Mesocorticolimbic dopaminergic systems and emotional states

We have used the technique of in vivo voltammetry with carbon fibre electrodes to investigate further the involvement of ascending mesencephalic dopaminergic systems in emotional states in freely moving rats. In Sprague-Dawley rats, forced locomotion caused an increase in extracellular DOPAC levels in the striatum and nucleus accumbens but not in the prefrontal cortex. Immobilization (4 min) or systemic injection of the anxiogenic agent methyl-beta-carboline carboxylate enhanced extracellular DOPAC in both prefrontal cortex and nucleus accumbens but not in striatum whereas tail-pinch provoked a selective increase in this parameter in the nucleus accumbens. These data suggest that mesolimbic and mesocortical dopaminergic systems can be specifically activated by certain kinds of anxiogenic stimuli. To evaluate the relationship between emotional status and the response of mesocortical dopaminergic neurons to stress, we investigated the effects of stressful conditions on dopamine metabolism in the prefrontal cortex of 2 genetically selected lines of rats which differ drastically in their level of emotionality. Introduction of the animals into an unfamiliar environment, application of a high-intensity loud noise or immobilization were associated with an increase in extracellular cortical DOPAC levels in the hypoemotional (RHA) but not in the hyperemotional (RLA) line. These results suggest that the increase in cortical dopamine metabolism induced by stress is not connected to the emotional reaction caused by the aversive nature of the stressor but may reflect activation of cognitive processes in an attempt to cope with the stressor.     

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.     

Neurochemical predisposition to self-administer morphine in rats.

Using in vivo microdialysis, this study attempted to determine whether a neurochemical predisposition to self-administer morphine could be identified. Extracellular levels of dopamine and its metabolites were measured bilaterally in the mesocorticolimbic and nigrostriatal systems of naive rats that were subsequently trained to self-administer morphine intravenously. There were several significant relationships between dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels and rates of morphine self-administration during both acquisition and asymptotic phases of testing. DOPAC and HVA levels in the striatum were inversely correlated with self-administration rates during the asymptotic phase whereas hemispheric asymmetries in striatal metabolite levels were inversely correlated with self-administration during the acquisition phase. DOPAC and HVA levels in in the right but not in the left side of the medial prefrontal cortex were positively correlated with self-administration rates during the acquisition phase; right/left asymmetries in cortical metabolite levels were also correlated with acquisition rates. There were no significant relationships between neurochemical indices and rates of bar-pressing for water. These results suggest that the normal variability in drug seeking behavior is at least in part attributable to individual differences in the organization and activity of brain dopamine systems. Furthermore, different mechanisms appear to be responsible for the initiation and maintenance of morphine intake: DA release in the nucleus accumbens appears to be a critical component of both mechanisms; DA release in the striatum appears to modulate maintenance and, in relationship to striatal lateralization, modulate initiation; DA release in the right but not in the left medial prefrontal cortex appears to be an important predictor of initiation.     

Food deprivation alters dopamine utilization in the rat prefrontal cortex and asymmetrically alters amphetamine-induced rotational behavior

The effects of 24 and 48 h of food deprivation on changes in the activity of dopaminergic (DAergic) neurons and d-amphetamine-induced rotational behavior were studied in male and female Long-Evans rats. Food deprivation selectively altered 3,4-dihydroxyphenylacetic acid (DOPAC) in the medial prefrontal cortex (PFC) but not in the nucleus accumbens or striatum: PFC DOPAC was significantly increased and decreased bilaterally after 24 and 48 h of food deprivation, respectively. Left > right hemispheric asymmetries were seen for DOPAC and DOPAC/DA in the control animals. In a separate experiment, 24 h of food deprivation enhanced right rotational behavior, while 48 h significantly increased left rotational behavior. The results are discussed in terms of food deprivation's effects on mesocortical DAergic neurons, previous work on cortical modulation of striatal function and how these effects on rotational behavior may be determined by brain asymmetry.     

