An AU at the first base pair of helix 3 elevates the catalytic activity of hepatitis delta virus ribozymes

Isradipine and darodipine are dihydropyridine calcium antagonists that affect the serotonergic pathways with a peculiar profile of effects because, at low dose (0.08 and 0.3 mg/kg, respectively) they facilitate, but at high dose (1.60 and 5.0 mg/kg, respectively) they inhibit the serotonergic neurotransmission. To investigate the mechanisms of these effects, the selective 5-HT1A receptor agonist 8-OHDPAT was injected S.C. to rats pretreated I.P. with isradipine (0.04-1.60 mg/kg) or darodipine (0.3-5.0 mg/kg). By stimulating presynaptic 5-HT1A autoreceptor, 8-OHDPAT induced signs of inhibition of the serotonergic neutransmission (i.e., decrease of the 5-HIIA/5-HT ratio), but it also produced behavioral effects by stimulating postsynaptic 5-HT1A receptors (i.e., forepaw treadings). A low dose of isradipine (0.08 mg/kg) or darodipine (0.3 mg/kg) antagonized the presynaptic, but enhanced the postsynaptic effects of 8-OHDPAT, suggesting relief of the autoreceptor-mediated inhibition of the 5-HT release. Thus, the amine released could stimulate postsynaptic receptors, adding its action to that of 8-OHDPAT. A high dose of isradipine (1.60 mg/kg) or darodipine (5.0 mg/kg) left unchanged, or also enhanced, the signs of inhibition of serotonergic neurotransmission displayed by 8-OHDPAT, reducing but not suppressing the increase in the behavioral response to the stimulation of postsynaptic 5-HT1A receptors. It was speculated that the effects of isradipine and darodipine on scrotonergic pathways of rat brain could be due to changes in the back-regulation of the neurotransmission, mediated by 5-HT1A autoreceptors. This mechanism of action could be extended to other dihydropyridine calcium antagonists, because blockade of L-type VSCC by these compounds appears to be involved in their effects on brain 5-HT turnover.     

In vivo electrophysiological characterization of 5-HT receptors in the guinea pig head of caudate nucleus and orbitofrontal cortex

The aim of the present study was to characterize in vivo the 5-HT receptor subtypes which mediate the effect of microiontophoretic applied 5-HT in the guinea pig head of caudate nucleus and orbitofrontal cortex. 5-HT and the preferential 5-HT2A receptor agonist DOI and the preferential 5-HT2C receptor agonist mCPP, suppressed the quisqualate (QUIS)-induced activation of neurons in both structures. The inhibitory effect of DOI and mCPP was not prevented by acute intravenous administration of the 5-HT1/2 receptor antagonist metergoline (2 mg/kg) and the 5-HT2A/2C receptor antagonist ritanserin (2 mg/kg) in the two regions nor by the selective 5-HT2A receptor antagonist MDL100907 (1 mg/kg) in the head of caudate nucleus. However, the inhibitory effect of DOI, but not that of mCPP, was antagonized by a 4-day treatment with metergoline and ritanserin (2 mg/kg/day; using minipumps implanted subcutaneously) in head of caudate nucleus, but not in orbitofrontal cortex. Microiontophoretic ejection of the 5-HT1A/7 receptor agonist 8-OH-DPAT and of the 5-HT1A receptor antagonist WAY100635 both suppressed the spontaneous and QUIS-activated firing activity of orbitofrontal cortex neurons. At current which did not affect the basal discharge activity of the neuron recorded, microiontophoretic application of WAY100635 and BMY7378 failed to prevent the inhibitory effect of 8-OH-DPAT. The inhibitory effect of gepirone, which is a 5-HT1A receptor agonist but devoid of affinity for 5-HT7 receptors, was also not antagonized by WAY100635. Altogether, these results suggest the presence of atypical 5-HT1A receptors in the orbitofrontal cortex. The present results also indicate that the suppressant effect of DOI may be mediated by 5-HT2A receptors in head of caudate nucleus and atypical 5-HT2 receptors in orbitofrontal cortex.     

