Fluvoxamine,a selective serotonin reuptake inhibitor,suppresses tetrahydrobiopterin levels and dopamine as well as serotonin turnover in the mesoprefrontal system of mice

Rationale Tetrahydrobiopterin (BH₄) is a coenzyme of tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH), rate-limiting enzymes of monoamine biosynthesis. According to the monoamine hypothesis of depression, antidepressants will restore the function of the brain monoaminergic system, and BH₄ concentration.Objective To investigate the effects of fluvoxamine on BH₄ levels and dopamine (DA) and serotonin (5-HT) turnover in the mesoprefrontal system, incorporating two risk factors of depression, social isolation and acute environmental change.Methods Male ddY mice (6W) were divided into two housing groups, i.e. group-housing (eight animals per cage; 35 days), and isolation-housing (one per cage; 35 days), SC injected with fluvoxamine (20 or 40 mg/kg; days 29–35), and exposed to 20-min novelty stress (day 35). The levels of BH₄, DA, homovanilic acid (HVA), 5-HT, and 5-hydroxyindoleacetic acid (5-HIAA) were measured in the prefrontal cortex and midbrain.Results Under the group-housing condition, novelty stress significantly increased BH₄ levels in both regions, and the HVA/DA ratio in the midbrain, whereas it did not change any parameters in either region under the isolation-housing condition. In the prefrontal cortex, fluvoxamine significantly decreased the 5-HIAA/5-HT ratio under the group-housing condition, and BH₄ levels and the HVA/DA ratio under the isolation-housing condition. In the midbrain, fluvoxamine significantly decreased all parameters, except for an increasing in the 5-HIAA/5-HT ratio under the isolation-housing condition.Conclusion Isolation-housing suppressed the increase of BH₄ levels and DA turnover elicited by novelty stress. Fluvoxamine suppressed BH₄ levels, and DA and 5-HT turnover. Fluvoxamine may have altered DA turnover by suppressing BH₄ levels.     

芬氟拉明合用电针对大鼠脑内中央灰质单胺类释放的影响

研究５－羟色胺释放剂芬氟拉明加强针刺镇痛前后大鼠脑内中央灰质腹侧部单胺类递质的变化 。方法;运用微透析及高效液相电化学检测方法。结果：电针后Ｎｏｒ的释放减少,而５－ＨＴ,５－ＨＩＡＡ和ＤＡ,ＨＶＡ在ＡＧ部位含量升高,当芬氟拉明合用电针时,５－ＨＴ,５－ＨＩＡＡ含量进一步升高,但Ｎｏｒ,ＤＡ及其代谢产物却无明显变化。结论：电针能促进ＤＡ和５－ＨＴ释放但抑制Ｎｏｒ释放。     

Increased dopaminergic and 5-hydroxytryptaminergic activities in male rat brain following long-term treatment with anabolic androgenic steroids

1. The effects of treating groups of rats with four different anabolic androgenic steroids (AAS) (testosterone, nandrolone, methandrostenolone, and oxymetholone) on 5-hydroxytryptamine (5-HT) and dopamine (DA) neurones in different brain regions were examined. The AAS was injected six times with 1 week's interval and the rats were sacrificed 2 days after the final injection. 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA), DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured. The effect on DA and 5-HT synthesis rate was analysed as the accumulation of 3,4-dihydroxyphenyl-alanine (DOPA) and 5-hydroxytryptophan (5-HTP), respectively, after inhibition of the amino acid decarboxylase with NSD-1015 (3-hydroxy-benzylhydrazine dihydrochloride). Additionally, the monoamine oxidase (MAO) activity was analysed in the hypothalamus. 2. The DOPAC + HVA/DA ratio was increased in the striatum in all treatment groups. However, the synthesis rate of DA was significantly increased only in the methandrostenolone treated group. 3. The 5-HIAA/5-HT ratio was increased in all treatment groups in the hippocampus, in the frontal cortex in the methandrostenolone-treated animals and in the hypothalamus in the testosterone- and oxymetholone-treated rats, while the 5-HT synthesis rate was not affected by the AAS-treatments. 4. The MAO-A activity was increased in the oxymetholone-treated rats while the other treatment groups were unaffected. The MAO-B activity was not changed. 5. The results indicate that relatively high doses of AAS increase dopaminergic and 5-hydroxytryptaminergic metabolism in male rat brain, probably due to enhanced turnover in these monaminergic systems.     

Alterations in the metabolism of serotonin and dopamine in the mouse brain following a single administration of allylnitrile, which induces long-term dyskinesia.

