5-HT) and noradrenaline uptake on the 5-HT output in rat brain. Local milnacipran administration increased the 5-HT output in frontal cortex and the midbrain raphe nuclei 7- and 10-fold by a Ca2+- and tetrodotoxin-dependent mechanism. However, the subcutaneous administration of milnacipran (1–60 mg/kg SC) elevated the 5-HT output much less in these areas (200–230% of baseline at 60 mg/kg). In hypothalamus, 10 mg/kg SC raised 5-HT levels to 170%. The 5-HT1A antagonist WAY-100635 caused a small potentiation of the effects of milnacipran. The baseline 5-HT output was unaffected by 2-week treatments with milnacipran (30 and 60 mg/kg·day). The distinct regional profile and the lack of enhancement of its effects by WAY-100635 and prolonged treatment suggest that milnacipran does not exert its antidepressant action through an enhancement of the serotonergic function.

Effects of ouabain on in situ cardiac sympathetic nerve endings

Using dialysis technique, the effects of ouabain on in situ cardiac sympathetic nerve endings were examined in anesthetized cats. Dialysis probes were implanted in the left ventricular myocardium, and the concentration of dialysate norepinephrine (NE) was used as an indicator of NE output at the cardiac sympathetic nerve ending. Locally applied ouabain dose-dependently (1, 10, 100 μM) increased dialysate NE levels. This finding suggested that ouabain causes an increase in NE efflux without any requirement for prior mobilization of NE from vesicular stores. Transection of sympathetic nerves innervating the heart, was without effect on the ouabain (100 μM)-induced increase in NE efflux. Pretreatment with a Ca 2+-channel blocker, ω-conotoxin GVIA (10 μg/kg iv) suppressed the ouabain-induced NE efflux. These data suggested that ouabain opened N-type calcium channels coupled to NE release without centrally mediated neural transmission. Furthermore, ouabain-induced NE efflux was suppressed by pretreatment with desipramine (neuronal NE uptake inhibitor, 100 μM). Our data suggest that the two mechanisms (exocytosis and carrier-mediated outward transport), to the same extent, contributed to the amount of NE efflux evoked by ouabain in in situ cardiac sympathetic nerve endings.

Effects of tramadol and its enantiomers on Concanavalin-A induced-proliferation and NK activity of mouse splenocytes: involvement of serotonin

The centrally acting analgesic drug tramadol is a 1:1 racemic mixture of two enantiomers, with different pharmacological properties. The (−)-tramadol preferentially inhibits noradrenaline uptake, whereas the (+)-tramadol inhibits serotonin uptake and binds to opioid receptors. Since tramadol has been shown to stimulate some immune responses in mice, in the present work we analyzed the effects of its enantiomers on the same parameters, with the aim to better characterize the mechanisms involved in such action of tramadol. The acute administration of 20 and 40 mg/kg of racemic tramadol and of 10 and 20 mg/kg of (+)-tramadol induced a significant and comparable stimulation of Concanavalin-A (Con-A) induced proliferation and of Natural Killer (NK) activity of splenocytes. On the contrary, the (−)-tramadol was devoid of any effect. The pretreatment with the serotoninergic antagonist metergoline (3.0 mg/kg) completely blocked the effects of both tramadol and (+)-tramadol. We suggest that the enhancement of the serotoninergic tone could be at the basis of the stimulatory effects exerted by tramadol on Con-A induced lymphoproliferation and NK activity.

The discriminative stimulus properties of LY233708, a selective serotonin reuptake inhibitor, in the pigeon.

Understanding the contribution of the various serotonin (5-HT) receptor subtypes to the behavioral effects of selective serotonin reuptake inhibitors (SSRIs) may contribute to the discovery of increasingly effective drugs for the treatment of conditions such as depression, panic and obsessive-compulsive disorders. A drug discrimination procedure was used to determine whether the administration of an SSRI was associated with a specific interoceptive stimulus cue and to what extent that cue was related to activation of the 5-HT(1A) receptor. Pigeons were trained to discriminate 20 mg/kg of the short acting, SSRI, LY233708 dihydrochloride dihydrate [(-)-cis-1-(6-chloro-1,2,3,4- tetrahydro-1-methyl-2-naphthalenyl)piperazine] from saline. LY233708 induced a specific, dose-related stimulus cue. The SSRIs, fluoxetine and citalopram, induced dose-related responding on the LY233708-associated key. In contrast, nisoxetine, a selective norepinephrine uptake inhibitor, induced responding on the saline-associated key. The prototypical 5-HT(1A) agonist, 8-OH-DPAT [8-hydroxy-(2-di-n-propylamino)tetralin] substituted for LY233708. This generalization was blocked by the selective 5-HT(1A) antagonist, WAY-100635 [N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide]. These data demonstrate that an SSRI can induce a specific, stable discriminative stimulus that appears to involve activation of the 5-HT(1A) receptor in the pigeon.