The effect of infant colic on maternal self-perceptions and mother-infant attachment

The 5-HT2A and 5-HT2C antagonists MDL 100,907 and SER-082 were tested with the 5-HT2A/C agonist DOI and the 5-HT1A/2A/2C agonist LSD in the Behavioral Pattern Monitor, which provides multiple measures of locomotor and investigatory activity. Previous investigations have shown that these measures load onto three independent behavioral factors: amount of activity, exploratory behavior, and behavioral organization. Rats pretreated with saline, MDL 100,907 (0.25-2.0 mg/kg), or SER-082 (0.5-1.0 mg/kg) were treated with saline, 0.25 mg/kg DOI, or 60 micrograms/kg LSD. All effects of DOI were blocked by all doses of MDL 100,907, but only by the highest dose of SER-082. While the effects of LSD on activity and exploratory behavior were largely unaffected, either pretreatment antagonized the effects of LSD on behavioral organization. Thus, all of these effects of DOI were attributable to 5-HT2A receptors, whereas the effect of LSD on behavioral organization was influenced by both 5-HT2A and 5-HT2C receptors.     

Hexadecylphosphocholine and 2-modified 1,3-diacylglycerols as effectors of phospholipase D

The effects of mesulergine (100 and 200 microg/kg s.c.), SB 206553 (1 and 2.5 mg/kg i.p.), RP 62203 (2.5 and 4 mg/kg i.p.) and ritanserin (630 microg/kg i.p.) were studied on the extracellular concentration of dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) in the nucleus accumbens of chloral hydrate-anesthetized rats, using intracerebral microdialysis. Mesulergine, a non selective serotonin2C/2B/2A (5-HT2C/2B/2A) receptor antagonist, significantly increased DA release, which reached a peak level (+ 20%) 60 min after drug injection and slowly returned back to baseline values. Mesulergine also caused a dose-dependent increase in DOPAC outflow. Pretreatment with mesulergine (200 microg/kg) did not change the inhibition of DA release induced by apomorphine (100 microg/kg), whereas it prevented the reduction of DOPAC outflow induced by apomorphine (100 microg/kg). Administration of SB 206553, a selective blocker of 5-HT2C/2B receptors, dose-dependently increased DA outflow. The dose of 2.5 mg/kg SB 206553 caused a linear increase of DA output which reached a peak (+75%) 40 min after injection, while 1 mg/kg induced a more gradual increase of DA release which peaked (+54%) 60 min after administration of the drug. Treatment with RP 62203, a selective 5-HT2A receptor antagonist, did not produce any significant effect on DA outflow. Administration of ritanserin, a mixed 5-HT2A/2C receptor antagonist, did not cause any significant change of DA and DOPAC outflow. Taken together, these data indicate that selective blockade of 5-HT2/2B receptor subtypes increases DA release in the rat nucleus accumbens.     

Evidence that an OX-2-positive cell can inhibit the stimulation of type 1 cytokine production by bone marrow-derived B7-1 (and B7-2)-positive dendritic cells

The present study was designed to compare the effects of typical and atypical antipsychotic drugs on extracellular dopamine (DA) levels in the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAC), using in vivo microdialysis with dual probe implantation in awake, freely moving rats. Amperozide (2 and 10 mg/kg), clozapine (5 and 20 mg/kg), and olanzapine (10 mg/kg), all of which are atypical antipsychotics, produced greater increases in extracellular DA levels in the mPFC than in the NAC. Olanzapine (1 mg/kg), risperidone (0.1 and 1 mg/kg), also an atypical antipsychotic, and S-(-)-sulpiride (25 mg/kg), a typical antipsychotic, produced comparable increases in extracellular DA levels in the mPFC and the NAC. S-(-)-sulpiride (10 mg/kg) and haloperidol (0.1 and 1 mg/kg), another typical antipsychotic, significantly increased extracellular DA levels in the NAC but not in the mPFC. The effects of the six antipsychotic drugs to increase extracellular DA levels in the mPFC relative to those in the NAC was positively correlated with the difference between their pKi values for serotonin (5-hydroxytryptamine, 5-HT2A) and DA-D2 receptors and was inversely correlated to their pKi values for D2 or D3 receptors, but was not for 5-HT2A receptors alone. These results are consistent with the hypothesis that the ability of antipsychotic drugs to produce a greater increase in prefrontal compared with NAC extracellular DA levels may be related, in part, to weak D2 and D3 receptor affinity relative to 5-HT2A receptor antagonism.     

