Effects of capsaicin on central monoaminergic mechanisms in the rat

Summary The acute and chronic effects of capsaicin (s.c.) on the monoamines in the preoptic region + hypothalamus (RPO-H), spinal cord, substantia nigra and striatum were studied. Levels of DOPA, DA, DOPAC, HVA, 3-MT, NA, Trp, 5-HTP, 5-HT and 5-HIAA were determined by means of liquid chromatography (HPLC-EC). In response to acute capsaicin treatment, the levels of DA, DOPAC and DA synthesis rate (DOPA formation) were increased in a dose-dependent manner in the RPO-H and spinal cord. The disappearance rate of NA was accelerated in both regions. In substantia nigra, increased DOPAC levels were found whereas the levels of 3-MT were decreased in striatum after acute capsaicin treatment. Only minor changes on the levels of 5-HT and 5-HIAA in the regions studied were noted. Neonatal or adult capsaicin treatment failed to affect the levels of NA, DA and 5-HT (measured two months or five weeks after injection, respectively) in the regions studied. A capsaicin injection to rats pretreated with the drug as adults did not affect either the monoamines in the RPO-H and spinal cord or the body temperature. In contrast, in rats pretreated with capsaicin as neonates, a second injection of the drug to adult animals elicited hypothermia and changes in monoamines similar to those observed in naive animals.     

Naltrexone administration effects on regional brain monoamines in developing rats

The effects of the opioid antagonist naltrexone (NALTX) daily administration (1 mg/kg SC) from birth on the levels of dopamine (DA), serotonin (5-HT), and their respective major metabolites, in the striatum, midbrain, and hypothalamus of 7-, 14-, and 22-day-old rats were investigated. Naltrexone treatment increased the striatal HVA/DA ratio on postnatal day 7. At day 14, two subpopulations (A and B) were found among the treated animals. The subpopulation A showed decreased HVA/DA and increased DOP AC/DA ratios, whereas the subpopulation B presented a higher DA concentration. No significant effect appeared on the striatal dopaminergic system in 22-day-old pups. The serotonergic system was affected by exposure to naltrexone only from day 14. The subpopulation A showed a reduction in all the parameters measured in the three regions studied, although in the subpopulation B, lower 5-HIAA/5-HT ratios appeared in the midbrain and hypothalamus. At 22 days of age NALTX treatment elevated striatal 5-HT and 5-HIAA and the ratio of 5-HIAA/ 5-HT in the midbrain and hypothalamus. These data suggest an endogenous opioid modulation on the central aminergic systems during the neonatal period and point out the consequences of opioid plasticity on related neurotransmitter systems.     

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.     

Monoaminergic activity at the level of the hypothalamus and striatum: relationship to anticipated feeding and pancreatic insulin responses

The present study examined monoaminergic activity at the level of the lateral hypothalamus (LH), ventromedial hypothalamus (VMH) and ventral striatum associated with the conditioned cephalic phase insulin release. Partially food-deprived male Wistar rats were divided into 3 groups. Two of the groups were conditioned to drink a 50% glucose solution each morning for 3 weeks; the control group received an amount of glucose equal to the amount drunk by the experimental animals with their afternoon meal. On test day, conditioned animals were sacrificed either just prior to glucose presentation or 2 min following consumption of the solution; control animals were sacrificed at the same time. Gas chromatography/mass spectrometry was used to determine the levels of the monoamines noradrenaline (NA), dopamine (DA) and serotonin (5-HT), as well as their principal metabolites dihydroxyphenylethyleneglycol, 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA) in the LH and VMH. DA and DOPAC levels were assayed in the striatum. Although serum glucose levels were unchanged, animals conditioned to drink glucose had significantly higher serum insulin levels. This increased insulin was associated with increased content of 5-HT and 5-HIAA at the level of the LH and VMH, increased NA content in the LH, increased DOPAC levels in the VMH as well as increases in the ratio of DOPAC to DA in the striatum. A regression analysis showed that 5-HIAA at the level of the LH related closely to serum insulin levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential stress coping in wild and domesticated sea trout

