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.     

Differential effects of kainic acid on dopamine and serotonin metabolism in ventral and dorsal striatal regions

The comparative effects of kainic acid (KA) on dopamine (DA) and serotonin (5-HT) metabolism in ventral and dorsal striatum were investigated. Local injection of KA into the caudate-putamen (CP) increased by 155% DOPAC (2,3-dihydrophenylacetic acid), by 114% HVA (homovanillic acid) and by 79% 5-HIAA (5-hydroxyindoleacetic acid) concentrations: with little or no effect on monoamine levels. The (DOPAC + HVA)/DA ratio increased from 0.33 ± 0.2 in vehicle-treated to 0.77 ± 0.1 in KA-treated CP. 5-HIAA/5-HT ratio increased from 2.7 ± 0.2 to 5.9 ± 0.1 after KA treatment. However, direct KA injections into the olfactory tubercle (OT), the most ventral part of the ventral striatum, did not alter significantly the levels of DA, 5-HT, DOPAC, HVA or 5-HIAA. Since KA is a neurotoxin which preferentially destroys perykaria and dendrites, leaving unchanged terminal boutons and axons of passage, the lack of effects on DA and 5-HT metabolism in OT suggests, that contrary to the CP, interneurons and projecting neurons in the OT play no role in inhibitory feedback mechanisms to control DA and 5-HT activities.     

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.     

Dopamine and 5-HT turnover are increased by the mGlu2/3 receptor agonist LY379268 in rat medial prefrontal cortex, nucleus accumbens and striatum

We have shown, using in vivo microdialysis sampling, that systemic administration of the selective group II metabotropic (mGlu) receptor agonist LY379268, like the atypical antipsychotic clozapine, increased extracellular levels of dopamine, dopamine metabolites DOPAC and HVA, and the major 5-HT metabolite 5-HIAA, in rat medial prefrontal cortex (mPFC). Here, we have compared the effects of LY379268 with clozapine as well as risperidone on ex vivo tissue levels of dopamine, DOPAC, HVA, 5-HT and 5-HIAA in multiple brain regions. One to two hours following administration of LY379268, mPFC tissue levels of DOPAC, HVA and 5-HIAA were increased in a dose-dependent manner. Increases evoked by LY379268 (10 mg/kg s.c.) at the 2 h point were 189, 245 and 139% of basal levels, respectively. These effects were reversed within 4 h of administration. Clozapine (10 mg/kg s.c.) and risperidone (1 mg/kg s. c.) also increased levels of the dopamine metabolites to a similar extent but were without significant effect on tissue levels of 5-HIAA. LY379268 (10 mg/kg s.c.) also increased tissue levels of DOPAC, HVA and 5-HIAA by 169, 221 and 134% of basal levels in nucleus accumbens, respectively, and by 131, 179 and 132% of basal levels in striatum, respectively. These data show that activation of mGlu2/3 receptors can increase the turnover of dopamine and 5-HT in the areas of the brain implicated in the actions of atypical antipsychotics.     

Fluoxetine increases the extracellular levels of serotonin in the nucleus accumbens

The effects of an IP injection of the monoamine uptake inhibitor fluoxetine on the extracellular concentration of serotonin (5-HT), dopamine (DA), 5-hydroxyindoleacetic acid (5-HIAA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the nucleus accumbens of awake and freely moving rats were examined using a push-pull perfusion technique. Baseline values of 5-HT, 5-HIAA, DA, DOPAC and HVA in the perfusates were approximately 0.07, 13, 0.8, 49 and 12 pmol/hr, respectively. The IP administration of 5 and 10 mg/kg fluoxetine dose-dependently elevated the amounts of 5-HT 3- and 13-fold, respectively, in the push-pull perfusate, with the maximum reached within one hour after drug administration. Moreover, 10 mg/kg fluoxetine also significantly decreased the levels of 5-HIAA in the perfusate as much as 50% within 2-3 hours. On the other hand, no significant effect of 5 or 10 mg/kg fluoxetine was observed on the contents of DA, DOPAC and HVA in the push-pull perfusates. The data indicate that fluoxetine, in accord with its role as a 5-HT uptake inhibitor, increases the physiologically active pool of 5-HT in the nucleus accumbens under in vivo conditions.     

