A dual mechanism for the anticonvulsant action of aminooxyacetic acid

The intramuscular injection of aminooxyacetic acid (AOAA) into mice elevated the concentration of gamma-aminobutyric acid (GABA) in the brain, inhibited glutamic acid decarboxylase activity and delayed the onset of isonicotinic acid hydrazide induced seizures. Analyses of these results and of those obtained previously by the authors and other workers indicated that the anticonvulsant action of AOAA involved two mechanisms. One, involving GABA metabolism, was most effective 6 h after AOAA administration, and the other, not involving GABA, was maximally effective 1.5 h after AOAA injection and was completely absent after 6 h. Depending on the convulsant agent under study, the mechanism of the anticonvulsant action of AOAA was purely of the GABA type, purely of the non-GABA type or a combination of both types.     

Modified approach for the selective treatment of temporal lobe epilepsy: transsylvian-transcisternal mesial en bloc resection

1. Intracerebronventricular (i.c.v.) injection of gamma-mangostin (10-40 nmol/mouse), a major compound of the fruit hull of Garcinia mangostana Lin., like ketanserin (10, 20 nmol/mouse, i.c.v.) inhibited 5-fluoro-alpha-methyltryptamine (5-FMT) (45 mg kg(-1), i.p.)-induced head-twitch response in mice in the presence or absence of citalopram (a 5-hydroxytryptamine (5-HT)-uptake inhibitor). 2. Neither the 5-FMT- nor the 8-hydroxy-2-(di-n-propylamino)tetralin (5-HT1A-agonist)-induced 5-HT syndrome (head weaving and hindlimb abduction) was affected by gamma-mangostin or ketanserin. 3. The locomotor activity stimulated by 5-FMT through the activation of alpha1-adrenoceptors did not alter in the presence of gamma-mangostin. 4. 5-HT-induced inositol phosphates accumulation in mouse brain slices was abolished by ketanserin. Gamma-mangostin caused a concentration-dependent inhibition of the inositol phosphates accumulation. 5. Gamma-mangostin caused a concentration-dependent inhibition of the binding of [3H]-spiperone, a specific 5-HT2A receptor antagonist, to mouse brain membranes. 6. Kinetic analysis of the [3H]-spiperone binding revealed that gamma-mangostin increased the Kd value without affecting the Bmax value, indicating the mode of the competitive nature of the inhibition by gamma-mangostin. 7. These results suggest that gamma-mangostin inhibits 5-FMT-induced head-twitch response in mice by blocking 5-HT2A receptors not by blocking the release of 5-HT from the central neurone. Gamma-mangostin is a promising 5-HT2A receptor antagonist in the central nervous system.     

In vivo labelling of the mouse brain 5-hydroxytryptamine1A receptor with the novel selective antagonist 3H-NAD-299

The in vivo labelling of 5-hydroxytryptamine (5-HT)1A receptors in the mouse brain was studied with the novel selective 5-HT1A receptor antagonist, NAD-299 ((R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran- 5-carboxamide hydrogen (2R,3R)-tartrate monohydrate). 3H-NAD-299 was injected in a tail vein and the radioactivity in various brain regions was determined. More than 90% of the radioactivity in hippocampus, 15 min after the injection, was intact NAD-299. At this time the amount of 3H-NAD-299 was highest in hippocampus followed by frontal cortex, mesencephalon, hypothalamus, striatum and cerebellum. The specific accumulation of radioactivity (after subtracting cerebellum values) in frontal cortex and hippocampus was maximal 10 to 30 min after the injection and had almost disappeared after 2 h. Saturation kinetics derived Bmax (pmol/g wet weight tissue) values of 19.6+/-2.0 in frontal cortex and 38.0+/-3.5 in hippocampus. The apparent Kd values expressed in nmol/kg 3H-NAD-299 injected, were 12.3+/-2.2 in frontal cortex and 20.3+/-3.1 in hippocampus. The 5-HT1A receptor antagonist, WAY-100,635 competitively inhibited the specific accumulation of 3H-NAD-299 and was about equipotent with unlabelled NAD-299 with ED50 values of 20-30 nmol/kg s.c. These compounds were about 10 times more potent than the 5-HT1A receptor antagonists, p-MPPI and NDL-249 and 100 times more potent than (S)-UH-301. 5-HT1A receptor agonists, e.g. 8-OH-DPAT and flesinoxan and partial agonists, e.g. pindolol, buspirone and ipsapirone had low potency in this in vivo assay. Spiperone and methiothepin inhibited the 3H-NAD-299 accumulation at 10 micromol/kg s.c. The alpha1-adrenoceptor antagonist, prazosin at 2 micromol/kg s.c. increased significantly the specific accumulation of 3H-NAD-299. Pretreatment of the mice with the non-selective, irreversible receptor antagonist, EEDQ produced a dose related long-lasting decrease in the accumulation of 3H-NAD-299. It is concluded that NAD-299 is a very suitable ligand for studies of 5-HT1A receptors in the brain in vivo.     