The effects of allylnitrile (ALN), which induces a long-term dyskinesia in mice, on the metabolism of serotonin (5-HT) and dopamine (DA) were studied after a single administration. One day after injection, ALN produced a significant increase in the levels of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA): 5-HT in the brain cortex, medulla oblongata plus pons, hypothalamus and midbrain; 5-HIAA in the cortex, medulla oblongata plus pons, striatum, hypothalamus and midbrain; the ratio of 5-HIAA/5-HT in the medulla oblongata plus pons, striatum and midbrain; HVA in the cortex and midbrain. These changes were not seen 10 and 35 days after injection when the animals were showing behavioral abnormalities. The present findings suggest that changes in 5-HT and DA metabolism are involved in the appearance of the dyskinetic syndrome.     

慢性不可预知应激诱导的抑郁大鼠血清中神经递质含量的动态变化

目的观察慢性不可预知应激(CUS)并配合孤养诱导模型大鼠抑郁样行为过程中神经递质水平的变化,探讨神经递质作为诊断抑郁症的客观、可量化标志物的可能性。方法 利用CUS并配合孤养模型建立抑郁大鼠动物模型,以体质量、糖水偏爱率和旷场实验(穿格数和直立次数等)结果评定大鼠行为学的动态变化;采用高效液相-荧光法(HPLC-FD)测定血清中5-羟色胺(5-HT)、去甲肾上腺素(NE)、肾上腺素(E)、多巴胺(DA)、左旋多巴(L-DOPA)、5-羟基吲哚乙酸(5-HIAA)、高香草酸(HVA)、3,4-二羟基苯乙酸(DOPAC)、酪氨酸(Tyr)和色氨酸(Trp)等10种神经递质的含量;应用SPSS软件对体质量、糖水偏爱率和旷场数据等行为结果进行主成分分析,并采用回归分析方法分析行为学与神经递质变化间的相关性。结果 ①与正常对照组相比,造模期间第14天,模型组直立次数显著降低(P<0.05);造模期间第22天,模型组体质量、糖水偏爱率、穿格数和直立次数均显著降低(P<0.05)。②与正常对照组相比,造模期间第6天,模型组Tyr和5-HIAA的含量显著降低(P<0.05);造模期间第9天,NE的含量显著降低(P<0.05);造模期间第22天,NE和5-HT的含量显著降低(P<0.05);造模期间第15和22天,NE,5-HIAA,HVA和5-HT的含量显著降低(P<0.05)。③NE,HVA和5-HT的变化趋势为降低的程度逐渐增大,与行为学结果变化趋势接近;而Tyr的变化趋势为先升后降,5-HIAA,L-DOPA,DA,DOPAC,Trp和E呈波动性变化。主成分分析结果显示,第一主成分可代表93.47%的信息,结果可靠;相关性分析结果表明,5-HT,NE和HVA与第一主成分的相关性好。结论 血清中神经递质在CUS诱导抑郁样行为过程中呈动态变化,其中NE,5-HT和HVA的变化可以在一定程度上反映大鼠的抑郁状态和程度,可作为诊断抑郁症的临床辅助指标。     

Endogenous nitric oxide decreases hippocampal levels of serotonin and dopamine in vivo

Nitric oxide (NO) modulates the levels of various neurotransmitters in the CNS. Here we determined whether the specific nitric oxide synthase (NOS) inhibitor 7-nitroindazole (7-NI), the non-selective inhibitor of guanylate cyclase (GC) and NOS, methylene blue (MB), the NO-precursor L-arginine (L-Arg), and the selective soluble GC inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) affect extracellular levels of serotonin (5-HT), dopamine (DA), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) in the rat ventral hippocampus by using microdialysis in freely moving animals. Local perfusion of 7-NI (1 mM) and MB (1 mM) significantly increased extracellular level of 5-HT, whereas DA was increased by 7-NI only. Systemic administration of 7-NI (50 mg kg(-1)) and MB (30 mg kg(-1)) increased the extracellular levels of 5-HT and DA. Extracellular levels of 5-HIAA was not influenced by local or systemic MB or 7-NI. In contrast, extracellular level of HVA was decreased by systemic MB and retrodialyzed MB, but was not influenced by 7-NI. Retrodialysis of L-Arg (2 mM) decreased the levels of 5-HT, DA, 5-HIAA and HVA in the hippocampus. Systemic administration of L-Arg (250 mg kg(-1)) decreased the level of 5-HT, but failed to influence DA, 5-HIAA and HVA. Local perfusion of ODQ (400 microM) did not affect 5-HT overflow in the hippocampus. We conclude that NOS inhibitors increased extracellular levels of 5-HT and DA in the rat ventral hippocampus after local or systemic administration, whereas the NO precursor L-Arg had the opposite effect. Thus, endogenous NO may exert a negative control over the levels of 5-HT and DA in the hippocampus. However, this effect is probably not mediated by cyclic GMP.     

