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PubMed1992

Effects of N-ethyl,N-nitrosourea on monoamine concentrations and metabolizing enzymes in mouse brain regions.

N-ethyl,N-nitrosourea is a well known alkylating agent and produces central nervous system-specific tumors in several laboratory animal species. In the present study, young male CD-1 mice were treated by i.p. injections of 0, 2, 8, or 32 mg/kg body weight N-ethyl,N-nitrosourea, twice a week for 3 weeks. Endogenous levels of brain monoamine neurotransmitters and their selected metabolites; norepinephrine (NE), dopamine (DA), 5-hydroxytryptamine (5-HT), vanillylmandelic acid (VMA), dihydroxyphenyl acetic acid (dopac), homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and dihydroxyphenylalanine (dopa) were measured using HPLC with electrochemical detection. N-ethyl,N-nitrosourea treatment caused an increase of NE and 5-HT in the hypothalamus and striatum. Increased levels of 5-HIAA were noticed in the same brain regions. Elevated levels of NE were also observed in the cerebral cortex, medulla oblongata and the cerebellum. The major metabolite of NE, VMA, was decreased in several brain regions to non-detectable levels. Histopathological examination of brain tissue did not reveal any pathologic lesions. The increases in brain amines were associated with increased activity of tryptophan hydroxylase in the hypothalamus and corpus striatum. Dopa-decarboxylase was elevated in the cerebral cortex at a low dose of N-ethyl,N-nitrosourea only, whereas the monoamine oxidase activity was unaltered. Results indicated that N-ethyl,N-nitrosourea exposure may cause an elevation of steady state levels of various biogenic amines in brain areas and these changes to some extent are consistent with the altered activity of metabolizing enzymes.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2004

Dopamine overflow is increased in olfactory bulbectomized rats: an in vivo microdialysis study.

Olfactory bulbectomy (OBX) in rats produces behavioral, physiological, and neurochemical changes that resemble symptoms of depression in humans. The procedure thus serves as a rodent model of affective disorder. Many of the behavioral effects of OBX resemble psychomotor agitation. The possible role of dysregulation of ventral striatal dopamine (DA) systems in this phenomenon was investigated. Basal levels of DA, norepinephrine (NE), homovanillic acid, dihydroxyphenylacetic acid, and 5-hydroxyindoleacetic acid were examined in the striatum of OBX and sham-operated controls using in vivo microdialysis. OBX rats exhibited significantly higher basal DA levels (192%) and lower NE levels (12%) than sham-operated controls. Locomotor activity in response to novelty and footshock stress was elevated in OBX rats. The finding of higher DA levels in striatum may explain this "agitation-like" behavior, a commonly observed phenomenon in the OBX model.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1999

Microdialysis studies of basal levels and stimulus-evoked overflow of dopamine and metabolites in the striatum of young and aged Fischer 344 rats.

The technique of intracranial microdialysis was used to investigate the effects of aging on the striatal dopaminergic system of the anesthetized Fischer 344 rat. Microdialysis probes were implanted into the striatum of young (2-8 months) and aged (24-28 months) urethane anesthetized rats. Striatal dialysate levels were analyzed for dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and serotonin (5-HT) by high performance liquid chromatography with electrochemical detection. As compared to the young animals, basal extracellular levels of DA and DOPAC were significantly decreased in two groups of aged animals. Stimulation with excess potassium added through the microdialysis probe produced a robust overflow of DA in the young and aged rat striatum, but the evoked overflow of DA was not diminished in the aged rat striatum as compared to young animals. In contrast, d-amphetamine-evoked overflow of DA was again robust in young and aged animals, but was greatly decreased in the aged rat striatum as compared to the signals recorded in the young rats. Taken together with previous reports, these data support the hypothesis that a major change in the regulation of DA release that occurs in aging involves changes in the function of the neuronal uptake of DA, which may be a compensatory property of DA neurons in senescence.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2002

Mecamylamine decreases accumbal dopamine output in mice treated chronically with nicotine.

