Behavioral depression and its neurochemical correlates at high doses of d-amphetamine in rats

D-Amphetamine at low doses (0.5–1.0 mg/kg; base i.p.) increased spontaneous motor activity (SMA) and induced stereotypy (ST) in rats with the peak effects occurring during the 2nd hr. Dopamine (DA) levels in the caudate nucleus (CN) and diencephalon-midbrain (DM) as well as the noreptnephrtne (NE) level in the DM were markedly elevated at 60 min postdrug. However, at high doses (2 mg/kg or more) the peak effect on SMA occurred during the 1st hr and was decreased, whereas ST was further enhanced; neurochemically, DA level in the DM and serotonin (5-HT) level in the pons-medulla (PM) showed most marked elevation. Decrease in SMA at high doses appears to be partly due to DA-related increase in ST and partly due to an enhanced inhibitory 5-HT mechanism.     

Behavioral and neurochemical effects of repeated administration of delta 9-tetrahydrocannabinol in rats

The effects of repeated administrations of Δ⁹-tetrahydrocannabinol (THC, 10 mg/kg i.p. twice daily at 8-hr interval) were investigated on spontaneous motor activity (SMA) in 2.5 hr daily sessions and on the levels of various neurotransmitters (e.g. norepinephrine, NE; dopamine, DA; serotonin, 5-HT) in different brain areas such as caudate nucleus (CN), pons-medulla (PM) and diencephalon-midbrain (DM) in rats. After a single dose of the drug, the SMA of rats decreased during the first hour postdrug along with a decrease of DA levels in the CN and DM and NE levels in the DM and PM, and increase of 5-HT levels in the DM and PM. Following repeated daily administration, the SMA gradually decreased during the first hour postdrug to a minimum on day 5, and then increased beyond the normal level on day 8 reaching its peak on day 10. The SMA then decreased again and remained close to the normal level on day 15 onwards. Concomitantly, DA and NE levels decreased to their minimum, and 5-HT levels increased to their maximum in the respective brain areas on day 5; the levels of neurotransmitters then gradually approached their normal up to day 15. Thus, during the first hour after repeated administration of THC, the changes in behavioral depression can be correlated to the changes in the brain neurotransmitter levels. During the second hour of THC action, SMA was enhanced. On its repeated administration, this increase was gradually reduced up to day 6 after which SMA was again increased to its peak between day 8 and day 10 and then decreased. These behavioral changes could also be correlated with the changes in DA and 5-HT levels in the brain areas during the second hour postdrug after repeated administration.     

Behavioural and neurochemical effects of repeated administration of cocaine in rats.

The effects of repeated administration of cocaine (15 mg/kg, i.p. twice daily at 8-hr intervals) were investigated on the spontaneous motor activity (SMA) and stereotypy (ST) as well as on the various neurotransmitters (e.g. norepinephrine, NE; dopamine, DA; serotonin, 5-HT; acetylcholine, ACh) in different brain areas (e.g. diencephalon-midbrain, DM; pons-medulla, PM; caudate nucleus, CN) in rats.Following repeated injections of cocaine, both SMA and ST gradually increased, reaching a peak in each case on about the 9th day, then gradually decreased up to the 18th or 20th day, after which the activities were maintained at minimum level which was slightly higher than normal levels. Concomitantly, the DA level in the CN and DM increased and 5-HT in the DM and PM decreased reaching their maximum or minimum levels following cocaine injections on the 9th day; these changes were gradually minimized by the 18th day and remained so up to the 30th day. There were also slight changes in NE and ACh levels. It thus appears that, following repeated cocaine administrations, the changes in the drug-induced behavioural effects can be correlated roughly with the changes in the DA level in the CN and the 5-HT levels in the DM and PM.     