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.     

Characterization of LY344864 as a pharmacological tool to study 5-HT1F receptors: binding affinities, brain penetration and activity in the neurogenic dural inflammation model of migraine

LY344864 is a selective receptor agonist with an affinity of 6 nM (Ki) at the recently cloned 5-HT1F receptor. It possesses little affinity for the 56 other serotonergic and non-serotonergic neuronal binding sites examined. When examined for its ability to inhibit forskolin-induced cyclic AMP accumulation in cells stably transfected with human 5-HT1F receptors, LY344864 was shown to be a full agonist producing an effect similar in magnitude to serotonin itself. After an intravenous dose of 1 mg/kg, rat plasma LY344864 levels declined with time whereas brain cortex levels remained relatively constant for the first 6 hours after injection. Oral and intravenous LY344864 administration potently inhibited dural protein extravasation caused by electrical stimulation of the trigeminal ganglion in rats. Taken together, these data demonstrate that LY344864 is a selective 5-HT1F receptor agonist that can be used to explore both the in vitro and in vivo functions of this receptor.     

5-Hydroxytryptamine induces forestomach hypomotility in sheep through 5-HT4 receptors

The effects evoked by 5-hydroxytryptamine (5-HT; serotonin) on forestomach myoelectric activity were investigated in conscious sheep. Myoelectric signals were recorded with electrodes chronically implanted in the reticulum, rumen (dorsal sac) and omasal body, and were analysed by a computer-based method. The 5-HT receptors and the neuronal pathways involved in these actions were studied. The intravenous (i.v.) infusion of 5-HT (8 micrograms kg-1 min-1 for 5 min) evoked an inhibition of activity of the whole forestomach. Methiothepin, injected i.v. at 0.1 mg kg-1, inhibited rumen secondary contractions and omasum activity. However, forestomach activity remained unchanged after the administration of 0.2 mg kg-1 of ketanserin, ondansetron, tropisetron, GR-113808, phentolamine, propranolol, domperidone and naloxone. Atropine (0.2 mg kg-1), hexamethonium (2 mg kg-1) or haloperidol (0.1 mg kg-1) abolished rumen secondary cycles and inhibited omasum activity. In addition, atropine also suppressed primary cycles. GR-113808 blocked all 5-HT-induced effects. Furthermore, atropine or hexamethonium prevented the 5-HT-evoked inhibition of reticulorumen primary cycles. In contrast, the remaining antagonists did not alter the 5-HT-evoked forestomach hypomotility. In conclusion, 5-HT induces inhibition of forestomach myoelectric activity through 5-HT4 receptors, these actions being mediated by cholinergic neural pathways involving muscarinic and nicotinic receptors. However, adrenergic, dopaminergic or opiate pathways are not implicated.     