Hypothalamic paraventricular nucleus lesions differentially affect serotonin-1A (5-HT1A) and 5-HT2 receptor agonist-induced oxytocin, prolactin, and corticosterone responses

A number of receptor subtypes mediate hormonal responses to serotonin (5-HT). To test the hypothesis that the hypothalamic paraventricular nucleus (PVN) mediates 5-HT1A and 5-HT2 receptor-mediated oxytocin, PRL, and corticosterone responses, we studied the effects of the 5-HT1A agonist ipsapirone and the 5-HT2A/2C agonist 1-(2,5-dimethoxy-4-iodophenyl)2-aminopropane (DOI) after surgical PVN lesions or sham operations. Chronically cannulated, conscious, freely moving, male Wistar rats were injected iv (1 mg/kg) shortly after (3-4 days) and 5 weeks after (35-37 days) the operations. In sham-operated rats, ipsapirone caused marked elevations in plasma PRL and corticosterone, but not oxytocin concentrations, whereas DOI increased plasma concentrations of all three hormones. Short term PVN lesions prevented ipsapirone-induced corticosterone and DOI-induced oxytocin responses. DOI-induced PRL and corticosterone responses were also markedly inhibited 3-4 days after lesioning, although small rises over the baseline values were still observed. The ipsapirone-induced PRL response was unaffected by the lesioning. Five weeks after PVN lesioning, partial recoveries were observed in ipsapirone- and DOI-induced corticosterone and DOI-induced oxytocin responses, whereas DOI-induced PRL responses remained suppressed. The present findings suggest that the PVN or neural pathways close to it mediate oxytocin, PRL, and corticosterone responses to the 5-HT2 receptor agonist DOI as well as corticosterone, but not PRL, responses to the 5-HT1A receptor agonist ipsapirone. The results after long term PVN lesioning show that the oxytocin and corticosterone responses may be partially restored with time after lesioning.     

Comparison of stimulus properties of fluoxetine and 5-HT receptor agonists in a conditioned taste aversion procedure

Pre-exposure to 5-hydroxytryptamine (5-HT) receptor agonists in conditioned taste aversion experiments was used to characterize the stimulus properties of fluoxetine. The taste aversion induced by fluoxetine (10 mg/kg) was completely prevented when mice were pre-exposed to fluoxetine or when they were pre-exposed to the preferential 5-HT1C receptor agonist MK 212. Pre-exposure to MK 212 also prevented the conditioned taste aversion induced by another serotonin uptake inhibitor, paroxetine. A partial attenuation of fluoxetine-induced conditioned taste aversion was seen after pre-exposure to a high dose of the 5-HT1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 1 mg/kg), but not to lower doses. No familiarization for the fluoxetine stimulus was obtained by pre-exposure to treatments with the mixed 5-HT1C/2 receptor agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI). With the reversed sequence, pre-exposure to fluoxetine prevented the conditioned taste aversion induced by MK 212 or 8-OH-DPAT and reduced that induced by DOI. It is concluded that the acute stimulus properties of fluoxetine mostly resemble those of a 5-HT1C receptor agonist. This supports the suggestion that the 5-HT1C receptor can play an important role in the therapeutic effect of 5-HT reuptake inhibitors.     

Discriminative stimulus properties of (±)-fenfluramine: The role of 5-HT? receptor subtypes.

