Effects of neonatal rat Borna disease virus (BDV) infection on the postnatal development of the brain monoaminergic systems

Effects of neonatal Borna disease virus infection (BDV) on the postnatal development of brain monoaminergic systems in rats were studied. Tissue content of norepinephrine (NE), dopamine (DA) and its metabolite, 3,4-dihydroxyphenol acetic acid (DOPAC), and serotonin (5-HT) and its metabolite, 5-hydroxyindole-3-acetic acid (5-HIAA) were assayed by means of HPLC-EC in frontal cortex, cerebellum, hippocampus, hypothalamus and striatum of neonatally BDV-infected and sham-inoculated male Lewis rats of 8, 14, 21, 60 and 90 days of age. Both NE and 5-HT concentrations were significantly affected by neonatal BDV infection. The cortical and cerebellar levels of NE and 5-HT were significantly greater in BDV-infected rats than control animals at postnatal days (PND) 60 and 90. Tissue content of NE in hippocampus was unaffected. In hippocampus, neonatally BDV-infected rats had lower 5-HT levels at PND 8 and significantly elevated levels at PND 21 and onwards. Neither striatal levels of 5-HT nor hypothalamic levels of 5-HT and NE were affected by neonatal BDV infection, suggesting that the monoamine systems in the prenatally maturing brain regions are less sensitive to effects of neonatal viral infection. 5-HIAA/5-HT ratio was not altered in BDV-infected rats indicating no changes in the 5-HT turnover in the brain regions damaged by the virus. Neither DA nor DOPAC/DA ratio was affected by neonatal BDV infection in any of the brain regions examined. The present data demonstrate significant and specific alterations in monoaminergic systems in neonatally BDV-infected rats. This pattern of changes is consistent with the previously reported behavioral abnormalities resulting from neonatal BDV infection.     

Effects of neurotensin on regional brain concentrations of dopamine, serotonin and their main metabolites.

The effects of neurotensin, 7.5 or 30 micrograms, on concentrations of DA, DOPAC, (HVA), serotonin 5-HT and 5-HIAA were measured in 8 regions of the rat brain either 5 or 30 min following intracerebroventricular administration. Regions examined include the frontal cortex, striatum, nucleus accumbens, amygdala, septum, hypothalamus, ventral tegmentum and substantia nigra. Results indicate that both doses of neurotensin significantly elevated concentrations of dopamine in the striatum and amygdala 5 min following injection. The effects of the peptide on DOPAC and HVA were more pervasive and enduring, with significant increases in metabolite levels occurring in both mesolimbic and nigrostriatal terminal regions. In order to assess effects on turnover of dopamine, the ratios of each metabolic to dopamine concentrations were examined. Results indicate that, while the DOPAC/DA ratio was elevated in many regions, the HVA/DA ratio was increased in all regions examined. The effects of neurotensin on serotoninergic parameters were less pervasive and more variable, with both increases and decreases in 5-HT and 5-HIAA concentrations being observed. The effects of the peptide on 5-HIAA/5-HT were limited to the nucleus accumbens, where this ratio was increased, and the ventral tegmentum, where 5-HIAA/5-HT was decreased. These findings reveal that the effects of the neurotensin on dopaminergic transmission are more widespread than previously reported in that all major dopamine pathways are affected by the peptide. Also, the observed changes in the ratios of both DOPAC and HVA to DA suggest that neurotensin enhances the turnover of this transmitter.     