The role of nicotinic acetylcholine receptor (nAChR) activation in accumbal dopamine (DA) release during chronic continuous nicotine treatment was studied by in vivo microdialysis in freely-moving mice. Nicotine was administered chronically to NMRI mice in their drinking water. On the 50th day of nicotine administration microdialysis samples were collected at 20 min intervals and their DA, 3,4-dihydroxyphenylacetic acid, homovanillic acid and 5-hydroxyindoleacetic acid contents were measured using a high-performance liquid chromatographic-electrochemical procedure. After collection of four baseline samples the nicotinic antagonist mecamylamine (2 mg/kg, s.c.) was given. The steady-state DA output was larger in the nicotine-treated mice than in the control mice. Mecamylamine reduced the DA output in the nicotine-treated but not in the control mice. Thus, after continuous 50-day administration nicotine still continues to activate nAChRs regulating accumbal DA release.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2001

The differential effect of angiotensin II and angiotensin 1-7 on norepinephrine, epinephrine, and dopamine concentrations in rat hypothalamus: the involvement of angiotensin receptors.

Angiotensin 1-7 has been recently claimed the active member of the angiotensins' family. In the present study we compared the effect of angiotensin II and angiotensin 1-7 on the concentration of dopamine, serotonin, epinephrine, and norepinephrine and some of their metabolites in the rat hypothalamus, where the levels of angiotensins are particularly high. Intracerebroventricular injection of angiotensin II, but not angiotensin 1-7, time-dependently elevated the levels of both epinephrine (p < 0.05) and norepinephrine (p < 0.05) in the hypothalamus and both effects could be prevented by intracerebroventricular injection of either AT(1) (candesartan), AT(2) (PD123319) or AT(1-7) (A-779) receptor antagonist. Neither angiotensin II nor angiotensin 1-7 produced any changes in the level of dopamine, dihydroxyphenylacetic acid, homovanilic acid, serotonin, 5-hydroxyindoleacetic acid, or tryptophan at any time point in comparison with the control groups. However, AT(1) but not AT(2) receptor blockade, unmasked the stimulatory effect of angiotensin 1-7 on dopamine concentration in the hypothalamus. Thus, angiotensin II and its active metabolite angiotensin 1-7 regulate selectively, albeit differentially, adrenergic, noradrenergic and dopaminergic systems in the hypothalamus, the effects that involve AT(1), AT(2) and AT(1-7) angiotensin receptors.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1986

High-performance liquid chromatography of biogenic amines and metabolites in brain, cerebrospinal fluid, urine and plasma.

A method for high-performance liquid chromatographic separation and electrochemical detection of biogenic amines and metabolites in a variety of biological matrices is described. The method employs either homogenization, precipitation or dilution followed by direct injection of the samples and permits the chromatographic resolution of dopamine, norepinephrine, epinephrine, serotonin (5-HT), 3,4-dihydroxyphenylacetic acid (DOPAC), 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in brain; 3-methoxy-4-hydroxyphenylglycol, DOPAC, 5-HIAA and HVA in cerebrospinal fluid; 5-HIAA, HVA and 5-HT in plasma; and 5-HIAA and HVA in urine. Alterations in chromatographic conditions, voltammetry and in vivo pharmacological manipulations are employed to verify the identity of the putative neurotransmitter and metabolite peaks in the biological samples.

Animals↗

PubMed1999

Cerebrospinal fluid monoaminergic metabolites differ in wild anubis and hybrid (Anubis hamadryas) baboons: possible relationships to life history and behavior.

The article reports monoaminergic metabolite [homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG)], values from the cerebrospinal fluid (CSF) of 27 wild baboons (Papio hamadryas) aged 40 to 140 months. Animals were either anubis, or anubis with hamadryas admixture; males of the latter subspecies generally have a reduced tendency to disperse from their natal groups. Overall, the values and interrelationships among the CSF monoamine metabolites resembled data reported from closely related, captive-housed animals. For example, age was significantly correlated with HVA concentrations (r = -60, p < .05), but not with the other metabolites. Notably, males characterized by hamadryas admixture had significantly higher concentrations of HVA, 5-HIAA, and MHPG (p < .05, respectively), a result possibly driven by differences in serotonergic activity. These data provide initial evidence that variation in central monoaminergic activity, as indicated by CSF monoamine metabolite concentrations, may reflect differences in behavior and life history that have taxonomic and, perhaps, evolutionary significance.

Age Factors↗

PubMed1990

Anticonvulsant activity of di-n-propylacetate and brain monoamine metabolism in the rat.