The role of serotonin 5-HT? receptors (5-HT?R) in the discriminative stimulus effects of fenfluramine was investigated. Male Sprague-Dawley rats were trained to discriminate (±)-fenfluramine (2 mg/kg ip) from saline using a 2-lever, water-reinforced paradigm. Drug-lever responding after fenfluramine was dose-dependent. The 5-HT2C/1BR agonist mCPP and the 5-HT2CR agonist MK 212 fully substituted, whereas the 5-HT2A/2CR agonist DOI partially substituted, for the training drug. The 5-HT2BR agonist BW 723C86 engendered saline-lever responding. The 5-HT2C/2BR antagonist SB 206553 completely antagonized the fenfluramine discrimination as well as the full substitutions of mCPP and MK 212 and the partial substitution of DOI. The selective 5-HT2AR antagonist M100907 partially suppressed the stimulus effects of fenfluramine, mCPP, and MK 212 and almost fully attenuated the partial substitution of DOI. RS 102221, a selective 5-HT2CR antagonist that does not cross the blood-brain barrier, did not alter the fenfluramine cue. Results demonstrate that the discriminative stimulus effects of fenfluramine are centrally mediated by 5-HT2CR and to some extent by 5-HT2AR. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Alterations in serotonergic responsiveness during cocaine withdrawal in rats: similarities to major depression in humans

BACKGROUND: Withdrawal from long-term cocaine use is accompanied by symptoms resembling major depression. Because acute cocaine affects serotonin (5-HT) neurons, and 5-HT dysfunction is implicated in the pathophysiology of depression, we evaluated the effects to 5-HT agonists in rats withdrawn from repeated injections of cocaine (15 mg/kg i.p., b.i.d., 7 days) or saline. METHODS: In the first study, prolactin (PRL) responses elicited by the 5-HT-releasing agent fenfluramine, the 5-HT1A agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), and the 5-HT2A/2C agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI) were examined as indices of postsynaptic 5-HT receptor function. In a second study, specific responses induced by 8-OH-DPAT, namely inhibition of brain 5-HT synthesis and stimulation of feeding, were examined as correlates of 5-HT1A autoreceptor function. RESULTS: Prior treatment with cocaine did not modify fenfluramine-evoked PRL release; however, the PRL secretory response to 8-OH-DPAT was blunted and the PRL response to DOI was potentiated after chronic cocaine treatment. Cocaine exposure did not alter the inhibitory effect of 8-OH-DPAT on 5-HT synthesis. 8-OH-DPAT-induced feeding was influenced by prior cocaine, but this effect was secondary to pronounced baseline hyperphagia in the cocaine-treated group. CONCLUSIONS: These data indicate that withdrawal from chronic cocaine renders specific subpopulations of postsynaptic 5-HT1A receptors subsensitive and 5-HT2A/2C receptors supersensitive. No evidence for cocaine-induced changes in 5-HT1A autoreceptor responsiveness was found. A survey of the literature reveals similarities in the profile of 5-HT dysfunction between rats withdrawn from cocaine and humans diagnosed with depression. We propose that withdrawal from chronic cocaine in rats may serve as a useful animal model of depressive disorders.     

Ascending afferent regulation of rat midbrain dopamine neurons

Standard, extracellular single-unit recording techniques were used to examine the electrophysiological and pharmacological responsiveness of midbrain dopamine (DA) neurons to selected, ascending afferent inputs. Sciatic nerve stimulation-induced inhibition of nigrostriatal DA (NSDA) neurons was blocked by both PCPA (5-HT synthesis inhibitor) and 5,7-DHT (5-HT neurotoxin), suggesting mediation by a serotonergic (5-HT) system. Direct stimulation of the dorsal raphe (which utilizes 5-HT as a neurotransmitter and inhibits slowly firing NSDA neurons) inhibited all mesoaccumbens DA (MADA) neurons tested. Paradoxically, DPAT, a 5-HT1A agonist which inhibits 5-HT cell firing, enhanced sciatic nerve stimulation-induced inhibition of NSDA neurons. MADA neurons were not inhibited by sciatic nerve stimulation and, therefore, could not be tested in this paradigm. In contrast to the dorsal raphe, electrical stimulation of the pedunculopontine tegmental nucleus preferentially excited slowly firing NSDA and MADA neurons. Thus, both excitatory and inhibitory ascending afferents influence the activity of midbrain DA neurons, and intact 5-HT systems are necessary for sciatic nerve stimulation to alter DA cell activity. However, the role that 5-HT plays in mediating peripheral sensory input remains unclear.     