Effects of L-dopa on self-stimulation and brain biogenic amines in rats

Effects of various doses of L-DOPA were tested on self-stimulation behaviour in rats with electrodes implanted in the posterior hypothalamus (PH) or area ventralis tegmentum (A10 area) as well as on the concentration of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) in the caudate nucleus (CN), diencephalon-midbrain (DM) and pons-medulla (PM). L-DOPA (50, 100 and 150 mg/kg. i.p.) showed a biphasic action on self-stimulation responding with an initial decrease for 40–60 min, followed by an increase for about an hour or more in rats with both PH and A10 electrodes. Both effects were more marked in rats with A10 electrodes. The effects of these doses on spontaneous motor activity were not significant. L-DOPA markedly increased DA levels in the CN and DM, and moderately decreased 5-HT, without significantly altering NE levels in the DM and PM. It appears that L-DOPA-induced changes in self-stimulation responding cannot be correlated with the increase of DA levels in the CN and DM. It is possible that this behaviour involves a system of several neurotransmitters, including biogenic amines and acetylcholine, and a sudden increase of one, such as DA, causes an imbalance in the multitransmitter system and disrupts the behaviour.     

Cocaine and regional brain monoamines in mice.

Cocaine HCl (0, 10, or 50 mg/kg) was injected into adult male ICR mice IP. Thirty minutes later, brains were removed and nine regions were isolated: olfactory bulbs (OB), olfactory tubercles (OT), prefrontal cortex (PC), septum (SP), striatum (ST), amygdala (AMY), hypothalamus (HT), hippocampus (HC), and thalamus (TH). Using high-performance liquid chromatography, concentrations of norepinephrine (NE), dopamine (DA), serotonin (5-HT), and their major metabolites were determined. At 10 mg/kg cocaine, NE levels were increased in the AMY and its metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), was decreased in the PC, AMY, and HT. DA levels were also increased in the AMY, while its intracellular metabolite, dihydroxyphenylacetic acid (DOPAC), was decreased in the ST and its extracellular metabolite, homovanillic acid (HVA), was decreased in the PC. 3-Methoxytyramine (3-MT) levels were not altered in any tissue. 5-HT levels were increased in the AMY, HT, and TH, while its metabolite 5-hydroxyindoleacetic acid (5-HIAA) was decreased in the OB and ST. MHPG/NE ratios were decreased in the PC, AMY, and HT as were those for HVA/DA. DOPAC/DA ratios were decreased in the ST and AMY and increased in the SP while those for 3-MT/DA were decreased in the TH and increased in the PC. 5-HIAA/5-HT ratios were decreased in the AMY, HC and TH. At 50 mg/kg cocaine, there was an increase in DA in the TH. There was a decrease in DOPAC, HVA, and 3-MT, as well as the DOPAC/DA ratio in the ST. In the OT, there was a decrease in DOPAC, the DOPAC/DA ratio, 3-MT, and the 3-MT/DA ratio.(ABSTRACT TRUNCATED AT 250 WORDS)     

Interaction of self-stimulation and ethanol-intake behaviors in rats.

The effect of ethanol (10% v/v) intake was studied on the rate of self-stimulation (SS) in rats implanted with bipolar electrodes in the posterior hypothalamus. The rats were divided into 3 groups: in Group A, 6 rats were trained to press a bar for SS, and allowed to drink water only; in Group B, 6 rats were trained also for SS, and in Group C, 5 rats were put on to rotarod performance and served as controls for the physical exercise incurred in SS schedule; rats of both Groups B and C were offered ethanol and water in free choice. At the termination of the experiment, the contents of norepinephrine (NE) and serotonin (5-HT) in diencephalon-midbrain (DM) and pons-medulla (PM), and dopamine (DA) contents in DM and caudate nucleus (CN) of these rats were estimated. While in Group A rats the SS rate decreased gradually, in Group B rats the SS rate increased significantly and their ethanol intake increased to approximately 60% of their total fluid intake (TFI). In Group C rats ethanol intake was low (about 30% of TFI), compared to Group B. Neurochemical studies in Group B and C showed increased NE and 5-HT contents in DM and PM and decreased DA contents in CN and DM, compared to controls. The interaction between the two reinforcing behaviors seems to be related to induced changes in the brain amines.     