1. Sodium di-n-propylacetate (DPA) treatment induced significant increases in brain contents of gamma-aminobutyric acid (GABA), 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA). Furthermore, the threshold for pentylenetetrazol (PTZ) clonic convulsions was also increased in response to DPA administration. 2. Pretreatment with inhibitors of monoamine synthesis alpha-methyl-p-tyrosine (AMPT) and p-chlorophenylalanine (PCPA) did not alter the anticonvulsant activity of DPA, but when given alone, both AMPT and PCPA caused significant decreases in brain monoamine contents and PTZ threshold seizures. 3. Experiments using probenecid suggest that the increases in 5-HIAA and HVA seen after DPA treatment could have resulted from inhibition of their active transport out of the brain. These data indicate that the anticonvulsant action of DPA is not dependent on changes in monoamine metabolism in the brain.

Animals↗

PubMed1985

Dopamine, serotonin, and acid metabolites in brain regions from the developing offspring of ethanol-treated rats.

Female rats were pair-fed control or ethanol liquid diets on a chronic basis prior to parturition. Six brain regions (hypothalamus, cerebellum, brain stem, cortex, corpus striatum, and hippocampus) were dissected from 19- and 35-day-old rat offspring for the determination of dopamine (DA), serotonin (5-HT), 3,4-dihydroxyphenylacetic acid (DOPAC), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA). DA, 5-HT, and the acid metabolites were separated simultaneously by reverse-phase HPLC and were quantitated using electrochemical detection. Between 19 and 35 days of age in control rats we observed an increase in the concentration of 5-HT and 5-HIAA in the corpus striatum and hippocampus and a decrease in these compounds in the cerebellum. In addition, there was a development-related decrease of 5-HIAA in the hypothalamus and an increase in the brain stem. During the same age period the concentration of dopamine increased in the hypothalamus and corpus striatum. There was also a development-related decrease in the concentration of DOPAC in the corpus striatum and an increase in the cortex as well as a decrease in HVA in the cerebellum and cortex. In comparison to age-matched control animals the 19- and 35-day-old offspring of ethanol-treated rats had a lower concentration of 5-HT and/or 5-HIAA in the cortex, cerebellum, and brainstem. In addition the 35-day-old offspring of ethanol-treated rats exhibited a decrease in DA and HVA in the cortex. The results of the present study suggest that in utero ethanol exposure affects both the serotonergic and dopaminergic systems in brain.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1988

In vivo dopaminergic activity from nucleus accumbens, substantia nigra and ventral tegmental area in the freely moving rat: basal neurochemical output and prolactin effect.

In this paper, by means of a push-pull perfusion technique, we have examined the local effect of ovine prolactin (oPRL) on the spontaneous in vivo dopaminergic (DAergic) activity of the nucleus accumbens (NAcc), substantia nigra (SN) and ventral tegmental area (VTA) of living male rats. First, we found a 2-fold spontaneous rise of 3,4-dihydroxyphenylacetic acid (DOPAC) output during the afternoon hours of the photoperiod only in the NAcc. In addition, native oPRL (10 ng/microliters for 20 min), but not boiled oPRL, perfused into the NAcc caused a significant elevation in DOPAC output without changes in homovanillic acid or 5-hydroxyindoleacetic acid. In a similar preparation, male rats bearing push-pull cannulae in the SN or VTA were infused locally with oPRL (10 or 50 ng/microliters) for 20 min. The hormone did not alter the efflux of DOPAC from these DA cell body/dendrite areas. These results indicate that oPRL can activate the mesolimbic DA system through local actions on DA presynaptic terminals of the NAcc without affecting the SN or VTA.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2005

Indirect biochemical evidence that reserpine methiodide produces selective depletion of peripheral biogenic amines in rats.

Reserpine, an alkaloid from Rauwolfia serpentina was widely used for its antihypertensive action in the past. In the present investigation, reserpine methiodide (RMI), a quaternary analogue of reserpine was synthesised and evaluated biochemically for its central and peripheral amine depleting actions in rats and compared with reserpine. The 24 h urinary excretion of vanillylmandelic acid (VMA), 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA), the respective metabolites of noradrenaline, serotonin and dopamine were estimated and considered as indirect biochemical indices for the amine depleting action of reserpine and RMI. The results indicate that RMI at doses of equal to and double the equimolar doses of reserpine was found to deplete the peripheral amines without affecting the central stores of the amines. The results further suggest that the quaternization of reserpine might restrict its transfer across the blood-brain barrier and could be the reason for its selective peripheral action.

Animals↗

PubMed1986

Effects of intraventricular methotrexate on cerebrospinal fluid monoamine metabolites in rhesus monkeys.