Differences in the sensitivity to purinergic stimulation of myelinating and non-myelinating Schwann cells in peripheral human and rat nerve

The administration of the 5-hydroxytryptamine (5-HT) precursor 5-hydroxytryptophan (5-HTP) (25 mg/kg i.p.), in combination with an inhibitor of peripheral 5-HTP decarboxylase, produced a dose-dependent increase in the ejaculation latency of male rats, and this effect was enhanced by additional treatment with the 5-HT1 receptor antagonist (-)-pindolol (2 mg/kg s.c.). The 5-HT2A/C receptor agonist (+/-) 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (0.125-0.5 mg/kg s.c.) did not by itself affect male ejaculatory behavior, but additional treatment with (-)-pindolol (2 mg/kg s.c.) produced a dose-dependent decrease in number of ejaculating animals. The increased ejaculation latency produced by 5-HTP was fully antagonized by treatment with the 5-HT1B receptor antagonist isamoltane (4 mg/kg s.c.), but not by ritanserin (2 mg/kg s.c.) treatment. The selective 5-HT1A receptor antagonist WAY-100635 (0.15 mg/kg s.c.) enhanced the inhibitory actions of 5-HTP on the male rat ejaculatory behavior, and this dose of WAY-100635 fully antagonized 8-OH-DPAT-induced facilitation (0.25 mg/kg s.c.) of the ejaculatory behavior. WAY-100635 (0.04-0.60 mg/kg s.c.) did not, by itself, significantly affect male rat sexual behavior. Taken together, the results suggest an inhibitory role for postsynaptic 5-HT1B receptors in the effects produced by 5-HTP on male rat ejaculatory behavior. Furthermore, 5-HTP-induced inhibition of male rat ejaculatory behavior is partially controlled by stimulation of inhibitory 5-HT1A autoreceptors, since the effects of 5-HTP were accentuated by treatment with (-)-pindolol, as well as by the more selective 5-HT1A receptor antagonist WAY-100635.     

Role of 5-HT1A receptors in the effects of acute chronic fluoxetine on extracellular serotonin in the frontal cortex

Fluoxetine 10 mg/kg i.p. significantly increased the extracellular concentrations of serotonin (5-HT) in the frontal cortex as assessed by in vivo microdialysis. This effect was significantly potentiated when 0.3 mg/kg s.c. WAY-100635, a 5-HT1A receptor antagonist, was administered 30 min before. WAY-100635 by itself had no effect on extracellular 5-HT. Twenty-four hours after chronic fluoxetine schedule (10 mg/kg/day i.p. x 14 days), basal extracellular 5-HT concentrations in the frontal cortex were higher than those of animals that had received the vehicle chronically. At 24 h after the last dose, a challenge dose of fluoxetine (10 mg/kg i.p.) raised extracellular 5-HT similarly in chronically vehicle or fluoxetine treated rats. At this same interval 25 micrograms/kg s.c. 8-OH-DPAT, a 5-HT1A receptor agonist, significantly reduced extracellular 5-HT only in the frontal cortex of rats treated chronically with the vehicle. Examining basal extracellular 5-HT, the effect of a challenge dose of fluoxetine and the effect of 25 micrograms/kg 8-OH-DPAT after 96 h washout, no differences were found between chronically fluoxetine and vehicle-treated rats. The results confirm that the ability of fluoxetine to stimulate 5-HT1A autoreceptors through an increase of endogenous 5-HT attenuates its effect on cortical dialysate 5-HT. Chronic fluoxetine increased the basal concentrations of extracellular 5-HT only when a substantial amount of its metabolite was present in the brain and during the desensitization of presynaptic 5-HT1A autoreceptors (24 h after the last dose). These effects, in fact, disappeared after 96 h washout. The continuous presence of the drug may, therefore, be necessary to maintain extracellular 5-HT at concentrations high enough to produce a therapeutic effect.     