Effect of chronic treatments with tandospirone and imipramine on serotonin-mediated behavioral responses and monoamine receptors

The effects of acute and chronic treatment of rats with the tricyclic antidepressant imipramine, the 5-HT1A receptor partial agonist tandospirone, or its metabolite 1-PP were compared on behavioral responses produced by the activation of 5-HT receptors and on brain monoamine receptors. The behaviors examined were the 5-HT behavioral syndrome elicited by the 5-HT1A receptor agonist 8-OH-DPAT and the head shake response produced by the 5-HT2 receptor agonist DOB. Drug treatments were administered either by subcutaneous infusion from implanted minipumps or by repeated injection and the effects of chronic drug treatment were assessed when the drug was present and absent at the time of testing. The infusion of tandospirone blocked elicitation of the 5-HT behavioral syndrome when tested after 1 or 14 days of drug treatment (drug present) and 24 hr after the drug was withdrawn (drug absent). When administered by injection, tandospirone blocked the production of the 5-HT syndrome 1 hr (drug present), but not 24 hr (drug absent), following either 1 day or 14 days of drug treatment. Chronic infusion of imipramine did not alter the 5-HT syndrome. Chronic, but not acute, injections of imipramine blocked the 5-HT syndrome when tested 1 hr but not 24 hr, after the final injection. Treatment with 1-PP did not alter the 5-HT syndrome. The head shake response was attenuated by acute and chronic injection of tandospirone either 1 or 24 hr after treatment, although chronic infusion of tandospirone did not alter this behavior. Head shaking was attenuated by the infusion and injection of imipramine after acute treatment, chronic treatment, or following drug withdrawal. Chronic injection of 1-PP also inhibited the head shake response 24 hr after injection, although 1-PP was ineffective at all other times and when given by infusion. The density of hippocampal 5-HT1A receptors was unaltered by the chronic drug treatments. 5-HT2 receptor density in frontal cortex was reduced by the chronic infusion of either tandospirone, imipramine, and 1-PP, but only by chronic injections of imipramine. The density of cortical beta-adrenergic receptors was reduced following chronic imipramine injections or infusion. The results suggest that both tandospirone and imipramine may regulate 5-HT-mediated responses and 5-HT2 receptor density, which may contribute to their efficacy as antidepressants, although their effects were dependent upon the method of administration and may involve different neuropharmacological mechanisms.     

FOS is induced by singing in distinct neuronal populations in a motor network

The acute and subacute effects of intracerebroventricularly (ICV) administered nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF) on locomotor activity were evaluated in awake adult rats. Immediately after ICV injection through an implanted cannula, locomotor activity was measured by a computerized system using infrared photocells, which allowed us to record locomotion, motility, and rearing simultaneously. A single dose of 5 microg mouse beta-NGF produced significant increases in horizontal ambulatory components of locomotor activity (locomotion and motility), but not vertical movement (rearing) 30-45 min after ICV administration. These increases lasted for at least 3-4 h. Systemic injection of 2.0 mg/kg mecamylamine, a central nicotinic receptor antagonist, inhibited the hyperactivity induced by NGF. Systemic injection of 0.5 mg/kg scopolamine, a muscarinic receptor antagonist, did not interfere with the NGF effects. Thus, while scopolamine induced marked increases in all three measures of behavior in both NGF and cytochrome-c-treated animals, locomotion and motility remained significantly higher in the NGF group. Immunohistochemistry demonstrated that NGF diffused readily from the ventricular space into brain parenchyma on the injected side and could be visualized 1 h after ICV injection. These results suggest that ICV administration of NGF increases locomotor activity by inducing acetylcholine release, and that nicotinic receptors are involved in the hyperactivity induced by NGF. ICV administration of 5 microg recombinant human BDNF had no significant effect on locomotor activity during the 0- to 4-h period after ICV injection. However, it produced significant decreases in locomotion, motility, and rearing 24-26 h later. Hence ICV administration of BDNF has entirely different effects on animal behavior from those evoked by NGF. While NGF elicits increases in ambulatory behavior within hours, BDNF causes delayed decreases in ambulatory behavior.     