4-fluorotranylcypromine, a novel monoamine oxidase inhibitor: Neurochemical effects in rat brain after short- and long-term administration

A series of acute and chronic experiments was conducted on 4-fluorotranylcypromine (FTCP), an analog of the monoamine oxidase (MAO)-inhibiting antidepressant tranylcypromine (TCP) in which the 4 position of the phenyl ring is protected from metabolism. These studies demonstrated that FTCP is a more potent inhibitor of MAO ex vivo than is the parent drug. Despite its similarity in structure to p-chloroamphetamine, FTCP does not cause a depletion of brain levels of 5-hydroxytryptamine (5-HT) after chronic administration; in fact, it increases brain 5-HT to levels similar to those produced by TCP. After chronic administration, FTCP produces a downregulation of β-adrenergic and tryptamine receptors, in common with TCP and several other antidepressants. Pretreatment of rats with iprindole or trifluperazine, drugs known to block cytochrome P450-mediated hydroxylation reactions and to elevate brain levels of TCP, had no effects on FTCP brain levels, suggesting that metabolic drug-drug interactions may be less of a concern with FTCP than with TCP. In vitro uptake experiments in prisms prepared from hypothalamus or striatum revealed that TCP and FTCP are both potent inhibitors of norepinephrine (NE) uptake; FTCP is a more potent inhibitor of 5-HT uptake than is TCP FTCP is a more potent releaser of 5-HT than is TCP.

4‐fluorotranylcypromine, a novel monoamine oxidase inhibitor: Neurochemical effects in rat brain after short‐ and long‐term administration

A series of acute and chronic experiments was conducted on 4-fluorotranylcypromine (FTCP), an analog of the monoamine oxidase (MAO)-inhibiting antidepressant tranylcypromine (TCP) in which the 4 position of the phenyl ring is protected from metabolism. These studies demonstrated that FTCP is a more potent inhibitor of MAO ex vivo than is the parent drug. Despite its similarity in structure to p-chloroamphetamine, FTCP does not cause a depletion of brain levels of 5-hydroxytryptamine (5-HT) after chronic administration; in fact, it increases brain 5-HT to levels similar to those produced by TCP. After chronic administration, FTCP produces a downregulation of β-adrenergic and tryptamine receptors, in common with TCP and several other antidepressants. Pretreatment of rats with iprindole or trifluperazine, drugs known to block cytochrome P450-mediated hydroxylation reactions and to elevate brain levels of TCP, had no effects on FTCP brain levels, suggesting that metabolic drug–drug interactions may be less of a concern with FTCP than with TCP. In vitro uptake experiments in prisms prepared from hypothalamus or striatum revealed that TCP and FTCP are both potent inhibitors of norepinephrine (NE) uptake; FTCP is a more potent inhibitor of 5-HT uptake than is TCP. FTCP is a more potent releaser of 5-HT than is TCP. Drug Dev. Res. 48:61–69, 1999. © 1999 Wiley-Liss, Inc.

Safety and pharmacokinetics of duloxetine, a potential new antidepressant with serotonin and norepinephrine uptake inhibition

Safety and pharmacokinetics of duloxetine, a potential new antidepressant with serotonin and norepinephrine uptake inhibition

Comparison of changes in the extracellular concentration of noradrenaline in rat frontal cortex induced by sibutramine or d‐amphetamine: modulation by α2‐adrenoceptors

1. The effects of sibutramine (0.25 - 10 mg kg-1, i.p.) on extracellular noradrenaline concentration in the frontal cortex of halothane-anaesthetized rats were compared with those of d-amphetamine (1 - 3 mg kg-1, i.p.) using in vivo microdialysis. The role of presynaptic alpha2-adrenoceptors in modulating the effects of these drugs on extracellular noradrenaline concentration were also investigated by pretreating rats with the selective alpha2-adrenoceptor antagonist, RX821002. 2. Sibutramine induced a gradual and sustained increase in extracellular noradrenaline concentration. The dose-response relationship was described by a bell-shaped curve with a maximum effect at 0.5 mg kg-1. In contrast, d-amphetamine induced a rapid increase in extracellular noradrenaline concentration, the magnitude of which paralleled drug dose. 3. Pretreatment with the alpha2-adrenoceptor antagonist, RX821002 (dose 3 mg kg-1, i.p.) increased by 5 fold the accumulation of extracellular noradrenaline caused by sibutramine (10 mg kg-1) and reduced the latency of sibutramine to reach its maximum effect from 144 - 56 min. 4. RX821002-pretreatment increased by only 2.5 fold the increase in extracellular noradrenaline concentration caused by d-amphetamine alone (10 mg kg-1) and had no effect on the latency to reach maximum. 5. These findings support evidence that sibutramine acts as a noradrenaline uptake inhibitor in vivo and that the effects of this drug are blunted by indirect activation of presynaptic alpha2-adreno-ceptors. In contrast, the rapid increase in extracellular noradrenaline concentration induced by d-amphetamine is consistent with this being mainly due to an increase in Ca2+-independent release of noradrenaline.