Effects of the serotonin agonists 8-OH-DPAT, buspirone, and DOI on water maze performance

We have previously reported that the serotonin 5-HT1A agonist 8-OH-DPAT and the 5-HT2c agonist TFMPP impair performance on a water maze. In the present report we extended those studies by examining a second 5-HT1A agonist, buspirone, to see whether its effects paralleled those of 8-OH-DPAT, and by testing the effects of the 5-HT2 agonist DOI. Unlike the open pool Morris water maze, the maze used in these experiments has alleys and doorways. The maze can be easily reconfigured to present rats with both previously learned or new maze challenges. Performance is assessed by time to reach the maze exit platform and the number of wrong doorways entered (errors). At doses that did not affect performance in a previously learned maze, the 5-HT1A agonists 8-OH-DPAT (0.1 mg/kg) and buspirone (1 mg/kg) slowed acquisition of a new maze configuration as measured by both swim time to the exit platform and errors committed. A higher dose of buspirone (10 mg/kg) completely blocked acquisition of a novel maze. In contrast. DOI slowed performance as assessed by swim time on both a well-learned maze as well as acquisition of a new maze, but did not affect error rate on either task, suggesting that this 5-HT2 agonist impaired performance by depressing motor activity. These experiments demonstrate that serotonin agonists, especially the 5-HT1A subtype, can impair learning.     

Tryptophan pretreatment augmentation of p-chloroamphetamine-induced serotonin and dopamine release and reduction of long-term neurotoxicity

The impact of tryptophan (TRP) pretreatment on the neurochemical effects of p-chloroamphetamine (PCA) was investigated. The neurotoxic effects of PCA on serotonin (5-HT) neurons, the acute effects of PCA on extracellular 5-HT and dopamine (DA), and the displacement by PCA of whole blood 5-HT were examined. TRP pretreatment (400 mg/kg of the methyl ester) significantly reduced the long-term (1 week) decrease in tissue 5-HT resulting from PCA (2 mg/kg, i.p., of the hydrochloride salt) in the prefrontal cortex and striatum, but not in the dorsal hippocampus. Microdialysis studies in awake animals showed that this pretreatment regimen resulted in augmented PCA-induced increases in extracellular 5-HT (4-fold) and DA (2-fold). TRP pretreatment also resulted in increased displacement of 5-HT from whole blood. The implications of these results toward possible mechanisms of action of PCA-induced neurotoxicity are discussed.     

Suppression of neocortical high-voltage spindles by nicotinic acetylcholine and 5-HT2 receptor stimulation

To investigate the roles of the nicotinic acetylcholine receptor and the serotonin (5-hydroxytryptamine; 5-HT) subtype 2 receptor in the modulation of rat thalamocortical oscillations, the effects of systemic (s.c.) administration of nicotine, a nicotinic acetylcholine receptor agonist, and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT2 receptor agonist, on neocortical high-voltage spindle activity occurring during quiet waking-immobility behavior in aged (28 months of age) and adult (7 months of age) rats were studied. Nicotine 0.1 and 0.3 mg/kg alleviated the age-related increase of neocortical high-voltage spindles, whereas in adult rats only nicotine 0.3 mg/kg was effective. DOI 0.3, 1.0 and 2.0 mg/kg suppressed high-voltage spindles in both aged and adult rats. In aged rats, a combination of subthreshold doses of nicotine (0.03 mg/kg) and DOI (0.1 mg/kg) decreased neocortical high-voltage spindles, whereas in adult rats two different subthreshold dose combinations (nicotine 0.03 or 0.1 mg/kg+DOI 0.1 mg/kg) had no effect. p-Chlorophenylalanine (400 mg/kg/day i.p. for 3 consecutive days) treatment decreased brain serotonin concentration (> 80% reduction), but did not affect high-voltage spindles. However, in both aged and adult rats, p-chlorophenylalanine treatment blocked the decrease in high-voltage spindle activity produced by DOI 0.3 mg/kg, though not the decrease produced by higher doses of DOI (1.0 and 2.0 mg/kg). It is important that, in adult rats, p-chlorophenylalanine treatment was able to abolish the decrease in high-voltage spindle activity seen after a relatively high dose of nicotine (0.3 mg/kg). The results suggest that nicotinic acetylcholine and 5-HT2 receptors may act in concert to suppress neocortical high-voltage spindling in rats, and that intact brain serotonergic systems may be important for some of the therapeutic effects of nicotine.     