Effects of ketamine on dopamine metabolism during anesthesia in discrete brain regions in mice: comparison with the effects during the recovery and subanesthetic phases

The effects of ketamine on the levels of dopamine (DA), norepinephrine (NE), 5-hydroxytryptamine (5-HT, serotonin) and their metabolites were examined in discrete brain regions in mice. A high dose of ketamine (150 mg/kg, i.p.) did not change DA metabolism in the frontal cortex, nucleus accumbens, striatum and hippocampus, but did decrease it in the brainstem during anesthesia. In contrast, during recovery from the ketamine anesthesia, the high dose increased the level of homovanillic acid (HVA) in all brain regions. A low subanesthetic dose of ketamine (30 mg/kg, i.p.) increased the concentrations of both 3,4-dihydroxyphenylacetic acid (DOPAC) and HVA only in the nucleus accumbens. The DA level was not affected by any ketamine treatment. During ketamine anesthesia, the content of 3-methoxy-4-hydroxy-phenylglycol (MHPG) was decreased in the brainstem, whereas during recovery from anesthesia, the MHPG level was increased in the frontal cortex, nucleus accumbens and brainstem. The NE content was not altered in any region by ketamine treatment. The concentration of 5-hydroxyindoleacetic acid (5-HIAA) was reduced in the frontal cortex, striatum, hippocampus and brainstem during ketamine anesthesia. The 5-HT level was unaltered in all regions except the brainstem where it was reduced. In contrast, after anesthesia, the concentrations of both 5-HT and 5-HIAA were increased in the striatum. During the subanesthetic phase, however, the levels of NE, 5-HT and their metabolites were unchanged. These neurochemical results are consistent with the electrophysiological findings that a high dose of ketamine does not change the basal firing rates of nigrostriatal DA neurons during anesthesia, while low subanesthetic doses significantly increase those of ventral tegmental DA neurons.     

Effects of nefiracetam,a novel pyrrolidone derivative,on brain monoamine metabolisms in mice

Summary The effects of acute and chronic administration of nefiracetam, a pyrrolidone derivative, on monoaminergic neurotransmitter systems in the mouse hippocampus, frontal cortex, hypothalamus, and striatum were studied. The levels of monoamines and of their metabolites were measured by high performance liquid chromatography with electrochemical detection on the first, 7th, and 14th days after nefiracetam was given. The neurochemical effects of nefiracetam were compared with those of oxiracetam and indeloxazine.Acute administration of nefiracetam (10 mg/kg, po) and oxiracetam (10 mg/ kg, po) had no effect on the levels of noradrenaline (NA), dopamine (DA), or 5-hydroxytryptamine (5-HT), or on the levels of their metabolites, 3-methoxy-4-hydroxyphenylglycol (MHPG), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA), in any of the regions examined. In contrast, a single dose of indeloxazine (10 mg/kg, po) decreased the levels of MHPG, DOPAC, and 5-HIAA in all regions examined.After chronic administration of nefiracetam (10 mg/kg, po, once daily), the levels of MHPG, DOPAC, and 5-HIAA were higher than control in all regions on the 14 th day only. Oxiracetam (10 mg/kg, po, once daily) similarly increased the levels of MHPG, DOPAC, and 5-HIAA in the hippocampus, frontal cortex, and striatum, but not in the hypothalamus. Conversely, indeloxazine (10 mg/ kg, po, once daily) decreased the levels of MHPG and 5-HIAA in all regions and the levels of DOPAC and HVA in the hippocampus and striatum as measured on the 7 th and 14 th days.These results show that nefiracetam has a delayed effect on brain monoaminergic metabolism, and that its effects are similar to those of oxiracetam, but clearly different from those of indeloxazine.     

Modification of gonadectomy-induced increases in brain monoamine metabolism by steroid hormones in male and female rats