Effect of desipramine on spontaneous arterial pressure oscillations in the rat

There has been no previous report on the effect of the noradrenaline uptake inhibitor desipramine on short-term variability of arterial pressure. Mean arterial pressure was recorded in 9 conscious resting rats during 4 consecutive 30-min periods: (1) under baseline conditions, (2) after desipramine administration (2 mg/kg i.v., followed by 1 mg/kg every hour), then after (3) cardiac autonomic blockade with methylatropine and atenolol, and (4) α-adrenoceptor blockade with phentolamine. Fast Fourier transform analysis was applied to beat-to-beat data after resampling at 10 Hz of consecutive 205-s time series. Desipramine did not change the mean level and overall variability of mean arterial pressure. However, spectral power in the mid-frequency (0.3–0.5 Hz) band containing the Mayer waves was reduced by more than 80%, and power in the low-frequency (0.05–0.2 Hz) band was enhanced by approximately 50%, especially due to the appearance of a major oscillation centred at 0.095±0.005 Hz. This slow oscillation was further enhanced after cardiac autonomic blockade and was abolished after α-adrenoceptor blockade. In conclusion, desipramine profoundly alters short-term arterial pressure variability in resting rats, mainly by shifting vasomotor waves from 0.4 to 0.1 Hz. Desipramine may prove a valuable pharmacological tool to study the dynamic aspects of arterial pressure control.

Determination of Norepinephrine in Microdialysis Samples by Microbore Column Liquid Chromatography with Fluorescence Detection Following Derivatization with Benzylamine

A microbore column liquid chromatographic method is described for the determination of norepinephrine (NE) in microdialysis samples from rat brain. The method is based on precolumn derivatization of NE with benzylamine in the presence of potassium hexacyanoferrate(III) resulting in a highly fluorescent and stable benzoxazole derivative. Typically, a 10-μl sample was mixed with 10 μl derivatization reagent containing 0.45 M Caps buffer (pH 12.0), 0.2 M benzylamine, 10 mM potassium hexacyanoferrate(III), andN,N-dimethylformamide (1:1:1:15, v/v). The derivatization was carried out at 50°C for 20 min. Under these conditions only NE and epinephrine produced high fluorescence yields at excitation and emission wavelengths of 345 and 480 nm, respectively, while fluorescence of other catechols and 5-hydroxyindoles was quenched by 10–100 times. The NE derivative was separated on a reversed-phase column (100 × 1.0 mm i.d., packed with C18 silica, 5 μm) within 10 min with no late eluting peaks. The mobile phase consisted of 40 mM Britton–Robinson buffer (pH 7.5) containing 1 mM didodecyldimethylammonium bromide and acetonitrile (34%, v/v), the flow rate was 40 μl/min. The limit of detection (signal-to-noise ratio of 3) for NE was 90 amol in 10 μl sample injected. Microdialysis samples were collected in 5-min intervals from the probes implanted in the hippocampus, frontal cortex, or hypothalamus of awake rats. The basal extracellular NE levels in the respective areas were 4.7 ± 0.9, 1.8 ± 0.3, and 0.8 ± 0.2 fmol/10 μl (mean ± SE,n= 7). Perfusion with a Ringer solution containing 100 mM K+increased hippocampal NE levels by 700%, while NE uptake inhibitors maprotiline and amitriptyline administered orally or subcutaneously increased extracellular NE in the frontal cortex by about 300%. On the other hand, reserpine (5 mg/kg) reduced cortical NE levels by 40% 3 h after the administration. This new fluorescence derivatization method provides better selectivity, sensitivity, and speed for NE determination than the electrochemical detection since no late-eluting compounds such as dopamine, serotonin, and their metabolites are detectable in the chromatograms of the microdialysis samples.