Endothelin induces dopamine release from rat striatum via endothelin-B receptors

The aim of the present study was to determine whether local administration of endothelin induces the release of dopamine in the rat striatum and to characterize and localize endothelin receptors in this brain region. Local injection of endothelin-1 (10 pmol) into the ventral striatum of urethane-anaesthetized rats caused an increase of 8 microM in the extracellular concentration of dopamine as measured by in vivo chronoamperometry. The peak increase in dopamine concentration occurred within 5 min of endothelin injection. Injection of the selective endothelin-B receptor agonist [Ala1.3,11.15]endothelin-1 (10 pmol) also caused an increase in extracellular dopamine concentration, suggesting that endothelin is acting at the endothelin-B receptor to elicit its effect. In rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway, the response to local injection of endothelin-1 (10 pmol) was significantly inhibited on the lesioned side as compared to the non-lesioned side. In contrast, pretreatment of the rats with the N-methyl-D-aspartate receptor antagonist dizocilpine maleate (5 mg/kg, i.p.) or the nitric oxide synthase inhibitor NG-nitro-L-arginine (3 mg/kg, i.p.) did not alter the endothelin-induced release of dopamine. In binding studies, addition of endothelin-1 displaced [125I]endothelin-1 with a Ki of 220 pM. The endothelin-B receptor antagonist BQ788 displaced [125I]endothelin-1 with a Ki of 120 nM, whereas the endothelin-A receptor antagonist BQ123 produced only a 25% displacement at 10 microM, suggesting that endothelin receptors in the striatum are of the endothelin-B subtype. In rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal dopamine system, [125I]endothelin-1 binding was reduced by 53% in lesioned striatum compared to non-lesioned striatum, with no difference in the Kd. These data provide evidence that endothelin acts on a homogeneous population of endothelin-B receptors within the striatum to cause the release of dopamine and that a significant proportion of these receptors is located on dopaminergic neurons.     

Lack of efficacy of 5-HT2A receptor antagonists to reduce brain damage after 3 minutes of transient global cerebral ischaemia in gerbils

Stimulation of the 5-HT2A receptors by serotonin has been reported to exert an excitatory effect on neocortical neurons in rats and mice, to facilitate ischaemia-induced release of excitatory amino acids and to mediate the vasomotor constrictor component of the response of blood vessels to 5-HT. 5-HT2A receptor antagonists have, therefore, been proposed as potential protectants against the effects of cerebral ischaemia. The aim of this study was to evaluate the effects of two relatively selective 5-HT2A receptor antagonists, ketanserin and ritanserin, on delayed hyperactivity and the ensuing neuronal degeneration induced by 3 minutes of bilateral carotid artery ligation in Mongolian gerbils. Effects were compared to that of flunarizine, which blocks calcium overload and served as a positive control in this paradigm. Temporal and/or rectal temperatures were measured and strictly controlled during the ischaemia and the early reperfusion phase. Locomotor activity was measured one day after the ischaemia and neuronal degeneration quantified 7 days later using an image analysis system (Quantimet 570, Leica). Global ischaemia in gerbils elicits hyperactivity associated with a delayed neuronal degeneration predominantly in the CA1 zone of the hippocampus. Ketanserin and ritanserin (3 and 10 mg/kg ip, twice daily for 3 days, pre- and postischaemia) did not protect the CA1 neurons against ischaemic damage. The postischaemic hyperactivity was inhibited only with the higher dose of ketanserin. As previously reported, flunarizine (30 mg/kg po) markedly reduced neuronal degeneration (-44.2%, p < 0.01) and totally abolished the ischaemia-induced hyperactivity. These data demonstrate that ketanserin and ritanserin are not effective protectants of the gerbil hippocampus against ischaemic damage when the body temperature of the animals is controlled, thus suggesting that 5-HT2A receptors are not directly implicated in the pathogenesis of global cerebral ischaemia in this model.     