Influence of formamidines on biogenic amine levels in rat brain and plasma

Biogenic amine levels in samples of whole brain and plasma following treatment of rats with chlordimeform (CDF), its two N-demethyl metabolites (DMC and DDC), p-chloroamphetamine (PCA), and harmaline were separated by high performance liquid chromatography equipped with fluorescence or electrochemical detection systems. At 1 hr following s.c. injection, CDF (200 mg/kg) caused a reduction in levels of norepinephrine (NE), 5-hydroxytryptamine (5-HT), and tyramine (TRM), an increase in dopamine (DA), and no change in levels of beta-phenethylamine (PEA) in samples of whole rat brain, whereas DMC (100 mg/kg) and DDC (25 mg/kg) effected reductions of brain levels of NE, 5-HT, TRM, and PEA with no change in DA. The effect of DMC (100 mg/kg) on NE and DA levels in brain was followed periodically for 24 hr. Following a significant decrease at 1 hr, NE levels increased to a maximum at 12 hr and remained higher than controls throughout the remainder of the 24 hr test period. DA levels increased during the initial 12 hr and remained significantly higher than controls for the remaining 12 hr. The influence of s.c. vs i.p. administration of DMC (100 mg/kg) on brain amine levels was examined. Intraperitoneal treatment generally resulted in lower amine levels in DMC and vehicle treated animals. Differences in treatment effects were similar for all amines except for 5-HT in which s.c. injection produced a slight reduction, while i.p. injection resulted in a two-fold increase.(ABSTRACT TRUNCATED AT 250 WORDS)     

Extracellular dopamine, norepinephrine, and serotonin in the ventral tegmental area and nucleus accumbens of freely moving rats during intracerebral dialysis following systemic administration of cocaine and other uptake blockers

Extracellular levels of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) were measured by microdialysis in conscious rats equipped with dual probes, one in the ventral tegmental area (VTA) and another one in the contralateral nucleus accumbens (NACC). Dialysate content of all amines in both regions was essentially abolished by local infusion of tetrodotoxin (1 μM) or Ca²⁺-free buffer. Injection of the selective DA uptake blocker GBR 12935 (15 mg/kg IP) increased DA, as well as NE and, to a lesser extent, 5-HT in the VTA; it increased DA more than 5-HT in the NACC. The selective NE uptake blocker desipramine (10 mg/kg IP) increased NE but also 5-HT in the VTA and NACC; the DA level was persistently enhanced in the VTA, whereas in the NACC it initially rose and then fell below baseline value. The selective 5-HT uptake blocker citalopram (15 mg/kg IP) was generally more effective in elevating dialysate level of 5-HT than that of other amines in both regions. Cocaine (20 mg/kg IP) was non-selective in enhancing all three amines in both regions. There is considerable crosstalk between monoamine systems occurring upon systemic administration of uptake blockers, and the VTA and NACC are notably different in the time course of the DA effect (long-lasting versus transient). Received: 25 February 1997 /Final version: 2 June 1997     

Influence of fluoxetine on the ability of bupropion to modulate extracellular dopamine and norepinephrine concentrations in three mesocorticolimbic areas of rats.

The finding that serotonin (5-HT) can modulate dopamine (DA) and norepinephrine (NE) release in the brain has led us to hypothesize that fluoxetine, a selective 5-HT reuptake inhibitor, may influence the ability of bupropion, a preferential DA and NE dual reuptake inhibitor, to modulate extracellular DA and NE concentrations in some brain areas. The present study was designed to evaluate this hypothesis by assessing the effects of fluoxetine on bupropion-induced changes in extracellular monoamine concentrations by means of in vivo microdialysis. Three mesocorticolimbic areas including hypothalamus (Ht), prefrontal cortex (Pfc) and nucleus accumbens (Acb) were selected based on their relevance to depression and antidepressant actions. In the Ht of untreated rats, bupropion dose-dependently (s.c.) increased extracellular DA and NE concentrations either in single injection study or in sequential injection study. Thus, 10 mg/kg of bupropion had no effect on the DA and NE concentrations, while 30 mg/kg of bupropion induced transient but significant increases (about 240% of the baselines), and 100 mg/kg of bupropion induced marked and persistent increases (over 600% of the baselines) in the DA and NE concentrations. In the rats pre-treated with fluoxetine (10 mg/kg, s.c., 90 min interval), the threshold dose of bupropion (10 mg/kg) significantly increased the DA and NE concentrations to more than 350% of the baselines, and 30 mg/kg of bupropion markedly increased the DA and NE concentrations to more than 570% of the baselines in the Ht. The fluoxetine pre-treatment also potentiated the DA increases induced by 10 mg/kg of bupropion in the Pfc (260% for bupropion alone vs 357% for the combination) and in the Acb (224% vs 645%). The bupropion-induced NE increases were potentiated by fluoxetine mainly in the Ht. Bupropion did not significantly affect the extracellular 5-HT concentrations in all the 3 brain areas tested. In summary, the present study demonstrated that bupropion can increase extracellular DA and NE concentrations in several mesocorticolimbic areas, which may have an impact on bupropion's antidepressant actions. Furthermore, fluoxetine can potentiate the bupropion-induced DA and NE increases, which may produce more effective and rapid antidepressant actions.     