Concentrations of monoamines (dopamine, DA; serotonin, 5-HT) and their major metabolites (homovanillic acid — HVA; dihydroxyphenylacetic acid — DOPAC; 5-hydroxyindolacetic acid — 5-HIAA) were measured in selected brain areas of chronically gonadectomized, steroid- or oil-treated male and female rats. Concentrations of DOPAC and HVA were markedly increased in the hypothalamus (male, female), striatum (male, female) and brainstem (male) following gonadectomy, whereas the levels of DA remained unaltered in most of the brain areas examined. Most of the changes were reversed or attenuated by chronic estradiol (EB) substitution. In contrast, chronic treatment with physiological concentrations of testosterone (TP) reduced indexes of DA turnover only in the striatum of ovariectomized (OVX) and brainstem of orchidectomized (ORDX) rats. ORDX-related increases in striatal levels of DOPAC and HVA were not reversed by either EB or TP. ORDX increased the levels of 5-HIAA (hypothalamus, striatum) and decreased those of 5-HT (hypothalamus, hippocampus). These changes were reversed by chronic treatment with either TP or EB. Brain metabolism of 5-HT remained unaltered following OVX.

Gonadectomy and chronic steroid replacement therapy appear to alter brain monoamine metabolism in a brain region and sex-dependent manner. Our data demonstrate that gonadectomy-related increases in the activity of brain monoaminergic neurons in both male and female rats was attenuated more effectively with physiological concentrations of estradiol than with testosterone. Insensitivity of monoaminergic neurons in a number of brain areas (e.g., hypothalamus, striatum) to the action of testosterone was evident in both sexes.     

Partial attenuation of chronic fluphenazine-induced changes in regional monoamine metabolism by D-alpha-tocopherol in rat brain.

Recent evidence has suggested a role for free radicals in tardive dyskinesia. We, therefore, investigated the effects of chronic administration of fluphenazine decanoate (FLU) and/or vitamin E (VIT E) on regional monoamine metabolism in rat brain. Chronic FLU caused significant increases in dopamine (DA) in nucleus accumbens and brainstem, significant decreases in dihydroxyphenylacetic acid (DOPAC) in frontal cortex, nucleus accumbens and hippocampus and significant decreases in homovanillic acid (HVA) in nucleus accumbens, caudate-putamen and brainstem. Coadministration of FLU and VIT E normalized HVA in caudate-putamen, nucleus accumbens and brainstem as well as DOPAC in nucleus accumbens and hippocampus. Chronic FLU caused significant increases in norepinephrine (NE) levels in all regions studied. VIT E attenuated FLU-induced increases in NE levels in nucleus accumbens and hippocampus. Significant increases in serotonin (5-HT) levels occurred in nucleus accumbens and hippocampus whereas significant decreases in 5-hydroxyindole-acetic acid (5-HIAA) occurred in all brain regions after chronic FLU. Coadministration of VIT E attenuated the changes observed in hippocampal 5-HIAA but potentiated the FLU-induced increases in 5-HT in this region. Our data suggest that VIT E can attenuate some of the FLU-induced changes in monoamine metabolism. Results are discussed in relation to possible involvement of free radicals in monoamine metabolism during chronic neuroleptic use.     

Changes in cortical and subcortical levels of monoamines and their metabolites following unilateral ventrolateral cortical lesions in the rat

Suction lesions were made in the anterior, posterior or both halves of the right ventrolateral cortex in rats. Six days later, levels of the monoamine neurotransmitters, norepinephrine (NE), dopamine (DA) and serotonin (5-HT), and their metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA), were measured in cortical and subcortical regions of lesioned rats and compared to values in sham-operated animals. NE and 5-HT were decreased in sections of ipsilateral (right) cortex including, and posterior to lesions, while 5-HIAA was increased throughout the ipsilateral cortex. Decreases in monoamines and increases in metabolites and metabolite:monoamine ratios (especially 5-HIAA:5-HT) were found in ipsilateral subcortical structures, including striatum, nucleus accumbens, hippocampus, hypothalamus, midbrain and brainstem, depending on the type of lesion. Subacutely, focal ventrolateral cortical lesions may profoundly alter the levels and utilization rates of monoamine neurotransmitters in widespread regions of the ipsilateral hemisphere.     

Ethanol alters monoamines in specific mouse brain regions.