Effect of oral administration of zanapezil (TAK-147) for 21 days on acetylcholine and monoamines levels in the ventral hippocampus of freely moving rats

Zanapezil (TAK-147 (3-[1benzylpiperdin-4-yl]-1-(2,3,4,5-tetrahydro-1 H-1-benzazepin-8-yl) propan-1-one fumarate)) is a selective acetylcholine (ACh) esterase inhibitor under investigation as a drug for Alzheimer's disease (AD) treatment. In this study, the effects of TAK-147 at 2 mg kg(-1) p.o. for 21 days, compared to donepezil (E2020), on the levels of ACh, catecolamines and indoleamines were investigated in the ventral hippocampus (VH) of freely moving rats by microdialysis-high-performance liquid chromatography. The results revealed that the VH contains 92.05+/-21.97 fmol 20 microl(-1) ACh and the following monoamines levels (pg 30 microl(-1)), norepinephrine (NE) 1.92+/-0.39, epinephrine (Epi) 1.91+/-0.183, 3-methoxy-4-hydroxyphenylglycol (MHPG) 11.53+/-3.22, normetanephrine 3.26+/-0.61, dopamine (DA) 0.77+/-0.23, 3,4-dihydroxyphenylacetic acid (DOPAC) 3.37+/-1.01, homovanillic acid (4-hydroxy-3-methoxyphenylacetic acid; HVA) 4.04+/-0.93, 3-methoxytyramine 0.64+/-0.13, serotonin (5-HT) 0.73+/-0.16 and 5-hydroxyindoleacetic acid (5-HIAA) 313.15+/-18.42. On the 21st day and prior to the last dose, TAK-147 increased ACh, Epi, DA and 5-HT, whereas E2020 increased MHPG, Epi and DA. Following the last dose, TAK-147 increased NE, whereas E2020 increased NE, ACh and 5-HT in addition to their effects prior to the last dose. TAK-147 decreased HVA : DA ratio, but only marginally decreased DOPAC : DA and 5-HIAA : 5-HT ratios. On the other hand, E2020 decreased ratios of HVA : DA, DOPAC : DA (prior to the last dose), and 5-HIAA : 5-HT (90-180 min after the last dose). Both drugs decreased MHPG : NE only at 180 min after the last dose. The results also showed that TAK-147 increased Epi : NE ratio prior to and for 120 min following the last dose, whereas E2020 increased the ratio only before the last dose. The present results show that TAK-147 at a subthreshold dose could differentially increase ACh and 5-HT, compared to MHPG increased by E2020. The last dose of each drug could extend their effects to other monoamines. The increase of the monoamines levels, in addition to that on the ACh, and decrease of their oxidation could be of value in the treatment of the AD, other dementic diseases and the cohort neurological disorders depending on the type of the monoamine underlying the disorder.     

Effects of pentylenetetrazol and trimethadione on feline brain monoamine metabolism

The effects of pentylenetetrazol on behavioral excitation and brain monoamine metabolism were compared by monitoring the EEG and assaying feline cerebrospinal fluid (CSF) for monoamine metabolites. After a non-convulsant dose of pentylenetetrazol, neither the concentrations of the 5-hydroxytryptamine (5-HT) metabolite, 5-hydroxyindoleacetic acid (5-HIAA), nor the dopamine(DA) metabolite, homovanillic acid (HVA), were altered in CSF if the rectal temperature of the cat was maintained. After a convulsant dose there was an increase in 5-HIAA and HVA levels. The norepinephrine (NE) metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), was also increased, but returned to control within 3 hr, while 5-HIAA and HVA levels were elevated for 24 hr. Trimethadione produced a transient decrease in HVA levels. When the convulsions, but not EEG excitation, are prevented by trimethadione pretreatment, brain monoamine metabolism is increased. Plasma tryptophan levels decreased after convulsant doses of pentylenetetrazol. Pentylenetetrazol was not detectable in plasma or CSF 24 hr after injection, while CSF 5-HIAA and HVA levels were still increased. These data show that pentylenetetrazol directly increases brain NE, DA and 5-HT metabolism while causing EEG excitatory changes, an effect which may precede convulsions.     