Effect of chronic nicotine administration on monoamine and monoamine metabolite concentrations in rat brain

The effects on rat brain tissue monoamine and monoamine metabolite concentrations of chronic nicotine administration at two doses (3 and 12 mg/kg/day) using constant infusion were studied. After 21 days of treatment, tissue concentrations of dopamine (DA), norepinephrine (NE), 5-hydroxytryptamine (5-HT), and several metabolites in striatum, hypothalamus, and frontal cortex were determined by high performance liquid chromatography with electrochemical detection. Compared with a control group, nicotine treatment significantly decreased NE in frontal cortex but not in other regions. The concentration of 5HT also was decreased in frontal cortex but increased in the hypothalamus at the higher dose of nicotine. The 5HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) was not significantly altered in any region. The 5HT index (5-HIAA/5-HT) was significantly decreased in the hypothalamus and increased in frontal cortex at the higher dose. Concentrations of DA and the metabolite homovanillic acid (HVA) were not significantly altered by nicotine. Nevertheless, significant decreases in the DA metabolite dihydroxyphenyl-acetic acid (DOPAC) were observed in both striatum and hypothalamus. Moreover, the DA index [(DOPAC + HVA)/DA] was significantly decreased in all three brain regions. In contrast to other studies using acute dose and in vitro perfusion paradigms that have reported increased CNS catecholamine release stimulated by nicotine, chronic administration appears to be associated with decreased catecholamine turnover in some brain regions.     

Effect of morphine applied by intrapallidal microdialysis on the release of dopamine in the nucleus accumbens

The effect of morphine, administered intrapallidally, on extracellular concentrations of DA, DOPAC, and HVA in the nucleus accumbens and striatum was studied in the behaving rat using the in vivo microdialysis technique. Unilateral application of morphine hydrochloride was perfomed through microdialysis probes into the rat ventral pallidum (10 μ1 of 0 2.6 4.0, 13.0, and 26.0 mM) or globus pallidus (10 μ1 of 0 and 26.0 mM). The levels of DA, DOPAC, and HVA were measured using the HPLC with EC detection in dialysates collected from the nucleus accumbens, anteromedial, and anterolateral striatum. Samples were taken every 45 min over 3 h before and over 5 h after morphine or vehicle administration. Administration of morphine into the ventral pallidum resulted in increased DOPAC and HVA concentrations in the nucleus accumbens. Pretreatment with naloxone (1 mg/kg, SC) abolished this effect of morphine. Administration of morphine into the globus pallidus resulted in increased DA, DOPAC, and HVA concentrations in the nucleus accumbens and DA in the anteromedial striatum. The levels of DA and metabolites in anterolateral striatum remained rather unchanged following morphine administered into the ventral pallidum or the globus pallidus. The changes in DA neurotransmission into the nucleus accumbens induced by morphine application into the ventral pallidum and globus pallidus are reminiscent of a phasic and tonic release of DA respectively. The results show that intrapallidal morphine increases DA neurotransmission in nucleus accumbens and suggest that the effect of morphine is mediated by ventral pallidum/mesolimbic and globus pallidus/thalamocortical pathways, depending on the site of injection.     

Changes of serotonin and dopamine metabolism in various forebrain areas of rats injected with morphine either systemically or in the raphe nuclei dorsalis and medianus

The regional brain metabolism of serotonin (5-HT) and dopamine (DA) was studied in rats injected with morphine either systemically or in the nuclei raphe medianus (MR) or dorsalis (DR). A subcutaneous injection of 10 mg/kg morphine significantly raised the levels of 5-hydroxyindoleacetic acid (5-HIAA) in the diencephalon, striatum, nucleus accumbens and cortex with no effect in the hippocampus. Similar changes in 5-HT metabolism were found in animals injected with 5 micrograms/0.5 microliter in the DR whereas morphine injected in the MR raised 5-HIAA levels only in the nucleus accumbens. A subcutaneous or direct injection of morphine in the DR significantly raised the levels of homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) in the striatum and nucleus accumbens, but injection in the MR was ineffective. All the effects of morphine were blocked by naloxone, injected either intraperitoneally (1 mg/kg) or directly in the raphe nuclei (2 micrograms/0.5 microliter). Pretreatment with parachlorophenylalanine, an inhibitor of serotonin synthesis, significantly reduced the effect of morphine injected in the DR on dopamine metabolism in the striatum and nucleus accumbens. The data suggest that a major mechanism by which morphine increases 5-HT metabolism in the rat forebrain is activation of 5-HT cells in the nucleus raphe dorsalis, and this action may contribute to the increased DA metabolism found in the animal injected with morphine in this brain area.     