Modification of norepinephrine and serotonin, but not dopamine, neuron firing by sustained bupropion treatment

RATIONALE: Bupropion is widely used in the treatment of depression and as an anti-craving medication for the cessation of tobacco smoking. Because it is a very weak inhibitor of norepinephrine (NE) and dopamine (DA) reuptake, its mechanisms of action remain to be elucidated. METHODS: Bupropion was administered subcutaneously via osmotic minipumps over 2 days to determine its effects on the spontaneous firing activity of NE, serotonin (5-HT), and DA neurons in the brain of anaesthetised male Sprague-Dawley rats. This treatment was used in order to obtain levels of the parent compound and its putatively active metabolites that would more adequately reflect the clinical condition than utilizing acute injections. RESULTS: When given by minipump for 2 days, bupropion produced a dose-dependent attenuation of the mean spontaneous firing NE neurons (7.5 mg/kg per day: 15%; 15 mg/kg per day: 61%; 30 mg/kg per day: 80%) which was reversed by the alpha 2-adrenoceptor antagonist idazoxan. At the highest regimen, the mean firing rate of 5-HT neurons was 100% higher than in control rats, but unaffected in NE-lesioned rats. In contrast, DA neurons in the ventral tegmental area displayed a normal firing rate during the latter bupropion treatment. CONCLUSIONS: Sustained bupropion administration decreased the firing rate of NE neurons due to an increased activation of their inhibitory somatodendritic alpha 2-adrenoceptors. This effect of the bupropion treatment would be attributable mainly to an enhancement of NE release and not to reuptake inhibition. This contention is based essentially on the observation that NE reuptake blockers leave unaltered the firing rate of 5-HT neurons, whereas bupropion enhanced it via a NE-dependent mechanism. The present study did not put into evidence any DA activity of bupropion at the level of the cell body of mesolimbic/cortical DA neurons at a regimen exerting profound alterations of the firing activity of NE and 5-HT neurons.     

Long-term effects of an Apocynum venetum extract on brain monoamine levels and beta-AR density in rats

The present study was designed to get further insight into the mode of antidepressant action of an extract prepared of the leaves of Apocynum venetum L. (AV). To evaluate biochemical changes, we used a high-performance liquid chromatography system to examine the effects of short-term (2 weeks) and long-term (8 weeks) administration of imipramine (15 mg/kg po) and an AV-extract (15, 60 and 250 mg/kg) on regional levels of serotonin (5-HT), norepinephrine (NE), dopamine (DA) and their metabolites in the rat hypothalamus, striatum and hippocampus. Pronounced changes in 5-HT, NE and DA levels were detected mainly after 8 weeks of daily imipramine treatment. Similar to imipramine, AV-extract reduced NE and DA concentrations after 8 weeks, whereas it failed to affect 5-HT levels. We speculate that the decrease in NE levels after chronic AV treatment might be based partly on the subsensitivity of presynaptic alpha(2)-receptors. In addition to the determination of central monoamine concentrations, quantitative radioligand receptor-binding studies were used to examine the effects of long-term administration of imipramine and AV-extract on beta-adrenergic binding in rat frontal cortex. [125I]CYP binding to beta-adrenergic receptors was found to be decreased after 8 weeks treatment with imipramine, whereas AV-extract had no effect on beta-receptor binding.     

Sulpiride in combination with fluvoxamine increases in vivo dopamine release selectively in rat prefrontal cortex.