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)     

Pizotifen increases 5-HIAA urinary excretion in male healthy volunteers

Summary A single dose of 0.5 mg pizotifen or a placebo was administered to 10 healthy male volunteers in a double blind cross-over trial. 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in hourly urine samples were determined by liquid chromatography with amperometric detection. The 5-HIAA levels were strongly correlated with the HVA levels in control samples (r=0.95, p<0.001). Pizotifen produced a significant increase in the urinary 5-HIAA/HVA ratio over the 3 hours following absorption of the drug (+0.21, +0.18, +0.19, p<0.05). The increase demonstrates an interaction between pizotifen and 5-HT metabolism, which may be involved in its antimigraine effect.     

芬氟拉明合用电针对大鼠脑内中央灰质单胺类释放的影响

目的:研究5-羟色胺释放剂芬氟拉明加强针刺镇痛前后大鼠脑内中央灰质(PAG)腹侧部单胺类递质的变化。方法:运用微透析及高效液相电化学检测方法。结果:电针后Nor的释放减少,而5-HT,5-HIAA和DA,HVA在AG部位含量升高(P<0.05,vs NS组)。当芬氟拉明合用电针时,5-HT,5-HIAA含量进一步升高,但Nor,DA及其代谢产物却无明显变化(P<0.05 vs NS EA组)。结论:电针能促进DA和5-HT释放但抑制Nor释放。芬氟拉明合用电针能进一步加强5-HT的释放。芬氟拉明加强针刺镇痛可能与进一步激活5-羟色胺系统有关。     

Cerebrospinal fluid 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) following probenecid in unipolar depressives treated with amitriptyline

Lumbar cerebrospinal fluid 5-HIAA, HVA, and the ratio 5-HIAA/HVA were measured followed probenecid administration in eleven patints with unipolar depression before and during treatment with amitriptyline (AMI). Control values were obtained from a group of inmate volunteers. Prior to treatment CSF 5HIAA formation in the depressives was not different from controls. During treatment with AMI, CSF 5-HIAA formation decreased. One patient with psychotic symptoms prior to AMI and two patients who developed psychotic reactions on AMI showed relatively low CSF 5HIAA formation prior to antidepressant therapy. Compared to controls CSF HVA values were higher in the depressives prior to AMI therapy.     

Naloxone-precipitated changes in biogenic amines and their metabolites in various brain regions of butorphanol-dependent rats

Influence of a naloxone (an opioid receptor antagonist) challenge (5 mg/kg, IP) on levels of biogenic amines and their metabolites in various brain regions of rats infused continuously with butorphanol (a μ/δ/κ mixed opioid receptor agonist; 26 nmol/μl/h) or morphine (a μ-opioid receptor agonist; 26 nmol/μl/h) was investigated using highperformance liquid chromatography with electrochemical detection (HPLC-ED). Naloxone precipitated a withdrawal syndrome and decreased the levels of: dopamine (DA) in the cortex and striatum, 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum, homovanilic acid (HVA) in the striatum, limbic, midbrain, and pons/medulla regions in butorphanol-dependent rats. However, the levels of norepinephrine (NE), serotonin (5-hydroxytryptamine; 5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) in the regions studied were not affected by naloxone-precipitated withdrawal. In addition, naloxone increased the HVA/DA ratio in the cortex, while this ratio was reduced in the limbic, midbrain, and pons/medulla. The reduction of 5-HIAA/5-HT ratio was also detected in the limbic area. In the animals rendered dependent on morphine, the results obtained were similar to those of butorphanol-dependent rats except for changes of 5-HIAA levels in some brain regions. These results suggest that an alteration of dopaminergic neuron activity following a reduction of DA and its metabolites in specific brain regions (e.g., striatum, limbic, midbrain, and pons/medulla) play an important role in the expression of the opioid withdrawal syndrome.     

Ethanol and delta-sleep-inducing peptide: effects on brain monoamines.

The brain content of dopamine (DA) and its metabolites [dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)] were the same in rats with different immobilization times in forced swimming test, while the serotonin (5-HT) concentration was higher in high active (HA, immobilization < 2 min) than low active (LA, immobilization > 5 min) animals. Ethanol (2 g/kg, PO) tended to increase the DA level in the striatum and nucleus accumbens in LA rats and decrease the 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) concentration in HA rats. delta-Sleep-inducing peptide (DSIP) injection reduced the level of 5-HT in the medial prefrontal cortex (MFC) in both groups, did not affect the concentration of DA or DOPAC, but increased HVA in the striatum of HA rats. DSIP injected before ethanol administration augmented the ethanol effects on 5-HT in the MFC and attenuated the action of ethanol on 5-HIAA in the nucleus accumbens. A relationship between the different levels of voluntary alcohol consumption and sensitivity to stress among LA and HA rats and the differences in DA and 5-HT concentrations is suggested. The use of LA and HA rats in developing models for testing of stress-shielding compounds is also described.     