Serotonin microinfusion into the ventral tegmental area increases accumbens dopamine release

The effects of microinfusion of serotonin (5-HT) agents as well as glutamate and muscimol into the ventral tegmental area (VTA) on dopamine (DA) release in the ipsilateral nucleus accumbens (ACC) were investigated in freely moving rats, using a push-pull perfusion procedure. The baseline values for DA, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were approximately 0.24, 8.4, 2.1 and 2.7 pmol/15 min, respectively, in the push-pull perfusate of the ACC. When microinfused into the VTA, glutamate (0.74 microgram) significantly (p less than 0.05) increased the contents of DOPAC (110%) and HVA (90%) over baseline levels in the perfusate. On the other hand, 0.5 microgram muscimol (a gamma-amino-n-butyric acid, GABA, agonist) significantly, (p less than 0.05) decreased both DA (40%) and DOPAC (20%) levels relative to baseline values. Administration of 2 micrograms 5-HT into the VTA caused a significant (p less than 0.05) elevation in the perfusate levels of DOPAC (80%) and HVA (70%) over baseline values. A similar effect was obtained with a nonselective 5-HT1 agonist but not with a selective 5-HT1A agonist. The results suggest that 5-HT innervations in the VTA may have an excitatory action possibly via 5-HT1B rather than 5-HT1A receptors on the mesolimbic DA system projecting to the ACC and that this DA system may also be regulated by glutamatergic and GABAergic (via GABAA receptors) inputs.     

Bilateral augmentation of dopaminergic and serotonergic activity in the striatum and nucleus accumbens induced by conditioned circling

The involvement of dopaminergic (DA) and serotonergic (5-HT) systems in circling was assessed by determining the neurochemical correlates of circling induced and maintained by two different schedules of water reinforcement. The conditioned circling paradigm was employed in an attempt to replicate reports that levels of DA and 3,4-dihydroxyphenylacetic acid (DOPAC) were increased in the striatum and nucleus accumbens septi (NAS) contralateral to the direction of circling. Rats trained to circle using a continuous schedule of reinforcement did not exhibit any changes in concentrations of DA, DOPAC, or homovanillic acid (HVA). Bilateral increases in 5-HT concentrations were observed in the striatum. Use of an intermittent schedule of reinforcement (FR-2) produced higher rates of circling. In rats maintained on the FR-2 schedule, no changes in DA or its metabolites were observed in the striatum. The ratio of HVA to DA was, however, increased bilaterally, suggesting a bilateral augmentation of DA utilization. Concentrations of DA were lower in the NAS contralateral to direction of turning. While NAS levels of HVA were elevated bilaterally when compared to non-circling controls, HVA was lower in the NAS contralateral to the direction of circling. DA utilization, as estimated by HVA: DA ratios, was increased bilaterally in the NAS. None of the measures of DA activity within the olfactory tubercle (OT) were influenced by circling. Turnover of 5-HT, as estimated by the ratio of 5-HT to 5-hydroxyindoleacetic acid (5-HIAA), was increased bilaterally in the striatum, NAS, and OT.(ABSTRACT TRUNCATED AT 250 WORDS)     

Invariance of the density of dopamine uptake sites and dopamine metabolism in the rat brain after a chronic treatment with the dopamine uptake inhibitor GBR 12783

Summary A chronic treatment (10 mg/kg, twice daily during 9 days) with the dopamine uptake inhibitor GBR 12783 was performed in rats at a dose increasing their locomotor activity.Forty-eight hours after the last administration, animals were sacrificed and³H mazindol binding was performed on brain slices. Autoradiographic analysis revealed no change in this binding relatively to control animals in regions with high dopamine contents: striatum, nucleus accumbens, olfactory tubercle, substantia nigra and ventral tegmentum area. The treatment did not either modify the levels of dopamine (DA) and metabolites (HVA, DOPAC) both in the striatum and the nucleus accumbens. Thus, early after the end of the treatment, the chronic blockade of the dopamine uptake complex regulates neither the dopamine uptake complex nor the dopamine metabolism.     

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.     

Selective changes in the contents of noradrenaline, dopamine and serotonin in rat brain areas during aging

This study examines the age-associated changes in noradrenaline (NA), dopamine (DA), 3,4-dihydroxyphenyl-acetic acid (DOPAC), serotonin (5-HT) and 5-hydroxy-3-indoleacetic acid (5-HIAA) in different brain areas of rats. DA and DOPAC concentrations in striatum increased at third month of age, remaining without significant variations until 12th month of age, and decreasing in 24-month-old rats. DA concentration dropped in hippocampus, amygdala and brainstem of 24-month-old-rats, whereas DOPAC levels decreased only in hippocampus. These changes suggest an age-dependent deficit of the dopaminergic system, presumably related to a reduced number/activity of DA nigrostriatal and mesolimbic neurons. An age-induced decline in NA content was found in the pons-medulla, the area containing NA neuronal bodies. Concentrations of 5-HT were reduced with aging in frontal cortex, showing a tendency to decrease in all brain areas examined. The increased 5-HIAA/5-HT ratio found in frontal cortex, amygdala and striatum suggests an age-related decreased synthesis and an accelerated 5-HT metabolism. The 5-HIAA content decreased in brainstem of the oldest rats. These findings point to a selective impairment of nigrostriatal and mesolimbic DA in aging rats, whereas reductions in NA were restricted to cell bodies region and 5-HT showed changes of different extent in areas of terminals and neuronal cell bodies.     