The power of support groups: influence on infant feeding trends in New Zealand

The effect of streptozotocin (STZ)-induced diabetes and a combination of chronic treatment with haloperidol (HPD) on dopamine (DA)D2, serotonin (5-HT) 5-HT1A and 5-HT2A receptors was investigated in rat brain. Rats were randomly assigned to one of four groups: vehicle-vehicle, STZ-vehicle, vehicle-HPD, and STZ-HPD groups. Four weeks after single administration of STZ (65 mg/kg IV) or vehicle (citrate buffer), rats received depot HPD (4 mg/kg IM) or vehicle (sesame oil) once a week for 4 weeks. Sixteen days after the last injection of HPD or vehicle, rats were sacrificed, and the density of binding sites was determined using [3H]spiperone as ligand in the striatum (D2),[3H]8-hydroxy-2-(di-n-propyl)-aminotetraline in the hippocampus (5-HT1A), and [3H]ketanserin in the frontal cortex (5-HT2A). The density of D2 receptors was significantly increased in the vehicle-HPD compared to vehicle-vehicle controls. However, striatal D2 receptor density of the STZ-HPD and the STZ-vehicle were not significantly different from the vehicle-vehicle group. A significant increase in cortical 5-HT2A receptor density was observed only in the group of STZ-vehicle. Treatment with STZ, HPD, or the combination thereof, did not affect the density of 5-HT1A receptors. The affinity constants for D2, 5-HT1A, and 5-HT2A receptors were not affected by any treatment. These results suggest that diabetic state may affect brain serotonergic activity via an increase in the density of 5-HT2A receptors. This may indicate an increased vulnerability to major depression in patients with diabetes. The lack of an effect of the combined chronic treatment with STZ and HPD on the D2 receptor density may correspond to the increased risk to develop tardive dyskinesia in patients with diabetes.     

Imaging 5-HT1A receptors with positron emission tomography: initial human studies with [11C]CPC-222

The novel radioligand [11C]CPC-222 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)-2-bicyclo [2,2,2]octane carboxamide) was evaluated as an in vivo probe of the 5-HT1A receptors using positron emission tomography (PET). Three human volunteers were imaged with PET over a 90 min period following intravenous injection of the radioligand. There was a high accumulation of the radioligand in brain regions with a high density of 5-HT1A receptors. The peak cortical concentration was 1.0-2.5% of the injected dose per litre. The ratio of radioactivity in receptor-rich regions to that of the cerebellum reached a plateau of 2.5-4.0 by 45 min after injection. Analysis of the plasma revealed no detectable amount of the potential metabolite, radiolabelled WAY-100634. This new radioligand has suitable properties to study the 5-HT1A receptors in man with PET.     

Estrogen effects on the hyperactivity induced by (+)-MDMA and cocaine in female rats.

This study compared the effects of estrogen (E) on the hyperactivity induced by (+)-3,4-methylenedioxymethamphetamine (MDMA) with E effects on cocaine-evoked hyperactivity in female rats. Sprague-Dawley rats were ovariectomized (OVX); half of them received a 17β-estradiol (E?) implant (OVX + E). Three weeks later, rats received saline, (+)-MDMA (1, 2, or 4 mg/kg) or cocaine (5, 10, or 20 mg/kg), and locomotor activity was monitored. OVX + E rats exhibited greater locomotor hyperactivity in response to both psychostimulants than did OVX rats. The enhanced response to cocaine appeared within 5 min following drug injection whereas the enhanced response to (+)-MDMA was delayed for approximately 30 min. The differential effects of E on hyperactivity may be due to the unique profiles of dopamine (DA) and serotonin (5-HT) in response to (+)-MDMA and cocaine. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

GR 127935 and (+)-WAY 100135 do not affect TFMPP-induced inhibition of 5-HT synthesis in the midbrain and hippocampus of Wistar-Kyoto rats