Effects of Antidepressants in Rats Trained to Discriminate the Beta-2 Adrenergic Agonist Clenbuterol

The ability of indirectly acting agonists such as norepinephrine uptake inhibitors, serotonin reuptake inhibitors, and atypical antidepressants to substitute for clenbuterol, a beta-2 adrenergic agonist, was examined in rats trained to discriminate 0.03 mg/kg clenbuterol and saline using a fixed-ratio 10 (FR 10) schedule with water reinforcement. The beta-2 selective adrenergic agonist clenbuterol produced an orderly dose–response relationship, and its discriminative stimulus effects were antagonized by the beta-adrenergic antagonist propranolol. It was found that the effects of tricyclic antidepressants and selective norepinephrine uptake inhibitors did not generalize to the discriminative stimulus effects of clenbuterol, with the exception of high doses of protriptyline. Moreover, compounds from other drug classes, including fluoxetine and phenelzine, did not substitute for clenbuterol. Atypical antidepressants, such as trazodone, rolipram, and bupropion also did not engender drug-appropriate responding. Prenalterol and dobutamine, both purported to be beta-1 adrenergic receptor agonists, partially substituted for clenbuterol, but at relatively high doses. The present results show that the antidepressants tested do not share discriminative stimulus effects with clenbuterol, a beta-2 adrenergic agonist.

Venlafaxine: acute and chronic effects on 5-hydroxytryptamine levels in rat brain in vivo

Venlafaxine is a dual serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline uptake inhibitor which has been claimed to have an onset of antidepressant action which is faster than for other comparable drugs. The effects of venlafaxine on brain 5-HT levels in vivo have not yet been examined. Acute administration of venlafaxine to rats by i.p. injection resulted in dose-dependent increases in cortical and hippocampal 5-HT levels, as measured by in vivo microdialysis, over the range 5–20 mg/kg. The effect of venlafaxine (10 mg/kg i.p.) was potentiated by prior administration of pindolol (10 mg/kg s.c.) in hippocampus but not in frontal cortex. Daily administration of venlafaxine (5 mg/kg i.p.) for 4 weeks did not change basal 5-HT levels in either brain area. The effect of 8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT, 0.2 mg/kg s.c.) to reduce 5-HT levels was unaffected by chronic venlafaxine at this dose, indicating that there was no change in sensitivity of presynaptic 5-HT 1A autoreceptors.

Histamine regulates food intake through modulating noradrenaline release in the para-ventricular nucleus

Histamine is one of the neurotransmitters suppressing appetite, but the interactions of histaminergic neurons with other neurons in satiety centers have not been clarified. Noradrenaline in the para-ventricular nucleus (PVN) has been shown to stimulate feeding. This study was designed to determine whether histamine modulates noradrenaline release via histamine H1-receptors in the PVN. Freely-fed rats were i.c.v. injected with an histamine H1-receptor antagonist, triprolidine (82 μg), and/or an alpha 2-adrenoceptor antagonist, rauwolscine (0, 20 and 40 μg), and food intake ( n=8 each) over 2 h was measured. Food intake was significantly ( p<0.01) increased in rats injected with triprolidine alone. The triprolidine-elicited increase in food intake was suppressed by rauwolscine at a dose of 40 μg. The noradrenaline content in perfusates collected by a microdialysis probe aimed at the PVN was significantly ( p<0.05) increased by the presence of triprolidine in the perfusates. The noradrenaline concentrations in perfusates collected from the PVN were elevated after tyramine (a noradrenaline uptake inhibitor) administration, but not when both tyramine and histamine were given. In conclusion, these results suggest that histamine inhibits noradrenaline release from hypothalamic nerve terminals in the PVN, and thus suppresses feeding behavior.

Dopaminergic Projection to the Nucleus Accumbens Mediates the Memory-Enhancing Effect of Angiotensins in Rats

It has been shown that the facilitatory effect of angiotensin II (AII) and its 3–7 fragment [AII(3–7)] on cognitive processes is mediated by the dopaminergic system. In the present study, the involvement of dopaminergic projection to the nucleus accumbens (NAS) and to the nucleus septi lateralis (NSL) in the expression of the positive effect of AII and AII(3–7) on the retrieval of passive avoidance after bilateral 6-OHDA induced lesions to NAS and NSL was evaluated. To protect noradrenergic neurons from destruction by neurotoxin, rats were pretreated intraperitoneally with 25 mg/kg of desmethylimipramine, an inhibitor of noradrenaline uptake, 30 min before surgery. Both peptides were given intracerebroventricularly, at the dose of 1 nmol each, 15 min before the retention testing. Bilateral 6-OHDA lesions to NAS totally abolished, and to NSL did not affect, the positive effect of angiotensins on recall of information in a passive avoidance situation. Moreover, bilateral 6-OHDA lesions to NAS but not to NSL significantly attenuated the locomotor activity of rats in an open-field test. Nevertheless, it had no essential significance on the evaluation of the influence of the disruption of the dopaminergic endings in both structures on the facilitatory effect of angiotensins on retrieval process. These results suggest that the dopaminergic projection to NAS, but not to NSL is involved in the expression of the facilitatory effect of AII and AII(3–7) on memory motivated affectively evaluated in a passive avoidance situation.

