Increase In DOPAC Research Articles

Ethanol concentration induces production of 3,4-dihydroxyphenylacetic acid and homovanillic acid in mouse brain through activation of monoamine oxidase pathway

First, we aimed to investigate ex vivo the effects of ethanol (EtOH) on levels of norepinephrine (NE), dopamine (DA), serotonin (5-HT), and their metabolites in the frontal cortex, hippocampus, and striatum of Aldh2-knockout (Aldh2-KO) and wild-type (WT) mice. Animals were treated intraperitoneally with saline (control) or EtOH (1.0, 2.0, or 3.0 g/kg). Brain samples were collected 60 and 120 min after EtOH injection, and monoamines and their metabolites were measured by HPLC-ECD. We found in both WT and Aldh2-KO mice that 3.0 g/kg EtOH increased the levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) and decreased the level of 3-methoxytyramine (3-MT). A 2.0 g/kg dose of EtOH also increased HVA, but there was not a consistent effect within the brain regions of Aldh2-KO and WT mice. There were inconsistent findings of genotype differences in the levels of DA, 5-HT, and their metabolites in the brain regions tested. None of the EtOH doses altered NE, DA, 5-HT, or 5-hydroxyindoleacetic acid contents in any of the brain regions studied. Second, we tested whether EtOH-induced increases in DOPAC and HVA are mediated by increased monoamine oxidase (MAO) or catechol-O-methyltransferase (COMT) activity. To test this, we used the MAO blocker clorgyline (2.0 and 4.0 mg/kg) and the COMT blocker tolcapone (15 and 30 mg/kg) alone or in combination with EtOH (3.0 g/kg). Clorgyline alone increased 3-MT and decreased DOPAC and HVA levels, whereas tolcapone alone increased DOPAC and decreased 3-MT and HVA levels. Surprisingly, the combination of EtOH with clorgyline (4.0 mg/kg) or tolcapone (30 mg/kg) further decreased 3-MT and increased DOPAC and HVA levels, an effect that reversed the inhibitor-induced decreases in HVA. These results suggest that a high concentration of EtOH can accelerate DA metabolism, as evidenced by the increase in DOPAC and HVA, and this effect is likely a consequence of increased degradation of DA by MAO.

Expression and impact of Lsamp neural adhesion molecule in the serotonergic neurotransmission system

Limbic system associated membrane protein (Lsamp) is a neural adhesion protein which has been recently found to be differentially expressed between serotonergic neuron subtypes. We have previously shown elevated serotonin (5-HT) turnover rate in Lsamp-deficient mice. The purpose of the current study was to elucidate the role of Lsamp in serotonergic neurotransmission.Chronic (18 days) administration of serotonin reuptake inhibitor (SSRI) escitalopram (10 mg/kg) significantly increased general activity in wild-type mice in the open field and protected exploration in Lsamp−/− mice in the elevated-plus maze. An important psychopathology-related endophenotype, elevated 5-HT turnover in the brain of Lsamp-deficient mice, was reproduced in the saline group. Escitalopram restored the elevated 5-HT turnover of Lsamp-deficient mice to a level comparable with their wild-type littermates, suggesting that high 5-HT turnover in mutants is mediated by the increased activity of serotonin transporter (SERT protein encoded by Slc6a4 gene). The baseline level of Slc6a4 transcript was not changed in Lsamp-deficient mice, however, our immunohistochemical analysis showed partial co-expression of Lsamp with both SERT and Tph2 proteins in raphe. Overactivity of SERT in Lsamp−/− mice is further supported by significant elevation of Maoa transcript and increase of DOPAC, another Mao A product, specifically in the raphe. Again, elevation of DOPAC was reduced to the level of wild-type by chronic SSRI treatment. The activity of Lsamp gene promoters varied in 5-HT producing nuclei: both Lsamp 1a and 1b promoters were active in the dorsal raphe; most of the expression in the median raphe was from 1b promoter, whereas Lsamp 1a promoter was almost exclusively active in the caudal subgroup of raphe nuclei. We suggest that Lsamp may have an impact on the integrity of serotonergic synapses, which is possibly the neurochemical basis of the anxiety- and sociability-related phenotype in Lsamp-deficient mice.

P.2.013 Dopamine D4 receptor activation improves performance in a rat model of ADHD

Our recent work (Cartmell et al., Journal of Neurochemistry, 75 (2000) 1147–1154) demonstrated that systemic injection of the potent, selective mGlu2/3 receptor agonist, LY379268, acutely increased extracellular levels of dopamine, its metabolites DOPAC and HVA, and the 5-HT metabolite, 5-HIAA, in rat medial prefrontal cortex (mPFC). Here, we compared the acute effects of LY379268 with those of clozapine and risperidone (atypical antipsychotics) on extracellular levels of both dopamine and 5-HT in the mPFC of freely-moving rats. Uptake blockers were included to minimize metabolism of monoamines near the probe area. One hour after injection, LY379268 (10 mg/kg s.c.), clozapine (10 mg/kg s.c.) or risperidone (1 mg/kg s.c.) maximally increased dopamine by 224, 257 and 234% of basal levels. These effects were followed by maximal increases in DOPAC and HVA levels 2 to 3.5 hours after administration. LY379268, at 3 and 10 mg/kg s.c., and risperidone (1 mg/kg s.c.) also increased dialysate 5-HT to 169, 179 and 140% of basal levels and 5-HIAA to 144, 154 and 121% of basal levels, respectively. These neurochemical changes in the mPFC could not be mimicked when LY379268 (3 or 30 μM) was administered locally via the microdialysis probe. These data demonstrate that increases in extracellular monoamines in the rat prefrontal cortex evoked acutely by the mGlu2/3 agonist, LY379268, are similar in profile to risperidone, not locally mediated, and can be elicited in the presence of uptake blockade.