Footshock and conditioned stress increase 3, 4-dihydroxyphenylacetic acid (DOPAC) in the ventral tegmental area but not substantia nigra

The effects of stress on dopamine (DA) metabolism in the mesencephalic DA cell body areas and DA terminal field regions were examined. Both mild footshock stress and exposure to a neutral stimulus previously paired with footshock resulted in a selective increase in the levels of the DA metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the prefrontal cortex as has been previously reported. Footshock stress also resulted in a slight but significant increase in DOPAC levels in the olfactory tubercles. DOPAC levels were selectively increased in the A10 cell body area (ventral tegmental area) but not A9 region (substantia nigra) by both footshock and the conditioned stress paradigm. These data indicate that the cell bodies of origin of the mesocortical dopaminergic system are activated by stress in contrast to those DA neurons innervating the striatum. It appears that mesocortical dopaminergic neurons exhibit different regulatory features than mesolimbic or nigrostriatal neurons.     

Effects of acute and chronic clozapine on dopaminergic function in medial prefrontal cortex of awake, freely moving rats

We previously showed that chronic administration of the clinically atypical and clinically superior antipsychotic drug clozapine selectively reduces dopamine (DA) release in the nucleus accumbens but not neostriatum, and that this effect appears mediated by anatomically selective mesolimbic DA depolarization blockade. The present study extends that research to another mesocorticolimbic DA locus, the medial prefrontal cortex. Acute clozapine challenge (5-40 mg/kg i.p.) produced dose-dependent increased extracellular levels of DA and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the medial prefrontal cortex of awake, free-moving rats as measured by in vivo brain microdialysis. Chronic clozapine treatment (20 mg/kg/day for 21 days) did not significantly change basal extracellular levels of DA, DOPAC or HVA. Acute clozapine challenge on day 22 in the chronic clozapine-treated animals produced no significant differences in medial prefrontal cortex DA, DOPAC or HVA as compared to chronic vehicle-treated animals, indicating that tolerance to clozapine does not develop in the mesocortical DA system, in contrast to the mesolimbic system. The DA agonist apomorphine (100 micrograms/kg) produced decreased basal extracellular levels of DA, DOPAC and HVA in medial prefrontal cortex of both chronic clozapine-treated and chronic vehicle-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

In vivo effects of the putative cognitive enhancer KA-672.HCl in comparison with 8-hydroxy-2-(di-N-propylamino) tetralin and haloperidol on dopamine, 3,4-dihydroxyphenylacetic acid, serotonin and 5-hydroxyindoleacetic acid levels in striatal and cortical brain regions

1. KA-672.HCl (7-methoxy-6-[3-[4-(2-methoxyphenyl)piperazin-1-yl]propoxy]-3,4-di methyl-2H-1-benzopyran-2-one hydrochloride), designed as a cognitive enhancer, has been investigated through behavioural and binding studies. However, little is known about its biochemical effects on the dopaminergic and serotoninergic system in vivo. 2. In the present study the authors investigated the effects of KA-672.HCl (0.1 mg/kg and 1 mg/kg), 8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT) (1 mg/kg), haloperidol (0.1 mg/kg) and a mixture of haloperidol and 8-OH-DPAT on dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT) and 5-hydroxyindolacetic acid (5-HIAA) levels, in striatum and cerebral cortex of rats. 3. Male Wistar rats received an intraperitoneal injection of the drugs or vehicle 1 hour before striatal and cortical brain tissues were dissected out for neurochemical analysis. 4. KA-672.HCl, 8-OH-DPAT and haloperidol significantly reduced striatal DA levels, whereas only KA-672.HCl significantly reduced cortical DA levels. 8-OH-DPAT and haloperidol induced a significant increase in cortical DOPAC levels but only haloperidol significantly elevated the striatal DOPAC content. In contrast, only the higher dose of KA-672.HCl elevated striatal DOPAC levels. Furthermore, KA-672.HCl significantly reduced striatal 5-HT levels and slightly elevated striatal 5-HIAA concentrations. 8-OH-DPAT significantly decreased striatal 5-HIAA levels. All substances were able to enhance the cortical and striatal DA turnover. 5. The cortical and striatal 5-HT turnover was significantly decreased following 8-OH-DPAT treatment and significantly increased in the striatum after haloperidol and KA-672.HCl treatment. 6. The data suggest that KA-672.HCl possesses D2 antagonistic as well as 5-HT1A agonistic properties. However, additional mechanisms of actions by interaction with other neurotransmitter systems such as acetylcholine, excitatory or inhibitory amino acids need to be determined.     