Ethanol (3.5 g/kg 60 min post-IP injection) produced the following changes in regional brain monoamine levels and in the respective metabolite/neurotransmitter ratios: for the noradrenergic system, MHPG was decreased in the amygdala and increased in the hypothalamus, while the MHPG/NE ratio was increased in the prefrontal cortex and the hypothalamus. For the dopaminergic system, DA was decreased in the olfactory tubercle, DOPAC was increased in the prefrontal cortex and septum, and DOPAC/DA was increased in the prefrontal cortex, septum, striatum, and hypothalamus. HVA was increased in the prefrontal cortex and septum, while HVA/DA was increased in the same regions plus the olfactory bulb. 3MT was decreased in the olfactory tubercle and striatum. The serotonergic system was not altered. The results demonstrate that ETOH produces selective regional changes in the concentration and utilization of monoamines in mouse brain with a predominant influence on dopaminergic systems and a lesser effect on noradrenergic activity.     

Late changes in cerebral monoamine metabolism following focal ventrolateral cerebrocortical lesions in rats

Twelve weeks after focal ventrolateral cerebrocortical suction lesions (ca. 12 X 4 mm) were made in rats, concentrations of the monoamines norepinephrine (NE), dopamine (DA), and serotonin (5-HT) and their metabolites were measured in several cortical and subcortical brain regions using high performance liquid chromatography with electrochemical detection. Widespread changes in the concentrations of monoamines, their metabolites, and metabolite:monoamine ratios were found in the hemisphere ipsilateral to unilateral (right) lesions, and bilaterally in animals with bilateral lesions. NE was decreased in undamaged dorsolateral cortex and hippocampus, and tended to be increased in striatum and midbrain ipsilateral to lesions. DA was increased in the hypothalamus of bilaterally lesioned animals, and also tended to be increased in striatum and midbrain. The changes of greatest magnitude and anatomical extent were found in the serotonin system: 5-HT was generally increased, and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) and the 5-HIAA:5-HT ratio were decreased throughout the cerebral hemispheres ipsilateral to lesions. These widespread changes in cerebral 5-HT metabolism were qualitatively different and smaller than those previously found at 6 days after cortical lesions, and suggest a biphasic response of the ipsilateral 5-HT system to ventrolateral cortical injury.     

Effect of neonatal nociceptin or nocistatin imprinting on the brain concentration of biogenic amines and their metabolites

Noradrenaline (NA), dopamine (DA), homovanillic acid (HA), serotonin (5HT) and 5-hydroxyindole acetic acid (5HIAA) content of five brain regions (hypothalamus, hippocampus, brainstem, striatum and frontal cortex) and the cerebrospinal fluid (CSF) was measured in adult (three months old) male and female rats treated neonatally with a single dose of 10 microg nociceptin (NC) or 10 microg nocistatin (NS) for hormonal imprinting. The biogenic amine and metabolite content of cerebrospinal fluid was also determined. In NC treated animals the serotonergic, dopaminergic as well as noradrenergic systems were influenced by the imprinting. The 5HT level increased in hypothalamus, the 5HIAA tissue levels were found increased in hypothalamus. Hippocampus and striatum and the HVA levels increased highly significantly in brainstem. Dopamine level decreased significantly in striatum, however in frontal cortex both noradrenalin and 5HIAA level decreased. Nevertheless, in NS-treated rats decreased NA tissue levels were found in hypothalamus, brainstem and frontal cortex. Decreased DA levels were found in the hypothalamus, brainstem and striatum. NS imprinting resulted in decreased HVA level, but increased one in the brainstem. The 5HT levels decreased in the hypothalamus, brainstem, striatum and frontal cortex, while 5HIAA content of CSF, and frontal cortex decreased, and that of hypothalamus, hippocampus and striatum increased. There was no significant difference between genders except in the 5HT tissue levels of NC treated rats. Data presented show that neonatal imprinting both by NC and NS have long-lasting and brain area specific effects. In earlier experiments endorphin imprinting also influenced the serotonergic system suggesting that during labour release of pain-related substances may durably affect the serotonergic (dopaminergic, adrenergic) system which can impress the animals' later behavior.     