Coadministration of atypical antipsychotics and selective serotonin reuptake inhibitors (SSRIs) enhances the release of monoamines such as dopamine (DA), norepinephrine (NE), and serotonin (5-HT) in the prefrontal cortex. To clarify the role of DA-D2/3 receptors in the combination effect, we examined the effects of coadministration of the selective DA-D2/3 antagonist sulpiride and the SSRI fluvoxamine on amine neurotransmitter release in rat prefrontal cortex. Sulpiride (10 mg/kg, i.p.) and fluvoxamine (10 mg/kg, i.p.) alone did not affect extracellular DA levels, while their coadministration caused a significant increase in DA levels. Sulpiride alone did not affect extracellular levels of 5-HT and NE in the prefrontal cortex, while fluvoxamine alone caused a marked increase in 5-HT levels and a slight increase in NE levels. Sulpiride did not affect the fluvoxamine-induced increases in extracellular levels of 5-HT and NE. The DA-D2/3 antagonist haloperidol (0.1 mg/kg) in combination with fluvoxamine also caused a selective increase in extracellular DA levels in the cortex. Coadministration of sulpiride and fluvoxamine did not affect extracellular DA levels in the striatum. Combination of systemic sulpiride and local fluvoxamine did not increase the DA levels, but that of systemic fluvoxamine with local sulpiride increased. The combination effect in increasing prefrontal DA levels was antagonized systemically, but not locally, by the 5-HT1A antagonist WAY100635 at a low dose. These findings suggest that the combination of prefrontal DA-D2/3 receptor blockade and 5-HT1A receptor activation in regions other than the cortex plays an important role in sulpiride and fluvoxamine-induced increase in prefrontal DA release.     

A TRH analog (DN-1417). Effects on the levels of monoamines and the metabolites in the various brain regions in rats

The effects of a TRH (thyrotropin-releasing hormone) analog, DN-1417 (gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-prolinamide citrate), on the levels of norepinephrine (NE), dopamine (DA), serotonin (5-HT) and the metabolites in the various brain regions of rats were determined by means of high performance liquid chromatography with electrochemical detection. DN-1417 (20 mg/kg, i.p.) produced marked decreases in the levels of NE, DA and 5-HT, especially in the nucleus accumbens, striatum and hypothalamus. The maximum effect was observed at 15 min after the administration. DA metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, increased significantly in the nucleus accumbens, striatum and hypothalamus, whereas 3-methoxy-4-hydroxyphenylglycol and 5-hydroxyindoleacetic acid remained unchanged. 3-Methoxytyramine increased significantly in the nucleus accumbens and striatum. Two week chronic administration of DN-1417 (20 mg/kg, i.p.) increased the levels of DA and NE in the nucleus accumbens and DA in the striatum. These results suggest that DN-1417 stimulates the turnover of the cerebral monoamines, especially the release of DA from the nucleus accumbens and striatum in the mesolimbic and nigro-striatal DAergic systems.     

Drug interactions with brain biogenic amines and the effects of amphetamine isomers on locomotor activity.

Administration of single IP doses of 1.0 or 4.0 mg/kg of d-amphetamine evoked an increase in mouse spontaneous motor activity (SMA); in contrast, 1.0 mg/kg of l-amphetamine had no significant effect, while 4.0 mg/kg caused a decreased SMA. Pretreatment with aMT or pargyline had little effect on the actions of the l-isomer, but reduced the magnitude and duration of the stimulatory effect of d-amphetamine. Pretreatment with p-chlorophenylalanine had little effect on the actions of d-amphetamine but completely abolished the depressant actions of the l-isomer. Reserpine pretreatment markedly reduced basal SMA levels; such pretreatment caused both d- and l-amphetamine to act as stimulants of SMA.     