In vivo effects of some histamine H1-receptor antagonists on monoamine metabolism in the mouse brain

Summary The in vivo effects of four Hr-antagonists, diphenhydramine, chlorpheniramine, mepyramine, and promethazine, on the metabolism of noradrenaline (NA), dopamine (DA), and 5-hydroxytryptamine (5-HT) were investigated in the whole mouse brain. Diphenhydramine and chlorpheniramine had no significant effect on levels of NA, 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), DA, and 5-HT, but they significantly decreased levels of 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA). In particular chlorpheniramine markedly decreased 5-HIAA levels at doses as low as 1 mg/kg, i. p. Mepyramine significantly decreased 5-HIAA levels but not those of other substances. High doses of promethazine significantly decreased NA levels but markedly increased those of MHPG, DOPAC, HVA, 5-HT, and 5-HIAA. The DA reduction induced by -methyl-p-tyrosine (-MT) was significantly inhibited by diphenhydramine, chlorpheniramine, and promethazine, but the -MT-induced NA decrease was significantly enhanced by promethazine. The 5-HIAA accumulations induced by probenecid were significantly inhibited by chlorpheniramine and mepyramine. These results suggest: (1) Diphenhydramine and chlorpheniramine inhibit the turnover of both DA and 5-HT by blocking their neuronal uptake. (2) Promethazine and mepyramine inhibit DA and 5-HT turnover, respectively, as a result of the inhibition of the uptake mechanism. (3) Promethazine increases NA turnover by enhancing NA release. The discriminative effects of these drugs on the monoamine systems may be related to some differences in their CNS actions. Send offprint requests to K. Saeki at the above address     

Changes in endogenous monoamines in aged rats

1. It has been documented that ageing may alter endogenous neurotransmitters. However, these results are controversial. Thus, in the present study, cerebral cortex and plasma from male Wistar rats aged 8 weeks and 6, 12 or 24 months were used to investigate the changes in monoamines using electrochemical detection. 2. A marked decrease in L-dihydroxyphenylalanine (L-DOPA) was observed in aged rats. Like the decrease in dopamine (DA), levels of 5-hydroxytryptamine (5-HT) and 5-hydroxyindolacetic acid (5-HIAA), the major metabolite of 5-HT, in aged rats were decreased in the cerebral cortex and plasma. Plasma levels of noradrenaline and levels of adrenaline in the cerebral cortex were also decreased in aged rats. Moreover, levels of 3,4-dihydroxyphenylacetic acid (DOPAC), a metabolite of DA, in the cerebral cortex and plasma were reduced by ageing. The level of homovanillic acid (HVA) in all samples was markedly increased with ageing. 3. The ratio of DOPAC/DA and 5-HIAA/5-HT, being closely linked with the activity of monoamine oxidase, was increased in the cerebral cortex and plasma with ageing. The ratio of HVA/DOPAC, an index of the activity of catechol-O-methyltransferase, was also higher in the cerebral cortex and plasma of aged rats. 4. These data suggest that ageing may alter endogenous monoamines in both the brain and peripheral tissues.     

Effects of pentylenetetrazol-induced kindling of seizures on rat emotional behavior and brain monoaminergic systems

The influence of pentylenetetrazol (PTZ)-induced kindling of seizures on the rat emotional behavior, the brain monoamine turnover rate measured in vitro, and correlation between behavioral and biochemical parameters, were examined in rats. The repeated administration of PTZ (35 mg/kg, ip) evoked kindled seizures in rats (Stage 4 or 5 of clonic-tonic convulsions-maximum). PTZ kindling caused selective changes in the rat emotional behavior, present in some models of anxiety only (a decreased freezing time in the conditioned freezing test and a decreased spontaneous and aversively conditioned ultrasonic vocalization). Simultaneously, PTZ kindling decreased the concentration of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the prefrontal cortex, decreased the DA (HVA/DA ratio) turnover rate in the striatum, and inhibited the serotonin (5-HT) metabolism (5-HIAA/5-HT ratio) in the hippocampus and the prefrontal cortex. Correlations between dopamine (DA) or 5-HT regional metabolic rates in brain structures and animal behavior were either abolished or reversed in PTZ-kindled animals. It is concluded that both DA and 5-HT systems contribute to the emotional effects of PTZ-induced kindling of seizures. The hypothesis is put forward that PTZ kindling-induced inhibition of the serotonergic innervation may lead to the compensatory increase in 5-HT(1A) receptors in the dentate gyrus of the hippocampus, thus evoking the anxiolytic-like changes in animal behavior.     