Twelve-month abstinence from alcohol and long-term drinking and marital outcomes in men with severe alcohol problems

In vivo microdialysis was used to investigate the mechanism behind the increase in extracellular dopamine (DA) induced by increase in extracellular serotonin (5-HT) level and 5-HT1 and 5-HT2 receptor activation. The following serotoninergic drugs were perfused in the absence or presence of nomifensine (5 microM) or tetrodotoxin (TTX; 2 microM): clomipramine (10, 500 and 1,000 microM), a selective 5-HT reuptake inhibitor; 8-OH-DPAT (50 and 500 microM), a 5-HT1A receptor agonist; and alpha-methyl-5-HT (1, 5 and 50 microM), a 5-HT2 receptor agonist. All the serotoninergic drugs studied increased DA extracellular output in a dose-dependent manner. The presence of nomifensine attenuated the effect of perfusion of clomipramine (500 microM) and completely abolished the effect of perfusion of 8-OH-DPAT (500 microM) and alpha-methyl-5-HT (5 microM) on DA extracellular output. Clomipramine (100-1,000 microM) perfusion produced a dose dependent increase in DOPAC extracellular output, which was stronger when clomipramine (500 microM) was co-perfused with nomifensine. 8-OH-DPAT and alpha-methyl-5-HT perfusion decreased DOPAC overflow. Addition of TTX to the perfusion fluid one hour before serotoninergic drugs perfusion, did not completely abolish the effect on dopamine extracellular output produced by the serotoninergic drugs. These data seem to indicate that increase in extracellular 5-HT level and 5-HT1 and 5-HT2 receptor activation increase in vivo DA extracellular output in the striatum mainly by a nonexocytotic mechanism involving DA uptake sites and, secondarily, by activation of 5-HT receptors.     

Vascular prosthesis in kidney transplantation

The new antidepressant mirtazapine was tested in two experimental procedures which can reveal direct or indirect 5-HT1A receptor agonistic effects. These procedures were observation for induction of lower lip retraction in rats and comparison of stimulus properties in cross-familiarization experiments with conditioned taste aversion in mice. Mirtazapine induced lower lip retraction in rats, as did the 5-HT1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT). However, the response to mirtazapine at doses up to 22 mg/kg remained below the maximum score obtained with 8-OH-DPAT (0.46 mg/kg). Blockade of the 5-HT1A receptors with pindolol (10 mg/kg) caused a strong reduction of the lower lip retraction induced both with mirtazapine and 8-OH-DPAT. In the cross-familiarization conditioned taste aversion experiments it was found that the conditioned taste aversion induced by mirtazapine (0.32 mg/kg) could be prevented if the mice were pre-exposed to injections with mirtazapine (0.22 and 0.46 mg/kg), 8-OH-DPAT (0.22 and 0.46 mg/kg) and after pre-exposure to the 5-HT reuptake inhibitor fluoxetine (22 mg/kg). No familiarization for the mirtazapine stimulus was obtained by pre-exposure to (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI) (0.46-4.6 mg/kg) and MK212 (2.2-22 mg/kg), being agonists for the 5-HT2A and 5-HT2C receptors, respectively. With the reversed sequence, the conditioned taste aversion induced by 8-OH-DPAT (0.22 mg/kg), DOI (1.0 mg/kg) and fluoxetine could be prevented only partially by pre-exposure to mirtazapine in a dose of 1 mg/kg. The conditioned taste aversion induced by MK 212 (4.6 mg/kg) was not affected by pre-exposure to mirtazapine (0.1-1.0 mg/kg). On the basis of these results, it can be concluded that mirtazapine has indirect 5-HT1A receptor agonistic properties which may play an important role in the therapeutic effect of this compound.     