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.     

Effect of acute administration of hypericum perforatum-CO2 extract on dopamine and serotonin release in the rat central nervous system

The hydromethanolic extract of Hypericum perforatum has been shown to be an effective antidepressant, although its mechanism of action is still unclear. In this study, in vivo microdialysis was used to investigate the effects of Hypericum perforatum-CO2 extract on dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) release in various areas of brain. Administration of Hypericum perforatum extract (1 mg/kg, p.o.) caused a slight, but significant increase of DA outflow both in the nucleus accumbens and the striatum. The maximal increase of DA efflux (+19.22+/-1.93%, relative to the control group) in the nucleus accumbens occurred 100 min after administration of Hypericum perforatum. In the striatum, the extract maximally enhanced DA outflow (+24.83+/-7.49 %, relative to the control group) 80 min after administration. Extraneuronal DOPAC levels were not significantly affected by Hypericum perforatum treatment. Moreover, Hypericum perforatum (1 mg/kg, p.o.) did not produce any significant effect on either 5-HT or 5-HIAA efflux in the ventral hippocampus. This study shows for the first time that Hypericum perforatum extract is capable of increasing in vivo DA release.     

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.     

Effects of neurotensin on regional concentrations of norepinephrine in rat brain

The effects of intraventricular administration of either 7.5 or 30 micrograms neurotensin on norepinephrine concentrations were examined in several brain regions at 5 or 30 min post-injection. Significant elevations in the level of this amine were found in the hypothalamus, nucleus accumbens and amygdala. Levels in striatum, ventral tegmentum, septum, frontal cortex and substantia nigra were not affected. The effects were most prominent 5 min after injection. Results are discussed in terms of behavioral changes induced by these doses of neurotensin.     

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.     

Central monoamine metabolism in the male Brown-Norway rat in relation to aging and testosterone

Concentrations of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), noradrenaline (NA), free 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were determined in brain regions of 5-, 20-, and 32-month-old male Brown-Norway rats using high pressure liquid chromatography. In view of the activating effects of sex steroids on peptide and monoamine transmitter systems and the declining plasma testosterone levels with aging, the effects of testosterone supplementation on age-related changes in central monoamine metabolism were also studied. Age-related decreases in monoamine metabolism were observed in nigrostriatal, mesocortical and coeruleohippocampal systems. Marked reductions in DOPAC (35%) and HVA (50%) occurred in the ventral tegmental area between 20 and 32 months of age. 5-HT and 5-HIAA levels showed reductions and increases depending on the brain region. Testosterone administration resulted in elevations of HVA in the substantia nigra and MHPG in the locus coeruleus and hippocampus, which were most pronounced in young animals. It is concluded that there are marked differences in age-related changes between nigrostriatal, mesocortical and coeruleohippocampal systems and that testosterone exerts a stimulatory influence on some aspects of monoamine metabolism in young but not in aged animals.     

In vivo neurochemical and behavioural effects of intracerebrally administered neurotensin and D-Trp11-neurotensin on mesolimbic and nigrostriatal dopaminergic function in the rat

The effects of intracerebral application of neurotensin on the behavioural responses to peripheral dopamine agonist administration to rats, and on the levels of DOPAC voltammetrically determined in the striatum and nucleus accumbens of the anaesthetized rat have been examined. Bilateral application of neurotensin to the nucleus accumbens, like the neuroleptic haloperidol, inhibited the hyperactivity response to the dopamine agonist, n,N-propylnorapomorphine, but, unlike haloperidol, its bilateral intrastriatal application failed to reduce the degree of stereotyped behaviour induced by peripheral apomorphine injection. In the halothane-anaesthetized rat, neurotensin, when applied to the ventral tegmental area, stimulated DOPAC production in the ipsilateral nucleus accumbens, while its application to the substantia nigra did not affect striatal DOPAC levels significantly. Following its intracerebroventricular injection, however, DOPAC levels were considerably enhanced in both regions. The 11-D-tryptophan-substituted analogue of neurotensin potently mimicked the effects of the peptide itself in all studies. The findings of these investigations further confirm in vivo that the functional antagonism of dopamine by neurotensin is selective for the mesolimbic system, and that the effects of neurotensin can be correlated with reports on the regional distribution of its high-affinity binding sites in the rat brain.