Wistar-Kyoto (WKY) rats display high emotivity (e.g. anxiety), compared to Wistar rats. The key role of serotonin (5-HT)1B/1D autoreceptors in 5-HT neurotransmission, and its consequences on emotivity, led us to measure the effects of the nonselective 5-HT1B/1D) receptor agonist m-trifluoromethyl-phenylpiperazine (TFMPP) on central tryptophan hydroxylase activity in male WKY and Wistar rats. In addition to strain-dependent differences in central 5-HT synthesis (WKY > Wistar), acute administration of TFMPP (1.5 and 3 mg/kg) decreased the amplitude of m-hydroxy-benzylhydrazine-elicited accumulation of hippocampal, striatal and cortical 5-hydroxytryptophan (5-HTP) in both strains. In midbrain, however, TFMPP decreased 5-HTP accumulation (but not tryptophan levels) in WKY rats only, whereas the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.2 mg/kg) decreased midbrain 5-HTP levels to a similar extent in both strains. Pretreatment of WKY rats with the selective 5-HT1B/1D receptor antagonist N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1, 2,4-oxadiozol-3-yl)-biphenyl-4-carboxamide (GR 127935, 1.5 and 3 mg/kg) slightly increased midbrain tryptophan hydroxylase activity but did not affect the negative effect of TFMPP on 5-HTP formation. Pretreatment with the 5-HT1A receptor antagonist (+)-N-tert-butyl-3-(4-[2-methoxyphenyl]piperazin-1-yl)-2-phenylpro panamide ((+)-WAY 100135; 3 mg/kg), which decreased the inhibitory effect of 8-OH-DPAT on midbrain 5-HTP levels by 50%, did not alter that of TFMPP. Lastly, neither reserpine (5 mg/kg), ketanserin (1 mg/kg) mianserin (2 mg/kg) nor idazoxan (1 mg/kg) pretreatments affected TFMPP-induced inhibition of midbrain 5-HTP formation, ruling out a role for monoamine release, 5-HT2 receptors and alpha2-adrenoceptors. Our data show that TFMPP, an agonist often used to stimulate 5-HT1B/1D receptors, may inhibit central 5-HT synthesis through nonserotonergic mechanisms.     

Deficits in D-fenfluramine-sensitive pool of brain 5-HT following withdrawal from chronic cocaine exposure

Recent head-twitch response (HTR) studies in mice have indicated that withdrawal from chronic cocaine exposure produces deficits in CNS conversion of L-tryptophan to 5-HT. In the present study, the ability of 5-HT releaser, d-fenfluramine, was utilized to induce the HTR in mice following abstinence from chronic cocaine exposure. d-Fenfluramine-induced HTR, is a 5-HT2A receptor-mediated phenomenon and its induction frequency can be regarded as an indirect but in vivo measure of basal brain 5-HT concentration. Thus, different groups of mice were injected with cocaine twice daily (0, 0.1, 0.5, 2.5, 5 or 10 mg/kg, i.p.) for either 7 or 13 days. At 24 h after last cocaine injection, the treated mice received d-fenfluramine (5 mg/kg, i.p.) and the induced HTR (mean+/-SEM) was recorded for the next 30 min. Cocaine attenuated the d-fenfluramine-induced HTR frequency by 30-37% in the 13-day regimen and significant effects were observed from 0.5 mg/kg dose. At 24 h withdrawal in the 7-day cocaine exposure group, the mean HTR frequencies were attenuated, however, they did not achieve statistical significance. Extended abstinence studies (i.e. 24, 48, 72 and 96 h postwithdrawal) from chronic cocaine exposure (0, 0.5 and 5 mg/kg/day for either 7 or 13 days) indicated that in the 7-day exposure group, significant reductions (26, 39 and 22%) in HTR frequency occurred at 48, 72 and 96 h following withdrawal from 0.5 mg/kg cocaine, whereas its 5 mg/kg dose failed to induce a significant effect. In the 13-day exposure group significant reductions in HTR frequency were observed at 24 h abstinence (27%) for the 0.5 mg/kg cocaine dose and at 24 and 48 h for the 5 mg/kg. Overall, these results indicate that abstinence from chronic exposure to cocaine produces enduring deficits in basal 5-HT concentration. Lastly, serotonergic function appears to be uniquely sensitive to chronic administration of low doses of cocaine.     

Myocardial bridging in a survivor of sudden cardiac near-death: role of intracoronary doppler flow measurements and angiography during dobutamine stress in the clinical evaluation

Studies were carried out using DBA/2 mice on the relationship between the behavioral effects of antagonists of different types of 5-HT receptors and the level of activity of alpha 2-adrenoceptors. The 5-HT1c receptor antagonists mianserin (2 mg/kg) and cyproheptadine (2 mg/kg) and the 5-HT2 receptor antagonist ketanserin (3 mg/kg) had no effect on movement activity, while the 5-HT3 and 5-HT4 receptor antagonists zacopride (1 mg/kg) and ICS 205-930 (1 mg/kg) reduced movement behavior in intact animals. On a background of treatment with the alpha 2-adrenoceptor blocker yohimbine (0.5 mg/kg), mianserin, cyproheptadine, and ketanserin inhibited movement activity and significantly reduced the sensitivity of animals to audiogenic convulsions. These data indicate that administration of alpha 2-adrenoceptor antagonists increases the efficiency with which serotonin receptors regulate behavior.     