Regional serotonin metabolism in the brain of transgenic mice lacking monoamine oxidase A.

The effect of a lack of the gene encoding monoamine oxidase A (MAO A) in transgenic Tg8 mice on the activity of tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin (5-HT) biosynthesis, and on the levels of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in the midbrain, hypothalamus, hippocampus, striatum, amygdala, and frontal cortex was studied. It was shown that mice with a genetic MAO A knockout differed from mice of the initial C3H/HeJ strain in having a higher level of 5-HT and a lower level of its metabolite, 5-HIAA, in all brain regions but the frontal cortex, where the changes were insignificant. Although the 5-HIAA/5-HT ratio in various brain regions differed considerably, the decrease of the 5-HT oxidative deamination index in Tg8 mice was similar in different brain regions (to 41-45% of control values), with the exception of the frontal cortex, where the decrease of the 5-HIAA/5-HT was somewhat smaller (to 54%). The presence of the remaining 45% +/- 1.9% of the control ratio value indicates rather effective oxidative deamination of 5-HT in MAO A knockout mice and explains the lack of severe behavioral and pathological consequences in MAO A genetic deficiency. An increase of TPH activity in mice lacking MAO A was found in the frontal cortex, hippocampus, and amygdala. No significant changes were found in the striatum, hypothalamus, and midbrain. The data show an effect of the MAO A gene mutation on TPH and indicate a uniform decrease of 5-HT catabolism in different brain regions except for the frontal cortex, which is somewhat more resistant to the lack of MAO A than other brain structures.     

Regional monoamine and metabolite levels in a feline brain tumor model

The presence of a brain tumor alters regional cerebral blood flow, oxygen consumption, and glucose utilization in adjacent and remote brain tissue, but its effect on brain neurotransmitter levels is unclear. In the present report, the levels of noradrenaline (NA), dopamine (DA), 5-hydroxytryptamine (5-HT), 3,4-dihydroxyphenyl-acetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindole-acetic acid (5-HIAA) in tumor tissue and gray and white matter obtained from cats with induced brain tumors were measured. Glioma cells (9L) were xenotransplanted into the central white matter of the right hemisphere, and 15 d later the brains were frozen in vivo. Samples of tumor, parietal (peritumor), temporal, and frontal gray and white matter were divided for analysis of water content and quantification of amines and their metabolites. The water content of white matter, but not gray matter, adjacent to the tumor was increased. Neurotransmitter amine and metabolite levels were much lower in the tumor than in brain tissue. In gray matter adjacent to the tumor, concentrations of DA and its metabolites HVA and DOPAC were significantly decreased from control, whereas 5-HIAA was increased. The NA, DA, HVA, and DOPAC levels were decreased in temporal gray matter, whereas all amine and metabolite levels were unchanged in frontal gray matter. These results indicate that altered neurotransmitter metabolism is one of the effects of the presence of a brain tumor.     

Metabolism of monoamine neurotransmitters in the evolution of infarction in ischemic striatum

Summary The time course of changes in monoamine metabolism in ischemic striatum was assessed by measurement of levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), serotonin (5-HT) and 5-hydroxy-indole-acetic acid (5-HIAA) 2, 4, 7 and 16 hours after irreversible unilateral carotid ligation in Mongolian gerbils with stroke. DA was reduced to 30% of the level in the contralateral non-ischemic striata by 2 hours after stroke, but DOPAC was significantly elevated (p < 0.01) to 227%, while HVA remained equal to control. At 4 hours after stroke, DOPAC was 86% of the contralateral non-ischemic striata but HVA had risen to 130%. At 7 hours after stroke, DOPAC in the ischemic striata was 148% of control, while HVA remained at 133%. By 16 hours after stroke, DA, DOPAC and HVA were depleted from the ischemic striata, corresponding to the time course for irreversible damage to the neurotransmitter uptake function of nerve terminals. 5-HT levels in the ischemic striata were 30% of control at 2 hours, 46% at 4 hours, 30% at 7 hours and 21% at 16 hours, while 5-HIAA remained equal to control throughout the time course. These studies indicate that monoamine metabolism continues in ischemic striatum for up to 8 hours after the onset of stroke following irreversible unilateral carotid ligation in the Mongolian gerbil, but metabolism of DA is disrupted by 16 hours after stroke while metabolism of 5-HT continues.     