Dysfunctional play and dopamine physiology in the Fischer 344 rat

Juvenile Fischer 344 rats are known to be less playful than other inbred strains, although the neurobiological substrate(s) responsible for this phenotype is uncertain. In the present study, Fischer 344 rats were compared to the commonly used outbred Sprague-Dawley strain on several behavioral and physiological parameters in order to ascertain whether the lack of play may be related to compromised activity of brain dopamine (DA) systems. As expected, Fischer 344 rats were far less playful than Sprague-Dawley rats, with Fischer 344 rats less likely to initiate playful contacts with a playful partner and less likely to respond playfully to these contacts. We also found that Fischer 344 rats showed less of a startle response and greater pre-pulse inhibition (PPI), especially at higher pre-pulse intensities. The increase in PPI seen in the Fischer 344 rat could be due to reduced DA modulation of sensorimotor gating and neurochemical measures were consistent with Fischer 344 rats releasing less DA than Sprague-Dawley rats. Fast scan cyclic voltammetry (FSCV) revealed Fischer 344 rats had less evoked DA release in dorsal and ventral striatal brain slices and high-performance liquid chromatography revealed Fischer 344 rats to have less DA turnover in the striatum and prefrontal cortex. We also found DA-dependent forms of cortical plasticity were deficient in the striatum and prefrontal cortex of the Fischer 344 rat. Taken together, these data indicate that deficits in play and enhanced PPI of Fischer 344 rats may be due to reduced DA modulation of corticostriatal and mesolimbic/mesocortical circuits critical to the execution of these behaviors.     

Strain differences in mesotelencephalic dopaminergic neuronal regulation between Fischer 344 and Lewis rats

Differences in the behavioral responses of Lewis and Fischer (F344) inbred rat strains to stress and psychoactive drugs have been related to differences in the expression of various regulatory proteins in regions containing mesolimbic dopamine (DA) neurons. The present study compared basal and stimulated neurochemical estimates of DA utilization and synthesis in mesocortical, mesolimbic and nigrostriatal DA terminal regions of these two strains. In unstressed control animals, the Lewis strain had lower DA concentrations in the dorsal striatum (ST; 80.3% of F344) and lower basal dihydroxyphenylalanine (DOPA) accumulation after m-hydroxybenzylhydrazine (NSD 1015) treatment in the medial prefrontal cortex (mPfx; 75.3% of F344). Similar differences were observed in vehicle-injected animals. No strain differences in basal neurochemistry were apparent in the nucleus accumbens shell (NAs) or core (NAc). In response to restraint stress, dihydroxyphenylacetic acid (DOPAC) to DA ratios in the mPfx, NAs and ST increased in the F344 but not the Lewis strain. However, restraint stress did not significantly increase DOPA accumulation in the F344 strain. This latter finding was not due to a deficit in synthesis capacity, as gamma-hydroxybutyric acid lactone (GBL) increased DOPA accumulation significantly more in F344 than Lewis animals. Finally, haloperidol increased DA utilization similarly in the two strains. Together these findings suggest that the inbred, behaviorally divergent F344 and Lewis rats have selective differences in mesocortical, nigrostriatal and mesolimbic DA neuronal regulation.     

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.     

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.     

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.     

Loss of dopamine terminals in the medial prefrontal cortex increased the ratio of DOPAC to DA in tissue of the nucleus accumbens shell: role of stress