Comparison of the effects of antidepressants on norepinephrine and serotonin concentrations in the rat frontal cortex: an in-vivo microdialysis study

The present study employed in-vivo microdialysis techniques in the freely moving rat to systematically compare the neurochemical effects of various antidepressant agents on extracellular concentrations of norepinephrine (NE) and serotonin (5-HT) in the frontal cortex. We found that acute administration of the tricyclic antidepressant, desipramine (3-30 mg/kg, s.c.) and the dual serotonin/norepinephrine reuptake inhibitor, venlafaxine (3-30 mg/kg, s.c.), produced dose-dependent and robust increases in cortical NE concentrations (498% and 403%, respectively). Conversely, acute injection of the selective serotonin reuptake inhibitors, fluoxetine (30 mg/kg, s.c.) and paroxetine (1-10 mg/kg, s.c.), did not alter forebrain NE concentrations. However, paroxetine did produce a significant increase in cortical NE concentrations (164%) when administered at 30 mg/kg. These changes in NE were not paralleled by 5-HT, which showed no increase following administration of desipramine, venlafaxine, paroxetine or fluoxetine. Combination treatment with the 5-HT1A receptor antagonist, WAY-100635 (0.3 mg/kg, s.c.), significantly enhanced extracellular 5-HT concentrations following venlafaxine (10 and 30 mg/kg), fluoxetine (30 mg/kg) and paroxetine (3-30 mg/kg). Alternatively, WAY-100635 produced no augmentation of the antidepressant-induced changes in extracellular NE. Collectively, these studies show that paroxetine, at low to intermediate doses, and fluoxetine are selective for 5-HT versus NE systems, whereas venlafaxine produces similar effects on both 5-HT and NE levels at the effective doses tested.     

Pharmacological studies with a GABA uptake inhibitor in rats with kindled seizures in the amygdala

The anticonvulsant effects of the inhibitor of the uptake of GABA, SKF 89976-A (N-[4,4-diphenyl-3-butenyl]-nipecotic acid), were investigated using the amygdala kindling seizure model in rats. The time course of activity of the racemic mixture, given orally, and the relative potencies of its d- and l-isomers, when given intraperitoneally, were tested. The drug SKF 89976-A was active, when given orally with anticonvulsant effects lasting 2-4 hr when given at 15 mg/kg, and 4-6 hr when given at 30 mg/kg. Peak inhibition of severity of seizures occurred at 1 hr after administration with an ED50 of 17.8 mg/kg. The d-isomer of SKF 89976-A was significantly more potent than the l-isomer and inhibited various parameters of kindled seizure activity in a dose-dependent manner. The l-isomer had significant effects on kindled seizures only at the largest dose (20 mg/kg). The ED50 of the d-isomer for inhibition of severity of seizures measured 0.5 hr after intraperitoneal injection, was 11.2 mg/kg and the antiseizure effects of the d-isomer lasted for 2-3 hr. Side effects of SKF 89976-A, such as sedation, abdominal muscle relaxation, rear limb splaying and ataxia, were seen at 30 mg/kg; there was a marked suppression of seizure activity with no side effects at smaller doses. The characterization of a biphasic kindled seizure allows for speculation regarding the role of GABAergic mechanisms in its pathogenesis and of the mechanism of action of SKF 89976-A.     

Tetrabenazine-induced depletion of brain monoamines: characterization and interaction with selected antidepressants

The peripheral administration of tetrabenazine (TBZ) induces rapid depletion of brain regional concentrations of norepinephrine (NE), dopamine (DA) and serotonin (5-HT). With respect to both dosage and time, striatal DA was most sensitive to the effects of TBZ while hypothalamic NE was least affected. Pretreatment with the monoamine oxidase (MAO)-inhibitor, clorgyline (1-6 mg/kg) dose-dependently prevented the reduction of all three monoamines for up to 60 min after TBZ (3 mg/kg). The TBZ-induced depletion of cortical NE was also significantly antagonized by desmethylimipramine (DMI) but was of shorter duration (up to 30 min after TBZ). DMI, however, did not influence the effect of TBZ on striatal DA or hypothalamic 5-HT. The protective effects of both clorgyline and DMI were also evident under the conditions of the behavioral TBZ test utilizing high doses of TBZ (20 mg/kg).     

d- and l-isomers of fenfluramine differ markedly in their interaction with brain serotonin and catecholamines in the rat