Atypical antipsychotics and the relevance of glutamate and serotonin.

In the present study, including 66 schizophrenic patients and 73 healthy controls, the effect of atypical antipsychotic treatment over a period of 14 weeks on psychotic symptoms and plasma levels of glutamate and monoaminergic metabolites was investigated. Treatment induced a modest reduction of psychotic symptoms in 42% of the patients (response criterion: Brief Psychiatric Rating Scale [BPRS] decrease >/=40%). Poor response was associated with severity of psychopathology, age and duration of disease. Glutamate at baseline was significantly higher in patients as compared to controls (p<0.01). During treatment, a significant further increase of glutamate, not related to response, was observed. Glutamate levels correlated significantly with negative symptom scores at baseline and weeks 3, 6 and 14 (p<0.05). At baseline, serotonin (5-HT) in plasma and 5-HT in platelets were significantly lower in the poor responders as compared to controls (p<0.05) and increased significantly during treatment (p<0.05). In the responders, treatment coincided with a decrease of 5-HT parameters. No differences in plasma levels of HVA, 5-HIAA and their ratio were observed between controls and response groups. The results of this study suggest an effect of atypical antipsychotics on glutamatergic neurotransmission and an association between lower pretreatment peripheral 5-HT parameters and response.     

Alterations in the metabolism of serotonin and dopamine in the central nervous system of mice displaying a persistent dyskinesia due to crotononitrile or 2-pentenenitrile

The effect of crotononitrile (4.22 mmol/kg, CRN) or 2-pentenenitrile (2.00 mmol/kg, 2-PN), which exhibit long-term dyskinesia, was examined on the metabolism of serotonin (5-HT) and dopamine (DA) in five brain regions of mice 1, 5, 12 and 35 days after dosing with CRN or 2-PN or vehicle (0.1 ml/25 g). One day after injection, CRN increased the level of the following substances and the ratio of 5-hydroxyindoleacetic acid (5-HIAA)/5-HT: 5-HT in medulla oblongata plus pons (144% of control); 5-HIAA in cortex (162%), striatum (166%), medulla oblongata plus pons (212%), hypothalamus (146%) and midbrain (167%); 5-HIAA/5-HT in medulla oblongata plus pons (148%) and midbrain (133%). The changes caused by 2-PN were as follows: DA levels in cortex (176% of control, 35 days after dosing); HVA levels in striatum (136%, 1 day); 5-HT levels in hypothalamus (141%, 35 days); 5-HIAA levels in striatum (150%, 1 day), medulla oblongata plus pons (159%, 1 day) and midbrain (146%, 1 day); 5-HIAA/5-HT in striatum (153%, 1 day) and midbrain (134%, 1 day). The results suggest that changes in the 5-HT system are involved in the appearance of the dyskinetic syndrome which was seen in mice 1–2 days after dosing with CRN or 2-PN.     

Effects of nimodipine on biogenic amines in discrete brain areas.

Discrete brain sections were obtained from rats after once or repeatedly given intraperitoneal nimodipine at doses ranging from 2.5 to 40 mg/kg. The single or the last treatment was carried out at 2-8 h before killing. The biogenic amine and metabolite content of the tissue samples were determined by high-performance liquid chromatography with electrochemical detection. The nimodipine-induced effects, chiefly regarding the brainstem, the thalamus-midbrain and the striatum, consisted of both an increase in 5-hydroxyindoleacetic acid (5-HIAA) levels and a decrease in dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels. Since the 5-HIAA/5-hydroxytryptamine (5-HT) ratio was increased, whereas the DOPAC/dopamine (DA) and HVA/DA ratios were decreased, it was argued that nimodipine activated the serotonergic and inhibited the dopaminergic systems. The first effect was enhanced by fasting and, likewise, by drug administration repeated for 5 days, while the second was not affected by fasting, but disappeared after 5 days' treatment. The data obtained appeared to substantiate the usefulness of nimodipine to treat some disorders of the central nervous system.