Characterization of monoamine release in the lateral hypothalamus of awake, freely moving rats using in vivo microdialysis

Extracellular levels of serotonin (5-HT), dopamine (DA) and their major metabolites 5-hydroxyindoleacetic acid (5-HIAA), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA), were measured in the lateral hypothalamus of awake, freely moving rats using microdialysis combined with HPLC and electrochemical detection. To characterize the factors which control 5-HT release, the effects of various drugs were assessed. TTX had a reversible inhibitory effect on the basal levels of 5-HT, 5-HIAA, DOPAC and HVA. Infusion of K+ concomitantly increased 5-HT and DA and decreased 5-HIAA and HVA. Imipramine increased extracellular levels of 5-HT and DA and decreased 5-HIAA levels; this effect was TTX-sensitive. Systemic pargyline increased extracellular 5-HT and markedly decreased the metabolic levels. Pargyline pretreatment in the presence of imipramine, infused through the dialysis probe, slowly increased 5-HT levels above that produced by the reuptake blocker alone. Infusion with AMPH produced a dramatic, TTX-insensitive, increase in 5-HT and DA and a decrease in the metabolic levels. These results provide evidence that (1) basal release of 5-HT in the lateral hypothalamus results from neuronal activity, (2) the metabolites in the extracellular fluid derive primarily from intracellular monoamine oxidase (MAO) activity, (3) 5-HT is mainly removed from the extracellular space by a reuptake mechanism, with minimal contribution of an extracellular MAO, and (4) the AMPH-evoked release of 5-HT and DA is a Na+ channel-independent process.     

The effects of himantane and cycloprolylglycine on the enzymatic linkage of monoamine synthesis in the rat brain

Using HPLC we studied the effects of new substances with antiparkinsonian activities, viz., himantane and cycloprolylglycine (CPG), on the contents of monoamines and their metabolites in the brain structures of Wistar rats under conditions of the inhibition of tyrosine and tryptophan hydroxylases. It was shown that 70 min after administration himantane induces a significant decrease in the level of noradrenaline in the nucleus accumbens (NA) and striatum. At 70 min after administration of CPG, we observed an increase in the DOPAC/DA ratio in the NA and the level of 5-HIAA in the striatum. At 24 h after CPG administration, we observed an increase in the HVA content and HVA/DA ratio in the hypothalamus and striatum. We found a decrease in 5-HIAA in all brain structures we studied at 24 h after administration of CPG, which was absent at 70 min after injection of the substance; the magnitude of 5-HIAA/5-HT decreased in the hypothalamus, nucleus accumbens, and hippocampus. Our results suggest that both substances we studied influence serotonergic transmission by inhibition of the MAO B enzyme.     