Various doses of fenfluramine isomers were compared for their ability to affect monoamine levels, metabolism and synthesis in the rat brain. d-Fenfluramine was more potent than l-fenfluramine in reducing serotonin (5-HT) and 5-hydroxy-indoleacetic acid (5-HIAA) at 4 h after their administration. After decarboxylase inhibition, a low dose of d-fenfluramine (2.5 mg/kg) reduced 5-HT synthesis, assessed as 5-hydroxytryptophan (5-HTP) accumulation, in the hypotalamus and lower brain-stem only, whereas a higher dose (5 mg/kg) reduced 5-HT synthesis in all brain regions examined except the striatum. A higher dose of l-fenfluramine (10 mg/kg) was required to reduce 5-HT synthesis. Metergoline, a 5-HT antagonist, did not modify the effects of fenfluramine isomers on 5-HT synthesis. One h after its administration l-fenfluramine 5-20 mg/kg significantly increased brain 3-methoxy-4-hydroxyphenylethylene glycol sulfate (MHPG-SO4), striatal homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) levels, while after 4 h only the highest dose raised HVA levels. No change of striatal HVA and DOPAC levels was seen 1 or 4 h after any dose of d-fenfluramine while the highest dose raised brain MHPG-SO4 levels. Neither l- nor d-fenfluramine changed striatal 3-methoxytyramine (3-MT) levels. The noradrenaline (NA) and dopamine (DA) levels were decreased 4 h after 10 and 20 mg/kg l-fenfluramine or 20 mg/kg d-fenfluramine. The results show that the d- and l-isomers of fenfluramine at relatively low doses have a specific action on brain 5-HT and catecholamines, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of formamidines on 5-hydroxytryptamine uptake and biogenic amine levels in rat platelets

Uptake of radioactive 5-hydroxytryptamine (5-HT) by platelets from rats treated intraperitoneally with the insecticide/acaricide chlordimeform (CDF) at 25 mg/kg was not significantly influenced at 1 h; however, uptake of this amine by platelets from rats treated with its N- monodemethyl metabolite (DMC) at the same dosage was significantly inhibited (37%). Two reversed phase high performance liquid chromatographic systems with electrochemical detection were developed with a capacity to separate 11 biogenic amines and related compounds. Only 5-HT, norepinephrine (NE), dopamine (DA), and 3,4-dihydroxyphenylacetic acid (DOPAC) were consistently detected in platelets and plasma samples. At 1 h and/or 24 h postinjection, CDF effected significant decreases in platelet levels of 5-HT, NE, and DA and plasma levels of 5-HT, whereas platelet and plasma levels of DOPAC were significantly increased. DMC effected significant decreases in both platelet and plasma levels of 5-HT. These in vivo studies confirmed previous in vitro experiments which demonstrated that formamidines inhibited uptake of 5-HT by platelets and released endogenous stores of amines from platelets.     

Some correlations between procaine-induced convulsions and monoamines in the spinal cord of rats

The relationships between the convulsions induced by the local anesthetic procaine and monoamines in the spinal cord were investigated in rats. The levels of dopamine (DA) and serotonin (5-HT) in the spinal cord were time-dependently increased after procaine (170 mg/kg, i.p.), which induced clonic convulsions, but the level of norepinephrine (NE) was unchanged. The rats that died during convulsions had a marked increase in DA. Phenobarbital (25 mg/kg, s.c.) produced both depletion of DA and elevation of 5-HT in the spinal cord and completely protected rats against convulsions. A 5-HT precursor, 5-hydroxytryptophan (5-HTP; 20-80 mg/kg, i.p.), suppressed the convulsions in a dose-dependent manner as shown by a decrease in the incidence and a prolongation of the latency, but a DA precursor, 3,4-dihydroxyphenylalanine (L-DOPA; 20-80 mg/kg, i.p.), markedly shortened the latency. Furthermore, the effect of L-DOPA on the convulsions was inhibited by the combination of 5-HTP. alpha-Methyl-p-tyrosine (20-80 mg/kg, i.p.) or DL-p-chlorophenylalanine (20-80 mg/kg, i.p.), an inhibitor of NE and DA or 5-HT biosynthesis, had a slight effect on the convulsions. These results suggest that procaine causes significant elevations of rat spinal DA and 5-HT in the convulsive process and suggest that dopaminergic and serotonergic neurons may be associated with procaine-induced convulsions.