We examined whether dopamine depletion in the medial prefrontal cortex of the rat differentially affects basal and evoked dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) content in the subareas of the neostriatum and nucleus accumbens. Loss of ≈80% of tissue dopamine content in the medial prefrontal cortex did not significantly alter basal tissue concentrations of dopamine or DOPAC or the DOPAC : dopamine ratio in either the nucleus accumbens core or shell or the medial or lateral neostriatum. However, tail pressure stress significantly increased the DOPAC : dopamine ratio in the nucleus accumbens shell of lesioned rats. Because dorsal and ventral areas of the medial prefrontal cortex preferentially innervate the core and shell, respectively, we sought to determine whether the selective effect of lesions on dopamine terminals in the shell of the nucleus accumbens are paralleled by greater dopamine loss in the ventral medial prefrontal cortex. 6-Hydroxydopamine decreased tissue concentrations of dopamine in both the dorsal (−74%) and ventral medial prefrontal cortex (−68%). In lesioned rats, few tyrosine hydroxylase-immunoreactive fibers remained in the dorsal medial prefrontal cortex whereas a dense innervation remained in the ventralmost area. The present data suggest that the influence of mesocortical dopamine neurons on the dopamine projection to the nucleus accumbens shell is expressed only under conditions of stress. Furthermore, lesion-induced alterations in dopamine neurons projecting to the nucleus accumbens shell are not due to a more extensive loss of dopamine terminals in the ventral than in the dorsal medial prefrontal cortex.     

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.     

Changes in the serotonergic, noradrenergic and dopaminergic levels in the brain of scrapie-infected rats

Levels of serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylethyleneglycol (DHPG) were determined by high-performance liquid chromatography in different brain areas of scrapie-infected rats, 8.5 months after intracerebral inoculation of a rat-adapted strain from mice brain (C 506). At this time, rats developed early clinical signs of the disease. Scrapie-infected rats showed a reduction in the levels of 5-HT and 5-HIAA (frontal cortex, hippocampus, mesolimbic structure). Concentrations of DHPG decreased in the frontal and parietal cortices but remained unchanged in the hippocampus. DOPAC levels decreased in the striatum but not in the mesolimbic structure. These results confirm that the serotonergic, noradrenergic and dopaminergic systems are altered in the brain of scrapie-infected rats. They can partly account for clinical signs of scrapie and are in agreement with the scarce data provided by the postmortem analysis of Creutzfeldt-Jakob disease brains.     

Effects of morphine treatment and withdrawal on striatal and limbic monoaminergic activity and ascorbic acid oxidation in the rat

Since ascorbic acid (AA) reportedly suppresses tolerance to and dependence on morphine in humans and rodents, levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-methoxytyramine (3-MT), 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), AA, dehydroascorbic acid (DHAA), uric acid, xanthine, hypoxanthine, glutamate and γ-amino-butyric acid (GABA) were determined by high-pressure liquid chromatography (HPLC) in the striatum and in the limbic forebrain of the rat following morphine treatment (single or repeated) and withdrawal. Single morphine administration (20 mg/kg s.c.) increased DOPAC + HVA/DA, 5-HIAA/5-HT and DHAA/AA ratios, uric acid levels, and decreased xanthine, hypoxanthine, glutamate and GABA levels in both regions. 3-MT levels were decreased in the striatum and increased in the limbic forebrain. After 7 days of morphine treatment, striatal DOPAC + HVA/DA and DHAA/AA ratios and uric acid levels were still higher and striatal and limbic xanthine levels still lower than in controls, while all other parameters were in the range of control values in both regions. Morphine treatment also increased the glutamate/GABA ratio in the striatum. In all morphine-treated rats, individual striatal DOPAC + HVA/DA and DHAA/AA ratio values were directly correlated. After a 48 h withdrawal period, both striatal AA oxidation and glutamate/GABA ratio further increased; limbic 3-MT levels further decreased, while all other parameters did not differ from control values. We conclude that: (i) tolerance to morphine-induced increase in hypoxanthine, xanthine and AA oxidation develops in the limbic forebrain faster than in the striatum; (ii) the morphine-induced increase in striatal and limbic AA oxidation may be considered a consequence of increased formation of reactive oxygen species due to increased DA, hypoxanthine and xanthine oxidative metabolism; (iii) a striatal excitotoxic imbalance characterizes the withdrawal state and may be taken into account to explain the further increase in striatal AA oxidation.     