Increased resting and exercise-induced oxidative stress in young IDDM men

The effects of local application of the 5-HT3 receptor agonist, 1-(m-chlorophenyl)-biguanide (CPBG), and i.p. administration of ethanol on the extracellular levels of dopamine (DA) in the ventral tegmental area (VTA) were studied using in vivo microdialysis. Adult female Wistar rats were implanted with microdialysis probes in the VTA at least 24 h before each experiment. Stable extracellular levels of DA (101 +/- 9 fmol/20 min) were established before initiating the experiments. Application of 10-250 microM CPBG through the microdialysis probe dose-dependently enhanced the extracellular concentrations of DA but did not alter the levels of either 3,4-dihydroxyphenylacetic acid or homovanillic acid in the dialysate. The effects of CPBG were reversible and dependent upon Ca2+. Co-perfusion with the 5-HT3 receptor antagonist, 3-tropanyl-indole-3-carboxylate (ICS 205-930), inhibited the effects of CPBG on enhancing extracellular DA levels. The i.p. administration of 2 g/kg ethanol significantly (p < 0.005) enhanced the levels of DA to 150% of baseline values; this ethanol-induced increase was prevented by local perfusion with 100 microM ICS 205-930. These results suggest that 5-HT3 receptors in the VTA are involved in regulating the somatodendritic release of DA and in mediating the stimulatory effects of ethanol on this neuronal system.     

Anxiolytic-like actions of BW 723C86 in the rat Vogel conflict test are 5-HT2B receptor mediated

The 5-HT2B receptor agonist, BW 723C86 (10, 30(mg/kg i.p. 30 min pre-test), increased the number of punishments accepted in a rat Vogel drinking conflict paradigm over 3 min, as did the benzodiazepine anxiolytics, chlordiazepoxide (2.5-10 mg/kg p.o. 1 h pre-test) and alprazolam (0.2-5 mg/kg p.o. 1 h pre-test), but not the 5-HT2C/2B receptor agonist, m-chlorophenylpiperazine (mCPP, 0.3-3 mg/kg i.p) or the 5-HT1A receptor agonist, buspirone (5-20 mg/kg p.o. 1 h pre-test). The effect of BW 723C86 was unlikely to be secondary to enhanced thirst, as BW 723C86 did not increase the time that rats with free access to water spent drinking, nor did it reduce sensitivity to shock in the apparatus. The anti-punishment effect of BW 723C86 was opposed by prior treatment with the 5-HT2/2B receptor antagonist, SB-206553 (10 and 20 mg/kg p.o. 1 h pre-test), and the selective 5-HT2B receptor antagonist, SB-215505 (1 and 3 mg/kg p.o. 1 h pre-test), but not by the selective 5-HT2C receptor antagonist, SB-242084 (5 mg/kg p.o.), or the 5-HT1A receptor antagonist, WAY 100635 (0.1 or 0.3 mg/kg s.c. 30 min pre-test). Thus, the anti-punishment action of BW 723C86 is likely to be 5-HT2B receptor mediated. This is consistent with previous reports that BW 723C86 exhibited anxiolytic-like properties in both the social interaction and Geller-Seifter conflict tests.     

5-HT2A/2C receptor agonists potentiate the discriminative cue of (+)-amphetamine in the rat

The possible effect of 5-HT2A/2C receptor agonists on an amphetamine-induced behavioral response was examined using the two-lever drug discrimination paradigm. The experiments were designed to investigate an interaction of the hallucinogenic 5-HT2A/2C agonists lysergic acid diethylamide (LSD) and 2,5-dimethoxy-4-iodoamphetamine (DOI), with the discriminative stimulus elicited by a relatively low dose of (+)-amphetamine (1.35 micromol/kg, 0.25 mg/kg, which produced approximately 50% selection of the drug lever). DOI and LSD did not produce amphetamine-like responding at any dose tested or time of administration. However, LSD alone was able to induce a drug-appropriate response in two of nine amphetamine-trained rats. Simultaneous administration of DOI or LSD with amphetamine was not significantly different from the response produced by amphetamine alone. Pre-administration of DOI (3 hr) or of LSD (2 hr) before amphetamine, however, evoked significant enhancement of the amphetamine cue. The results suggest that the enhanced behavioral response to amphetamine may be due either to an increased sensitivity of dopaminergic neurons in the mesolimbic area, or to an enhanced release of dopamine by amphetamine.