Previous work suggested that methotrexate (MTX) may cause encephalopathy by inhibiting biosynthetic pathways for dopamine and serotonin in the brain. We examined this issue by measuring the neurotransmitter metabolites homovanillic acid and 5-hydroxyindoleacetic acid in the lumbar CSF of rhesus monkeys receiving continuous intracerebroventricular infusions of MTX or dichloromethotrexate. Infusion of the lowest dose (0.05 mg/day) produced a large (300%) rise in homovanillic acid levels and a modest elevation in 5-hydroxy-indoleacetic acid. During higher dose infusion, which was associated with clinical encephalopathy, the biogenic amine metabolites fell from their previous elevated levels. In one encephalopathic monkey, an injection of 1 mg of leucovorin produced a marked elevation in CSF monoamine metabolites within 1 hour and rapid clinical recovery. In contrast, leucovorin produced no change in monoamine metabolites in control animals. The data suggest that MTX may block egress of monoamine metabolites from CSF at the lower doses and suppress neurotransmitter turnover at toxic doses which cause encephalopathy. Serial measurements of CSF monoamine metabolites deserve further investigation as biochemical markers for toxic effects of MTX on neuronal metabolism in the CNS.

Animals↗

PubMed1984

Discrete regional distribution of biochemical markers for the dopamine, noradrenaline, serotonin, GABA and acetylcholine systems in the monkey brain (Cebus Apella). Effects of stress.

Brains from Cebus Apella monkeys have been mapped biochemically using a cryo-section technique which enables exact micro-dissectioning of tissue. Two neurotransmitters; noradrenaline (NA) and gamma-amino-butyric acid (GABA) were measured by gas chromatography-masspectrometry technique. In addition biochemical markers reflecting metabolic activity in the dopamine (homovanillic acid, HVA, 3, 4-dihydroxyphenylacetic acid, DOPAC), serotonin (5-hydroxyindoleacetic acid, 5-HIAA), noradrenaline (4-hydroxy-3-methoxy-phenylglycol, HMPG), acetylcholine (choline acetyltransferase, CAT) and GABA (glutamic acid decarboxylase, GAD) transmitter systems were assayed. The distribution of these transmitter markers roughly corresponded to earlier studies in other non-human primates, whereas similar studies on the human brain generally show lower concentrations and enzyme activities. One monkey exposed to severe stress immediately before death deviated from the normal animals with regard to HVA, 5-HIAA, GAD and GABA. For the study of neuroleptic drugs, and notably their neurological side-effects, Cebus Apella monkeys have turned out to be particularly useful. In our laboratory we have employed this species of monkey to develop a model for acute dystonia and tardive dyskinesia (Gunne and Barany 1976, 1979, Barany et al. 1979). As a first step in the topological mapping of brain neuro-chemistry in these animals we here present data from normal monkeys, not treated with neuroleptics. During the ongoing project there was an unplanned "stress experiment" in one monkey, which had a nightly fight with a cage partner and had to be sacrificed the morning after due to severe wounds. The present communication describes a method for obtaining well-defined samples from monkey brains and presents the data on homovanillic acid (HVA), 3.4-dihydroxyphenylacetic acid (DOPAC), 5-hydroxyindoleacetic acid (5-HIAA), noradrenaline (NA), 4-hydroxy-3-methoxy-phenyl glycol (HMPG), choline acetyltransferase (ChAT), glutamic acid decarboxylase (GAD), and gamma-amino-butyric acid (GABA) in discrete regions from 7 drug-naive control monkeys. Also data from the stressed animal are presented.

Animals↗

PubMed1997

[Experimental study of methamphetamine psychosis--role of glutamate and nitric oxide in methamphetamine-induced dopaminergic and serotonergic neurotoxicity in the rat brain].