Effect of chronic m-CPP on locomotion, hypophagia, plasma corticosterone and 5-HT2C receptor levels in the rat

1. The present study examined 5-HT2C receptor agonist-induced behavioural tolerance and 5-HT2C receptor down-regulation in adult rat brain. The effect of chronic subcutaneous infusion of the 5-HT2C receptor agonist, m-chlorophenylpiperazine (m-CPP, 10 mg kg(-1), day(-1)), for 14 days was examined on daily food intake, the ability of acute m-CPP (2.5 mg kg(-1), i.p.) to induce hypolocomotion in a novel arena and elevate plasma corticosterone levels and on ex vivo cortical [3H]-mesulergine binding and hippocampal 5-HT2C receptor protein levels. 2. Before chronic infusion, m-CPP (2.5 mg kg(-1), i.p.) attenuated the number of turns and rears made in a novel open field arena. In contrast, while m-CPP still elicited this hypolocomotion following 14 days, saline infusion, no such hypolocomotion occurred in rats given chronic m-CPP (10 mg kg(-1) day(-1)), indicating that almost complete tachyphylaxis of this behaviour occurred with chronic 5-HT2C receptor agonist injection. 3. During chronic infusion of m-CPP, rats consumed less food per day than saline-treated controls. Acute challenge with m-CPP following two weeks, treatment still attenuated food intake over the next four hours (by 43% and 30%, respectively from that on the previous day) in saline and m-CPP infusion groups, showing that only partial tolerance to 5-HT2C receptor agonist-induced hypophagia occurred. 4. In naive home cage rats, plasma corticosterone was elevated in a dose-dependent manner 35 min after m-CPP injection (0.5, 1 and 3 mg kg(-1), i.p.) but levels were comparable to control values 16 h after m-CPP (2, 5 and 10 mg kg(-1), i.p.). Sixteen hours after a single m-CPP injection (2.5 mg kg(-1), i.p.), plasma corticosterone levels were comparable in a group of rats which had received 14 days infusion of m-CPP or saline. However, following a similar acute m-CPP injection (2.5 mg kg(-1), i.p., - 16 h) in rats previously infused for 14 days with m-CPP, plasma corticosterone levels were lower than those in a separate group which received no chronic infusions (but only acute m-CPP injection), even though the plasma m-CPP levels were comparable in both groups. The data are consistent with the proposal that chronic m-CPP induced some down-regulation of hypothalamic 5-HT2C receptors which contribute, in a tonic manner, to plasma corticosterone secretion under the conditions investigated. 5. Chronic m-CPP infusion reduced the amount of [3H]-mesulergine binding (by 27%, without altering the KD) in membranes prepared from parietal/occipital/temporal cortex (under conditions to exclude binding to 5-HT2A receptors) and 5-HT2C receptor protein-like immunoreactive levels measured by radioimmunoassay in the hippocampus by 38%, confirming that 5-HT2C receptor down-regulation had occurred. 6. Even after 14 days m-CPP infusion only partial behavioural tolerance and 5-HT2C receptor down-regulation were observed, which may vary in different brain regions of the rat. Thus the hypophagia produced by m-CPP may involve activation of 5-HT2C receptors in the hypothalamus, where there is a greater receptor reserve or which are more resistant to agonist-induced down-regulation than 5-HT2C receptors in limbic areas (striatum and nucleus accumbens) mediating m-CPP-induced hypolocomotion.     