Offspring of wild and sea-ranched (domesticated) sea trout (Salmo trutta) originating from the same river, were reared under identical hatchery conditions from the time of fertilization. At one year of age individual fish were exposed to two standardized stressors; transfer to a novel environment, with or without a simultaneous predator exposure. Blood plasma concentrations of glucose and cortisol were analyzed along with brain levels of dopamine (DA), 3,4-hydroxyphenylacetic acid (DOPAC, a major DA metabolite), serotonin (5-hydroxytryptamine, 5-HT), and 5-hydroxyindoleacetic acid (5 HIAA, a major 5-HT metabolite). Transfer to a novel environment, alone as well as in combination with predator exposure, resulted in elevated plasma concentrations of glucose and cortisol. Moreover, exposure to these stressors resulted in elevated brain levels of 5-HT and 5-HIAA, as well as elevated brain 5-HIAA/5-HT and DOPAC/DA ratios. Wild trout displayed significantly higher post stress plasma glucose levels than domesticated fish. Similarly, following stress, brain 5-HIAA/5-HT and DOPAC/DA ratios were significantly higher in wild than in domesticated fish. These differences were not caused by differences in brain levels of 5-HIAA and DOPAC, but instead by differences in brain 5-HT and DA concentrations. These results suggest that domestication results in attenuated stress responses in trout, and that alterations in brain monoamine neurotransmission are part of this effect.     

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.     

Amyotrophic lateral sclerosis: changes of noradrenergic and serotonergic transmitter systems in the spinal cord.

Noradrenaline (NA), dopamine (DA), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were measured in discrete subdivisions of cervical, thoracic and lumbar spinal cord segments obtained at autopsy of 4 subjects with amyotrophic lateral sclerosis (ALS) and 7 control patients. NA concentrations in thoracic and lumbar spinal cord of ALS patients were 2- to 4-fold higher compared with values obtained in control patients. 5-HT levels were unchanged at the cervical and thoracic level and slightly above normal in lumbar spinal cord, while the concentration of 5-HIAA was lowered in cervical and thoracic, but within the control range, in lumbar spinal cord. As a result, the molar ratios of 5-HT/5-HIAA were increased at all spinal levels in ALS. No difference in spinal DA concentration was found between ALS and control patients. The changes in the noradrenergic and serotonergic transmitter systems reported here most probably reflect a decreased release of these transmitter substances in ALS spinal cord. Since lack of the facilitatory monoaminergic influence would necessitate an increase in the excitatory, potentially neurotoxic glutamatergic input onto the motoneurones, we hypothesize that this could contribute to the progressive loss of spinal motoneurones in amyotrophic lateral sclerosis.     

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.     

Spinal cord monoaminergic system response to age and cold-acclimatization in Muscovy duckling

Summary. The effect of age and cold acclimatization on the regional distribution of monoamines in duckling spinal cord was studied. In thermoneutral controls (TN), the high dopamine (DA) to norepinephrine (NE) ratios (0.25 at 4 weeks of age and 0.15 at 6 weeks of age) suggest the presence of specific (non precursor) dopaminergic pools in cervical spinal cord. DA levels and the ratio of DA to NE were lowered by age and cold exposure in the cervical cord. In TN ducklings, serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) showed a decline with age in the spinal cord, indicating that this system is affected with development, whereas cold exposure prevents this decrease. The contents of 5-HT (+58%), 5-HIAA (+93%) and the ratio of 5-HIAA to 5-HT (+50%) are higher in the cervical spinal cord of cold acclimated than in TN ducklings. These results indicate that central monoaminergic systems are markedly affected by age and cold exposure. Received November 11, 1999; accepted March 6, 2000     

Topographical dopamine and serotonin distribution and turnover in rat striatum

Topographic distribution of dopamine (DA), serotonin (5-HT), dihydroxyphenylacetic acid (DOPAC), hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) was determined in rat striatum using high-pressure liquid chromatography (HPLC) with electrochemical detection. The ratios of DOPAC:DA and 5-HIAA:5-HT were calculated as indices of turnover of DA and 5-HT. There was a rostro-caudal gradient for both DA and 5-HT, with DA highest in rostral striatum and 5-HT highest in caudal striatum (P less than 0.01). DA concentrations in the coronal plane showed a homogeneous distribution except at the level of the globus pallidus. DOPAC also showed a rostro-caudal gradient and concentrations were significantly increased in the nucleus accumbens (P less than 0.01). DOPAC:DA ratios were significantly increased in both the nucleus accumbens and the ventromedial striatum as compared to the remaining striatal punches. 5-HT was more heterogeneously distributed in the coronal plane with concentrations highest in the ventromedial and the ventrolateral quadrants, where they were 2-3-fold higher than in dorsal striatum (P less than 0.01). Concentrations of 5-HIAA were highest in the nucleus accumbens and ventromedial striatum but HIAA-5-HT ratios were highest in the dorsolateral striatum (P less than 0.01). DA turnover is therefore highest in limbic innervated (n. accumbens and ventromedial) striatum while 5-HT turnover is highest in sensorimotor innervated (dorsolateral) striatum. These findings provide further evidence for functional compartmentalization within the striatum.     