The present study examined effects of a high dose of methamphetamine (MA) (5mg/kg, s.c., x 4) on extracellular concentrations of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), 5-hydroxyindoleacetic acid (5-HIAA) and glutamate in rat striatum (ST) and nucleus accumbens (NA) using microdialysis. The toxic dose of MA markedly increased extracellular DA, and decreased DOPAC and 5-HIAA in both ST and NA. The increase in DA release was not different in magnitude between ST and NA. Extracellular glutamate showed a delayed increase in ST, but not in NA. Tissue contents of serotonin (5-HT) and 5-HIAA significantly decreased in both ST and NA, whereas those of DA, DOPAC and HVA decreased in ST but did not change in NA. These data suggest that the marked increase of DA release is not directly related to the MA-induced dopaminergic neurotoxicity. The increase in glutamate release found only in ST may be related to the dopaminergic damage in ST. However, enhancement in glutamate release did not appear to be essential for the serotonergic neurotoxicity. Nitric oxide (NO) has recently been recognized as a novel neuronal messenger. Taking into account the relationship between NMDA receptor activation and NO formation, the present study examined effects of a NO synthesis inhibitor, N omega-nitro-L-arginine methyl ester (LNAME) on MA-induced decreases in contents of the monoamines and their metabolites, in order to clarify whether the MA-induced dopaminergic and serotonergic neurotoxicity would be mediated by NO synthesis. Coadministration with LNAME (30 mg/kg, i.p., x2), reduced the MA-induced decreases in contents of DA, DOPAC and HVA in ST, but not reduced the MA-induced decreases in contents of 5-HT in ST and NA. These findings suggest that the MA-induced dopaminergic, but not serotonergic neurotoxicity, may be related to the neural process such as NO formation caused by the activation of postsynaptic DA receptor.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1979

Urinary neurotransmitter metabolites in drug-free chronic schizophrenic patients measured by gas chromatography selected positive ion monitoring.

The free urinary metabolites, homovanillic, indoleacetic and 5-hydroxyindoleacetic acid were measured in 24 h urines obtained from seven highly selected drug-free chronic schizophrenic patients and seven mentally normal control subjects on a low amine diet. Gas chromatography selected ion monitoring of silylated extracts was used to assay each metabolite using its own deuterated form as an internal standard. In the electron impact mode the positive ion fragments used to quantitate the amount of each metabolite in the urine were, respectively, m/z 209/211 for homovanillic acid, 319/321 for indoleacetic acid and 290/292 for 5-hydroxyindoleacetic acid. It was found essential that each compound be assayed using its own deuterated derivative as the internal standard. When expressed per mg creatinine, the homovanillic and 5-hydroxyindoleacetic acid levels of the chronic schizophrenic patients were in the normal range, but indoleacetic acid was slightly and statistically significantly higher, p = 0.01.

Acids↗

PubMed1994

Changes in cerebrospinal fluid neurochemistry during treatment of obsessive-compulsive disorder with clomipramine.

BACKGROUND: This study examined the effect of long-term (mean, 19 months) treatment with clomipramine hydrochloride on cerebrospinal fluid (CSF) levels of several neuropeptides and monoamine metabolites in children and adolescents with obsessive-compulsive disorder. METHODS: The CSF levels of corticotropin-releasing hormone, vasopressin, somatostatin, and oxytocin and of the monoamine metabolites 5-hydroxyindoleacetic acid, homovanillic acid, and 3-methoxy-4-hydroxyphenylglycol were measured in 17 children and adolescents with obsessive-compulsive disorder before and after long-term treatment with clomipramine. RESULTS: Treatment resulted in significant decreases in CSF levels of corticotropin-releasing hormone (mean +/- SD, 175 +/- 32 vs 152 +/- 25 pmol/L, P < .03) and vasopressin (mean +/- SD, 1.30 +/- 0.57 vs 0.86 +/- 0.54 pmol/L, P < .02) and a trend toward a decrease in somatostatin levels (mean +/- SD, 21.3 +/- 8.5 vs 15.3 +/- 9.8 pmol/L, P < .06). Treatment also significantly increased CSF oxytocin levels (mean +/- SD, 6.05 +/- 1.60 vs 6.70 +/- 1.44 pmol/L, P < .01). Significant changes in CSF monoamine metabolite levels with treatment included significant decreases in CSF levels of 5-hydroxyindoleacetic acid (mean +/- SD, 109 +/- 31 vs 77 +/- 23 pmol/mL, P < .001), CSF homovanillic acid (mean +/- SD, 273 +/- 111 vs 237 +/- 101 pmol/mL, P < .04), and 3-methoxy-4-hydroxyphenylglycol (mean +/- SD, 42.4 +/- 10.2 vs 36.1 +/- 4.8 pmol/L, P < .02) and a significant increase in the homovanillic acid-5-hydroxyindoleacetic acid ratio (mean +/- SD, 2.44 +/- 0.46 vs 3.42 +/- 0.84, P < .0001). CONCLUSIONS: These neuropeptide results coupled with evidence that central administration of corticotropin-releasing hormone, vasopressin, and somatostatin to laboratory animals increases arousal and acquisition of conditioned behaviors whereas central administration of oxytocin has opposite behavioral effects are consistent with a role for these neuropeptides in the pathophysiologic processes and pharmacologic treatment of obsessive-compulsive disorder.