Excessive release of [formula omitted]noradrenaline and glutamate in response to simulation of ischemic conditions in rat spinal cord slice preparation: effect of NMDA and AMPA receptor antagonists

In the present study we investigated the effects of NMDA and non-NMDA glutamate receptor antagonists on the ischemia-evoked release of [ 3 H] noradrenaline from rat spinal cord slices. An in vitro ischemia model (oxygen and glucose deprivation) was used to simulate the ischemic conditions known to cause neuronal injury. Spinal cord slices were loaded with [ 3 H] noradrenaline and superfused with Krebs solution in a micro-organ bath. Both axonal stimulation and ischemia increased the release of [ 3 H] noradrenaline, but the release in response to glucose and oxygen deprivation was [Ca 2+] o independent. Dizocilpine (MK-801), an NMDA receptor antagonist, suppressed the release of [ 3 H] noradrenaline produced by ischemia, while it enhanced the release of [ 3 H] noradrenaline evoked by electrical field stimulation. In contrast, LY300168 (GYKI-53655) [(±)-3- N-methylcarbamyde-1-(4-aminophenyl)-4-methyl-1.8-methylene-dioxy-5 H-2.3-benzodiazepine] and its (−)isomer LY303070 (GYKI-53784) [(−)-3- N-methylcarbamyde-1-(4-aminophenyl)-4-methyl-1.8-methylene-dioxy-5 H-2.3-benzodiazepine] AMPA receptor antagonists, had no effect on the release of [ 3 H] noradrenaline evoked by either electrical stimulation or ischemia. Desipramine, a noradrenaline uptake inhibitor, potentiated the release of [ 3 H] noradrenaline evoked by ischemia, while in the absence of [Ca 2+] o but under conditions when [ 3 H] noradrenaline release was further increased, it reduced the release. Dizocilpine also decreased glutamate and aspartate release, measured by high performance liquid chromatography, during ischemia. It is concluded that glutamate release and NMDA receptors, but not AMPA receptors, are involved in the acute effect of oxygen and glucose deprivation on the excessive release of noradrenaline and that this release is not related to physiological axonal conduction.

Hypo- and Hypersalivation Induced by Psychoactive Drugs

Psychoactive drugs can have profound effects on salivation: apart from affecting the amount of saliva secreted (i.e. causing either hypo- or hypersalivation), they may also modify the composition of the saliva. Hyposalivation leads to the subjective experience of ‘dry mouth’ (xerostomia) which, in addition to causing subjective discomfort, may be associated with dental caries and oral infections. On the other hand, hypersalivation leads to ‘drooling’ (sialorrhoea), which can be a source of social embarrassment and can be associated with parotitis, choking and even aspiration pneumonia. Both xerostomia and sialorrhoea can impair patient compliance. Antidepressants [tricyclic antidepressants, noradrenaline (norepinephrine) reuptake inhibitors], lithium, antipsychotics of the phenothiazine class and (α2-adrenoceptor agonists (e.g. clonidine and lofexidine) are commonly associated with hyposalivation and xerostomia, whereas both classical and novel antipsychotics can cause sialorrhoea. However, only clozapine-induced sialorrhoea, occurring in about 30% of patients treated with the drug, is of any major clinical significance The salivary glands receive a dual sympathetic (noradrenergic) and parasympathetic (cholinergic) innervation, and psychoactive drugs may affect either the gland cells themselves or their neural control. The effects of psychoactive drugs on the autonomic control of salivation is mediated via their multiple actions at neuroreceptors and synaptic mechanisms. Blockade of muscarinic cholinoceptors and α1-adrenoceptors, inhibition of noradrenaline uptake and stimulation of (α2-adrenoceptors may lead to hyposalivation, whereas stimulation of muscarinic cholinoceptors and dopamine D2 receptors, blockade of (α2-adrenoceptors and depletion of noradrenaline from central stores may result in hypersalivation It is important that the clinician is familiar with the effect of each class of drug on salivation, so that he/she can mitigate these by the judicious choice of drug and dosage schedule, and, if necessary, by providing symptomatic treatment for these distressing, and occasionally dangerous, adverse effects