Effects of 8-OHDPAT administration into the dorsal raphe nucleus and dorsal hippocampus on fear behavior and regional brain monoamines distribution in rats

The effects of R(+)-8-hydroxy-dipropylaminotetralin (8-OHDPAT) administration into the dorsal raphe nucleus (DRN) or bilaterally into the dorsal hippocampus (HIP) on fear behavior in a modified version of the light-dark transitions test and regional brain monoamines (NA, DA, 5-HT) and their metabolites (MHPG, DOPAC, 5-HIAA) in the hypothalamus, midbrain central gray matter, amygdala, hippocampus and pons were examined. The experiments were performed on 36 male, 3-month old Wistar rats. Administration of 8-OHDPAT (200 ng) into the DRN reduced time out from the illuminated part of the chamber and time of motionless behavior in the illuminated part, increased the number of returns from the dark to illuminated part and number of head dipping from the dark to illuminated part without effect on time of motionless behavior in the dark part and on time of locomotor activity in the illuminated as well as in dark part of the chamber. HPLC analysis showed reduction of 5-HT content in the midbrain and amygdala, reduction of 5-HIAA content in pons, increased 5-HIAA/5-HT ratio in the hippocampus and increased DOPAC/DA ratio in the hypothalamus, midbrain, hippocampus and pons without affecting the MHPG/NA ratio and NA content. The administration of 8-OHDPAT (100 ng per site) into the HIP reduced time out from the illuminated part of chamber, time of locomotor activity in the illuminated part and head dipping from the dark to illuminated part without effect on the number of returns from the dark to illuminated part, time of locomotor activity in the dark part and time of motionless in the illuminated as well as in the dark part of chamber. HPLC analysis showed reduction of NA content in the hypothalamus, amygdala and pons, increased the MHPG content in all the investigated structures, increased MHPG/NA ratio in all the investigated structures except the hypothalamus. Dopamine content decreased in the hypothalamus and amygdala, and DOPAC/DA ratio increased in the amygdala and hippocampus. Concentrations of 5-HT, 5-HIAA and 5-HIAA/5-HT ratio were unchanged. The results obtained indicate that 8-OHDPAT acting on the pre-synaptic 5-HT1A receptors decreases fear behavior and acting on 5-HT1A post-synaptic receptors increases fear behavior in the light-dark transitions test. The neurochemical base of anxiolytic and anxiogenic effects evoked by 8-OHDPAT is being discussed.     

Cytomegalovirus infection of the developing brain alters catecholamine and indoleamine metabolism

Tissue concentrations of noradrenaline (NA), serotonin (5-HT), dopamine (DA) and selected metabolites were measured in the spinal cord, cerebellum, cerebral cortex and caudate-putamen of developing mice following intraventricular inoculation with murine cytomegalovirus (MCMV) on postnatal day 10. MCMV-infected animals exhibited transient signs of neurological impairment, including apparent hypertonicity of hindlimb extensors and abnormal gait, beginning on days 14-16 and continuing for 3-5 days. At the onset of neurological impairment, tissue concentrations of NA were significantly reduced in the spinal cord (20%), cerebellum (32%) and cerebral cortex (40%) of infected animals. Levels of 5-HT were significantly increased in the caudate-putamen (50%), while 5-hydroxyindoleacetic acid (5-HIAA) was increased in both the spinal cord (94%) and caudate-putamen (65%). The ratio of 5-HIAA/5-HT, which is frequently used as an estimate of turnover of 5-HT, was significantly increased in the spinal cord (90%) at the onset of neurological impairment. In the caudate-putamen of MCMV-infected animals, there were significant increases in the tissue levels of DA (37%), homovanillic acid (HVA, 41%) and 3,4-dihydroxyphenylacetic acid (DOPAC, 34%). All neurochemical parameters were normal in the MCMV-infected animals by postnatal day 70, approximately 50 days after the resolution of neurological signs. These results indicate transient alterations in monoamine metabolism in the developing nervous system during the pathogenesis of cytomegalovirus-induced movement and postural disorders.     

Gonadal influences on spinal cord and brain monoamines in male rats

Concentrations of norepinephrine (NE), dopamine (DA), 3,4-dihydroxy phenylacetic acid (DOPAC), serotonin (HT) and 5-hydroxyindoleacetic acid (HIAA) were measured by high-performance liquid chromatography-electrical detection (HPLC-ED) in homogenates of lumbosacral spinal cord, mediobasal hypothalamus and cerebral cortex of male rats. The effects of castration and testosterone propionate (TP) (20 micrograms/day X 2 days) were compared. Castrated animals had the highest levels of DA and DOPAC in the cerebral cortex and NE, HT and HIAA in the spinal cord, as well as decreased hypothalamic DOPAC. Testosterone treatment returned spinal cord monoamine concentrations to intact control levels. These findings point to the spinopetal monoaminergic pathways as sensitive targets for androgen action.     