Adolescent↗

PubMed1990

In vivo evidence that 5-hydroxytryptamine (5-HT) neuronal firing and release are not necessarily correlated with 5-HT metabolism.

The relationship between 5-hydroxytryptamine release, metabolism and unit activity has been investigated in the anaesthetized rat. 5-Hydroxytryptamine release and metabolism were monitored in vivo by the measurement of extracellular 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in the frontal cortex using in vivo voltammetry combined with nafion-coated and uncoated electrically pretreated carbon fibre electrodes. The monoamine oxidase inhibitor pargyline (100 mg/kg) increased extracellular 5-hydroxytryptamine and decreased 5-hydroxyindoleacetic acid. The 5-hydroxytryptamine releaser fenfluramine (10 mg/kg i.p.) acutely increased extracellular 5-hydroxytryptamine while having no effect on 5-hydroxyindoleacetic acid and the effect on extracellular 5-hydroxytryptamine was markedly reduced in rats pretreated (four weeks) with 5,7-dihydroxytryptamine. 8-Hydroxy-2-(di-n-propyl-amino) tetralin (10 micrograms/kg i.v.), an agonist at the 5-hydroxytryptamine1A somatodendritic autoreceptor, inhibited 5-hydroxytryptamine neuronal firing in the dorsal raphe nucleus and decreased extracellular 5-hydroxytryptamine during the period when firing was inhibited but did not alter extracellular 5-hydroxyindoleacetic acid. In contrast 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridin-4-yl) (RU 24969), which is an agonist at the terminal autoreceptor in the rat, had no effect on 5-hydroxytryptamine neuronal firing but decreased 5-hydroxytryptamine and 5-hydroxyindoleacetic acid. The results support the view that extracellular 5-hydroxyindoleacetic acid is not a good index of 5-hydroxytryptamine release and that under specific circumstances 5-hydroxytryptamine neuronal firing, release and metabolism are independent of one another.

Action Potentials↗

PubMed1999

Variations of nucleus accumbens dopamine and serotonin following systemic interleukin-1, interleukin-2 or interleukin-6 treatment.

The effects of systemically administered interleukin-1beta (1.0 microg), interleukin-6 (1.0 microg) and interleukin-2 (1.0 microg) on in vivo variations of monoamines were assessed in the nucleus accumbens. Administration of interleukin-1beta did not affect extracellular accumbal dopamine, provoked a modest rise of homovanillic acid, and prevented the decline of dihydroxyphenylacetic acid ordinarily seen in saline treated rats. Also, interleukin-1 provoked a modest increase of extracellular 5-hydroxyindoleacetic acid from the nucleus accumbens. Following exposure to the stress of a series of air-puffs, a still greater increase of accumbal 5-hydroxyindoleacetic acid was evident. In contrast to interleukin-1, systemic administration of interleukin-6 and interleukin-2 both induced marked reductions of interstitial dopamine levels. The air-puff exposure further enhanced these effects in rats that had received the cytokine treatment. As well, interleukin-6 and interleukin-2 were both found to reduce the homovanillic acid response associated with the stress, and interleukin-2 promoted a decline of homovanillic acid levels. Treatment with interleukin-6, like that of interleukin-1, prevented the decline of dihydroxyphenylacetic acid ordinarily observed over time, while interleukin-2 was without effect in this respect. Finally, interleukin-6 provoked a modest rise of 5-hydroxyindoleacetic acid, which was most apparent following air-puff exposure, while administration of interleukin-2 did not affect accumbal 5-hydroxyindoleacetic acid. It is suggested that the cytokines may influence the release of biogenic amines in the nucleus accumbens, but the profile of changes were cytokine-specific. As well, it appeared that the cytokines, particularly interleukin-1 and interleukin-6, may act synergistically with the stressor in promoting the amine variations. Systemic administration of cytokines clearly influenced monoamine activity at the nucleus accumbens, a region associated with both rewarding and aversive events. Thus, it may be expected that cytokine treatments may affect behavior. Moreover, it seems that the effects of interleukin-1 and interleukin-6 may be influenced by the presence of stressful stimuli. It ought to be underscored that although cytokines share features with the effects of stressors, most notably the variations of hypothalamic-pituitary-adrenal hormones, the pattern of central neurochemical changes elicited by the cytokines could be distinguished from the amine variations ordinarily associated with stressors.

3,4-Dihydroxyphenylacetic Acid↗