Effect of acetylsalicylic acid on formalin test and on serotonin system in the rat brain

1. Acetylsalicylic acid (ASA; 400 mg/kg, i.p.) increased serotonin (5-HT) content in rat brain but did not modify the number or the affinity of 5-HT1A receptors in the pons and the cerebral cortex, whereas the number of cortical 5-HT2 receptors decreased significantly. 2. Pretreatment with parachlorophenylaline (100 mg/kg/day for 4 days) depleted 5-HT brain content but modified neither the serum levels of salicylates nor the 5-HT2 cortical receptor characteristics, and it abolished the antinociceptive effect of ASA, 400 mg/kg, in the first phase of the formalin test. 3. These data support the involvement of the central serotonergic system in the antinociceptive activity of ASA.     

Acute effects of dietary fatty acids on the fatty acids of human milk

1. Effects on 5-HT function of sibutramine and its active metabolites, BTS 54 354 and BTS 54 505, were compared with fluoxetine, (+)-fenfluramine and (+)-amphetamine. 2. In vitro sibutramine weakly inhibited [3H]-5-HT uptake into brain synaptosomes. BTS 54 354, BTS 54 505 and fluoxetine were powerful [3H]-5-HT uptake inhibitors, whereas (+)-fenfluramine and (+)-amphetamine were very much weaker. Conversely, whilst sibutramine, its metabolites and fluoxetine did not release [3H]-5-HT from brain slices at < or = 10(-5)M, (+)-fenfluramine and (+)-amphetamine concentration-dependently increased [3H]-5-HT release. 3. Sibutramine and fluoxetine had no effect on 5-hydroxytryptophan (5-HTP) accumulation in either frontal cortex or hypothalamus at doses < 10 mg kg(-1). In contrast, (+)-amphetamine ( > or = 3 mg kg(-1)) reduced 5-HTP in hypothalamus, whilst (+)-fenfluramine (> or =1 mg kg(-1)) decreased 5-HTP in both regions. 4. Sibutramine (10 mg kg(-1) i.p.) and fluoxetine (10 mg kg(-1) i.p.) produced slow, prolonged increases of extracellular 5-HT in the anterior hypothalamus. In contrast, (+)-fenfluramine (3 mg kg(-1) i.p.) and (+)-amphetamine (4 mg kg(-1) i.p.) induced rapid, short-lasting increases in extracellular 5-HT. 5. Only (+)-fenfluramine (10 mg kg(-1)) altered 5-HT2A receptors in rat frontal cortex when given for 14 days, producing a 61% reduction in receptor number and a 18% decrease in radioligand affinity. 6. These results show that sibutramine powerfully enhances central 5-HT function via its secondary and primary amine metabolites; this effect, like that of fluoxetine, is almost certainly mediated through 5-HT uptake inhibition. By contrast, (+)-fenfluramine enhances 5-HT function predominantly by increasing 5-HT release. (+)-Amphetamine, though weaker than (+)-fenfluramine, also enhances 5-HT function by release.     

Decrease in gastric sensitivity to distension by 5-HT1A receptor agonists in rats

Using an in vivo model for evaluation of gastric sensitivity in awake rats, we aimed to determine whether 5-hydroxytryptamine 1A (5-HT1A) agonists modify pain threshold and gastric compliance specifically through 5-HT1A receptors. Isobaric gastric distensions were performed with a barostat using steps of 5 mm Hg in male rats equipped with a gastric balloon and electrodes implanted in the neck muscles. Gastric distension at 15 or 20 mm Hg induced a typical posture associated with contractions of the neck muscles. Rats received drugs 30 min before gastric distension. The 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), administered intraperitoneally (0.5 mg/kg) increased gastric pain threshold and gastric tone. These effects were reproduced when administered centrally (0.05 mg/kg) and blocked by intracerebroventricular administration of the 5-HT1A antagonist WAY 100635. Flesinoxan (4 mg/kg, intraperitoneally), another 5-HT1A agonist reproduced the effects of 8-OH-DPAT on pain threshold and gastric tone and the alpha2-receptor antagonist yohimbine did not modify the action of 8-OH-DPAT. Our results indicate that activation of 5-HT1A receptors at the level of the central nervous system increases gastric tone and decreases gastric sensitivity to distension.