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.     

Effect of chronic naltrexone administration and its withdrawal on the regional activity of neurons that contain norepinephrine, dopamine and serotonin

A method is described that permits the simultaneous quantitation of norepinephrine (NE), dopamine (DA) serotonin (5-HT) and their respective major metabolites, 3-methoxy-4-hydroxy phenylglycol (MHPG), 3-methoxytyramine (3-MT), dihydroxyphenyl acetic acid (DOPAC) and 5-hydroxyindole acetic acid (5-HIAA) in discrete brain regions. The ratio of MHPG/NE, DOPAC/DA and 5-HIAA/5-HT was used to assess the effects of the chronic administration of the narcotic antagonist, naltrexone, and its withdrawal on the regional activity of neurons that contain NE, DA and 5-HT respectively. Chronic administration of naltrexone (8 days) is associated with a significant increase in the ratio of 5-HIAA/5-HT and DOPAC/DA in the frontal cortex and dorsal hippocampus respectively. Under this condition the thalamic concentration of 3-MT in 4 of 8 animals is also significantly elevated. In contrast, the mesolimbic forebrain exhibited a decrease in the MHPG/NE ratio (4 out of 8 animals). One day following naltrexone pellet removal the above ratios, as well as the mean content of 3-MT in the thalamus, returned to control values. At this time the content of 3-MT in the thalamus (5 of 5 animals) and frontal cortex (3 of 9 rats) was appreciably elevated, while its content in the dorsal hippocampus was significantly reduced (6 of 9 rats). These data suggest that the activity of several central monoaminergic neuronal systems are regulated by an opioid input that is tonically active.     

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.     

Effects of 5-hydroxytryptophan on extracellular serotonin in the spinal cord of rats with experimental allergic encephalomyelitis.

Serotonin (5-HT) and the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA) were collected by in vivo dialysis in the lumbar spinal cord of control rats and rats with hindlimb paralysis induced by experimental allergic encephalomyelitis (EAE). Both 5-HT and 5-HIAA were significantly decreased in baseline samples from EAE rats compared to controls. This decrease in extracellular 5-HT and 5-HIAA in the EAE rats was accompanied by marked morphological changes in spinal cord axons and axon terminal plexuses that were stained for 5-HT-like immunoreactivity. The 5-HT precursor, 5-hydroxytryptophan (5-HTP)-increased 5-HT and 5-HIAA levels in dialysate samples from both control and EAE animals. However, the 5-HTP-induced increase in extracellular 5-HT was significantly greater in the EAE rats than in the controls, despite a lower baseline 5-HT level in the EAE animals. In contrast to 5-HT, both baseline and post-5-HTP levels of 5-HIAA were significantly higher in control animals than in EAE animals. The decreased extracellular 5-HT and 5-HIAA in baseline samples from the EAE rats compared to controls is probably a consequence of the damage to descending 5-HT axons and axon terminals that occurs during the disease. The larger increase in extracellular 5-HT in EAE animals after precursor injection may reflect both decreased 5-HT reuptake from the extracellular space by damaged 5-HT terminals and disruption of the blood-brain barrier that allows entry into the central nervous system of 5-HT that was synthesized from 5-HTP in the periphery.     

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.     

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.     

Variations of monoamines and their metabolites in the human brain putamen

The levels of the monoamines dopamine (DA), serotonin (5-HT) and norepinephrine (NE) and the monoaminergic metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were measured with HPLC-ECD in 42 samples from human brain putamen. The influence of gender and of age was investigated and correlations between the monoamines were established. The DAergic system shows a significant difference between males and females, with females having lower DA and higher DOPAC levels and a higher DOPAC/DA ratio than males. No gender-related differences of 5-HT and its metabolites were observed, nor of NE. Three different age groups (group 1: 0–9.9 years; group 2: 10–59.9 years; group 3: 60 years and older) were defined according to previous studies on ontogenesis and senescence in human brain. An increase in 5-HT levels, decrease in 5-HIAA levels a d a decrease in the 5-HIAA/5-HT ratio were observed after the first decade of life. Changes in the DAergic system were seen in senescence, with decreasing DA levels and an increase in the HVA/DA ratio. DOPAC, HVA and the DOPAC/DA ratio are unaffected. NE is similar in all age groups. The analysis of the relation of the levels of the three monoamines proved a strong correlation between the DAergic and 5-HTergic systems. The nature of this relationship might have an impact on neuro-psychiatric disorders and brain function.