Comparative effects of the neurotoxins N-chloroethyl-N-ethyl-2-bromobenzylamine hydrochloride (DSP4) and 6-hydroxydopamine on hypothalamic noradrenergic, dopaminergic and 5-hydroxytryptaminergic neurons in the male rat

The intracerebroventricular (i.c.v.) administration of 6-hydroxydopamine (6-OHDA; 50 micrograms X 3) and the systemic administration of DSP4 (50 mg/kg X 2; i.p.), alone and in combination, were compared for their abilities to alter the concentrations of norepinephrine (NE), dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and 5-hydroxytryptamine (5-HT) in selected hypothalamic and extra-hypothalamic (striatum, frontal cortex, hippocampus) regions of the male rat brain. DSP4 markedly lowered NE concentrations in extrahypothalamic regions, and within the hypothalamus produced a mild and variable reduction of NE without altering concentrations of DA, DOPAC or 5-HT. 6-OHDA markedly lowered NE concentrations in all brain regions, but was without effect on DA, DOPAC and 5-HT concentrations in any region analyzed. Combined treatment with DSP4 and 6-OHDA did not produce additional effects on levels of NE, DA and DOPAC over either drug alone, but did cause a mild reduction of 5-HT in several brain regions. These results indicate that systemic treatments with DSP4 per se are not as effective as i.c.v. 6-OHDA in depleting NE in the hypothalamus, and that when the two neurotoxins are administered there appears to be some destruction of 5-HT neurons.     

Effects of Newcastle disease virus administration to mice on the metabolism of cerebral biogenic amines, plasma corticosterone, and lymphocyte proliferation

Newcastle disease virus (NDV) administration to mice increased concentrations of plasma corticosterone, with a maximal effect at 8 h. This elevation of plasma corticosterone concentrations was not observed in hypophysectomized animals in which the completeness of the hypophysectomy was verified by functional tests. NDV administration consistently increased concentrations of free tryptophan in all brain regions examined (prefrontal cortex, hypothalamus, and brain stem). It also caused an activation of cerebral catecholamine and indoleamine metabolism as determined by measurement of the amines and their catabolites. 3-Methoxy,4-hydroxyphenylethyleneglycol (MHPG), the major catabolite of norepinephrine (NE), homovanillic acid (HVA), a major catabolite of dopamine (DA), and 5-hydroxyindoleacetic acid (5-HIAA), the major catabolite of serotonin (5-HT), were all increased in both hypothalamus and brain stem. Ratios of catabolites to the parent amine, considered to be an index of utilization of the neurotransmitters, were increased for NE, DA, and 5-HT in the hypothalamus and for DA and 5-HT in the brain stem. This pattern of changes resembles that observed following stressors such as footshock or restraint. There were also significant increases of tryptophan, HVA, dihydroxyphenylacetic acid (DOPAC), and 5-HIAA in hypophysectomized relative to sham-operated mice. The NDV treatment also increased thymus weights and markedly decreased the proliferative responses of isolated spleen cells to phytohemagglutinin, concanavalin A, pokeweed mitogen, and Escherichia coli lipopolysaccharide. These changes were not caused by increased circulating corticosterone because they were present at equal magnitude in hypophysectomized mice. Thymosin alpha 1 concentrations in the plasma were not altered by NDV or hypophysectomy. These results indicate that administration of NDV to mice can initiate neurochemical and endocrine responses like those observed during stress and can also cause immunosuppression. They are thus consistent with the hypothesis that a virus can be a stressor.     

Attenuating effects of the isolated rearing condition on increased brain serotonin and dopamine turnover elicited by novelty stress

Isolation and acute environmental change are risk factors in human depression. In the present study, we investigated the differences in the brain monoamine activity of rats between two rearing conditions, isolated and group. Moreover, we examined the responses to novelty stress. Male F344 rats aged 11 weeks were divided into the above two groups. Four weeks later they were further divided into non-stress and stress groups. The latter received 20 min exposure to novelty stress. Isolation significantly changed brain monoamine levels, with the levels of dopamine (DA) in the nucleus accumbens and midbrain, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the midbrain, and 5-hydroxyindoleacetic acid (5-HIAA) in the hippocampus increasing. Serotonin (5-HT) levels also increased in all brain areas except the raphe nuclei. HVA levels in the raphe nuclei decreased. Novelty stress significantly altered brain monoamine levels. DA, DOPAC, and HVA levels in the prefrontal cortex decreased, as did those of 5-HT in the prefrontal cortex and hippocampus. DA levels in the nucleus accumbens increased. Isolation attenuated the enhanced brain monoamine turnover elicited by novelty stress. The enhanced DA turnover ratio in the prefrontal cortex of the group-reared group was attenuated in the isolated-reared group, and the unchanged DA turnover ratio in the nucleus accumbens of the group-reared group declined in the isolated-reared group. The enhanced 5-HT turnover ratio in the prefrontal cortex, nucleus accumbens, and hippocampus of the group-reared group was attenuated in the isolated-reared group. Isolation may exacerbate adaptation to stress, and be related to the etiology of human depression.     