Neurochemical changes in the substantiae nigrae and caudate nuclei following acute unilateral intranigral infusions of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

Acute unilateral intranigral infusions of MPTP at doses (200 micrograms) which produce robust contralateral rotation in the rat induced significant neurochemical changes in the ipsilateral as well as contralateral nigrostriatal systems. There were pronounced increases in the levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the ipsilateral substantia nigra and a significant decrease in the levels of DA in the ipsilateral caudate nucleus while opposite changes occurred in the contralateral substantia nigra and caudate nucleus. The DOPAC:DA and HVA:DA ratios were significantly higher in the ipsilateral caudate nucleus indicating increased activity of the ipsilateral nigrostriatal DA neurones. The levels of noradrenaline and 4-hydroxy-3-methoxyphenylethyline glycol (MHPG) increased and decreased significantly in the ipsilateral and contralateral substantia nigra, respectively, but there were no significant changes in the caudate nuclei. The levels of serotonin (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) increased significantly in the ipsilateral substantia nigra and caudate nucleus as well as in the contralateral caudate nucleus but did not increase significantly in the contralateral substantia nigra. The 5-HIAA:5-HT ratio was significantly decreased in the contralateral caudate nucleus indicating a reduced activity of the contralateral nigrostriatal 5-HT neurones. The data thus indicate that MPTP applied to one substantia nigra is capable of producing profound neurochemical changes not only locally but also in the ipsilateral striatum as well as in the contralateral nigrostriatal system. Previous neuropharmacological studies have suggested that the rotation induced by intranigral MPTP may be mediated via dopamine released from dendrites in the pars reticulata in response to MPTP.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Free and conjugated 3, 4-dihydroxyphenylacetic acid and homovanillic acid in brain dopaminergic areas at basal state and after pipotiazine activation

Summary We have determined free and conjugated 3, 4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in discrete brain areas of rats.Conjugated HVA or DOPAC accounted for 22–38% of total acids in striatum, mesolimbic tissue or prefrontal cortex. Activation of dopamine (DA) metabolism by a single injection of pipotiazine palmitic ester (PPZ), a long-lasting neuroleptic, increased free acid levels (DOPAC and HVA) at either dose and conjugate levels after 32 or 50 mg/kg. 48 hours after PPZ-32 mg/kg, the observed increases of conjugates could exceed in some cases those of corresponding free acids.About half of total DOPAC and HVA were conjugated in hypothalamus, PPZ moderately increased free DOPAC (at 32 mg/kg) but did not elevate significantly the conjugated form.It is concluded that sulfation is an important pathway for DOPAC and HVA metabolism in brain and that the determination of both free and conjugated DOPAC or/and HVA may shed additional lights on regional DA metabolism and the effect of drags thereon.     

Alterations in calmodulin content and localization in areas of rat brain after repeated intermittent amphetamine.

To assess whether calmodulin (CaM) could have a role in the behavioral sensitization induced by repeated intermittent amphetamine, CaM content was determined in several brain areas from rats repeatedly administered saline or amphetamine. Rats were treated with amphetamine using an escalating dose paradigm and withdrawn for either 4 weeks (withdrawn group) or 30 min (non-withdrawn group). CaM content was measured in cytosol and 100,000 x g membrane fractions from striatum, limbic forebrain, medial prefrontal cortex, hippocampus and cerebellum. In the withdrawn group, CaM was significantly increased in both striatal membranes and cytosol and in the mesolimbic membranes from amphetamine-treated rats. There were no changes in CaM in the medial prefrontal cortex, hippocampus or cerebellum. In the non-withdrawn group, there was no significant change in CaM in striatal or mesolimbic fractions but CaM was significantly decreased in cytosol of the medial prefrontal cortex and hippocampus as compared to saline controls. This decrease could be related to the tolerance that has developed to the amphetamine after the repeated treatments. In the withdrawn group, challenge with a low dose of amphetamine (1 mg/kg) elicited a translocation of CaM from membranes to cytosol in the striatum and limbic forebrain of rats repeatedly treated with amphetamine, but not in saline-treated rats. Our findings that the change in CaM occurs in striatum and limbic forebrain, requires time after treatment to develop and exhibits persistence after withdrawal correlate with known characteristics of behavioral sensitization to amphetamine. These results suggest that CaM could contribute to neurochemical events underlying behavioral sensitization to amphetamine.