Functional aspects of dopamine metabolism in the putative prefrontal cortex analogue and striatum of pigeons (Columba livia)

Dopamine (DA) in mammalian associative structures, such as the prefrontal cortex (PFC), plays a prominent role in learning and memory processes, and its homeostasis differs from that of DA in the striatum, a sensorimotor region. The neostriatum caudolaterale (NCL) of birds resembles the mammalian PFC according to connectional, electrophysiological, and behavioral data. In the present study, DA regulation in the associative NCL and the striatal lobus parolfactorius (LPO) of pigeons was compared to uncover possible differences corresponding to those between mammalian PFC and striatum. Extracellular levels of DA and its metabolites (homovanillic acid [HVA], dihydroxyphenylacetic acid [DOPAC]) and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) were investigated by in vivo microdialysis of urethane-anesthetized pigeons under basal conditions and after systemic administration of D-amphetamine. DA was reliably determined only in LPO dialysates, and DA metabolite levels were significantly higher in LPO than in NCL. The HVA/DOPAC ratio, indicating extracellular lifetime of DA, was more than twice as high in NCL than in LPO dialysates. After amphetamine, DA increased in LPO while still being undetectable in NCL, and DA metabolites decreased in both regions. 5-HIAA slightly decreased in NCL dialysates. Amphetamine effects were delayed in NCL compared with the striatum. In conclusion, effects of amphetamine on the pigeon's ascending monoamine systems resemble those found in mammals, suggesting similar regulatory properties. The neurochemical differences between NCL and LPO parallel those between associative regions, such as PFC and dorsal striatum in mammals. They may reflect weaker regulation of extracellular DA, favoring DAergic volume transmission, in associative than striatal forebrain regions.     

The levels of monoamines and their metabolites in the brain structures of rats with an experimental anxiodepressive state induced by administration of an inhibitor of dipeptidyl peptidase 4 in the early postnatal period

In a model of an experimental anxiodepressive state induced by postnatal administration of an inhibitor of dipeptidyl peptidase 4 (DPP-4), we studied peculiarities of the turnover of dopamine (DA), noradrenaline (NA), and serotonin (5-HT) in the brain structures of rats at ages of 1, 3, and 7 months. In males, the major changes in the functional activity of the DA system, which are related to a decrease in DA turnover according to the HVA/DA ratio, were observed in the striatum. In males at an age of 7 months, we found an increase in the NA level in the hypothalamus. In females, changes in the state of the DA system included a decrease in the level of DA and its metabolites in the nucleus accumbens (1 and 3 months), the level of DOPAC in the hypothalamus (3 months), and the level of DA in the striatum (7 months). At all ages, in the hippocampus of females, we found an increase in the functional activity of 5-HT, according to the 5-HIAA/5-HT and 5-HIAA level. In the frontal cortex of females at an age of 3 months we found a decrease in the 5-HIAA/5-HT ratio and an increase in the DOPAC/DA ratio, while at the age of 7 months, we observed an increase in 5-HT. These changes in the activity of the central monoaminergic systems may reflect specific features of the functioning of the pathological system of the anxiodepressive state in the CNS that determine the character of the formation and dynamics of emotional behavioral disturbances of male and female rats.