Pb and Cd poisoning during development alters cerebellar and striatal function in rats

The present study was designed to examine more fully the neurochemical and behavioral interactions that derive from continued lead and cadmium poisoning in pups, whose mothers were exposed via drinking water (300 mg/l of Pb and 10 mg/l of Cd) throughout pregnancy and lactation. At weaning, these metals produced an increase in DOPAC, 5-HT and 5-HIAA contents in cerebellum, but the monoamine contents in striatum remained unaltered. The cerebral energetic metabolism was modified by the Cd–Pb exposition only in striatum. On the other hand, the Na+/K+-ATPase activity was inhibited significantly in both regions at PN21, whereas the alkaline phosphatase activity was not affected by the treatment. The intoxicated animals showed a short-term normocitic anemia, but revealed long-term alterations in the motor activity in open-field, where they showed an increase in both ambulating and rearing. So, it can be concluded that perinatal exposure to lead and cadmium provoke neurochemical alterations in cerebellum and striatum that can be related with the changes in motor activity observed in the adulthood.

Biphasic dose-related effects of morphine on dopamine release

The effects of morphine on extracellular dopamine levels in brain have never been studied over a wide range of doses within a single study. This has made it difficult to make definitive interpretations of drug interactions with morphine. An inhibition of morphine-induced increases in dopamine could be interpreted as either antagonism or potentiation depending the shape of the morphine dose–response curve. Accordingly, the aim of the present study was to determine the effects of a wide range of morphine doses (0, 5, 10, 20 and 30 mg/kg, i.p.) on extracellular dopamine, DOPAC and HVA levels in the nucleus accumbens and striatum of awake and freely moving female Sprague–Dawley rats. The results show that, in both brain regions, the dose–response curve for morphine-induced increases in dopamine is non-monotonic while the dose–response curve for morphine-induced increases in DOPAC and HVA is monotonic in the nucleus accumbens. The results of this study are discussed in terms of their implications for interpreting drug interactions with morphine and with relationship to morphine's mode of action at mu and kappa opioid receptors.

Characterization of vinpocetine effects on DA and DOPAC release in striatal isolated nerve endings

The effect of vinpocetine, a nootropic drug with anti-ischemic potential, on the release of DA and its main metabolite, DOPAC, was investigated in striatum isolated nerve endings under resting and depolarized conditions. Vinpocetine does not modify the baseline release of DA or the exocytotic release of DA evoked by high K +, but inhibits the release of DA evoked by veratridine reversal of the DA transporter. In addition to these results, which confirm the vinpocetine selective blockade of voltage-sensitive presynaptic Na + channels (VSSC) previously reported [Neurochem. Res. 24 (1999) 1585], vinpocetine increases DOPAC release either under resting, veratridine or high K + depolarized conditions. This latter effect, which does not involve VSSC, was characterized. The parallel determination of the released and retained catecholamine concentrations revealed that vinpocetine increases DOPAC release at the expense of internal DA in a dose-dependent manner (low μM range). In contrast to vinpocetine, the selective MAO-A inhibitor, clorgyline, increases DA and decreases DOPAC formation. The combined action of vinpocetine and clorgyline does not indicate, however, that the activation of MAO is the mechanism responsible for the increase in DOPAC caused by vinpocetine. Reserpine, although more potent and efficient than vinpocetine, qualitatively exerts the same pattern of changes on DA and DOPAC concentrations. It is concluded that, in addition to the inhibition of presynaptic VSSC permeability, which selectively inhibits the transporter-mediated release of all neurotransmitters, vinpocetine increases DOPAC by impairing the vesicular storage of DA. Our results indicate that the cytoplasm extravesicular DA is metabolized by MAO to DOPAC. Most of the DOPAC formed is exported to the extracellular medium.

Acute increases in monoamine release in the rat prefrontal cortex by the mGlu2/3 agonist LY379268 are similar in profile to risperidone, not locally mediated, and can be elicited in the presence of uptake blockade

Our recent work (Cartmell et al., Journal of Neurochemistry, 75 (2000) 1147–1154) demonstrated that systemic injection of the potent, selective mGlu2/3 receptor agonist, LY379268, acutely increased extracellular levels of dopamine, its metabolites DOPAC and HVA, and the 5-HT metabolite, 5-HIAA, in rat medial prefrontal cortex (mPFC). Here, we compared the acute effects of LY379268 with those of clozapine and risperidone (atypical antipsychotics) on extracellular levels of both dopamine and 5-HT in the mPFC of freely-moving rats. Uptake blockers were included to minimize metabolism of monoamines near the probe area. One hour after injection, LY379268 (10 mg/kg s.c.), clozapine (10 mg/kg s.c.) or risperidone (1 mg/kg s.c.) maximally increased dopamine by 224, 257 and 234% of basal levels. These effects were followed by maximal increases in DOPAC and HVA levels 2 to 3.5 hours after administration. LY379268, at 3 and 10 mg/kg s.c., and risperidone (1 mg/kg s.c.) also increased dialysate 5-HT to 169, 179 and 140% of basal levels and 5-HIAA to 144, 154 and 121% of basal levels, respectively. These neurochemical changes in the mPFC could not be mimicked when LY379268 (3 or 30 μM) was administered locally via the microdialysis probe. These data demonstrate that increases in extracellular monoamines in the rat prefrontal cortex evoked acutely by the mGlu2/3 agonist, LY379268, are similar in profile to risperidone, not locally mediated, and can be elicited in the presence of uptake blockade.

In Vivo Effects of Deltamethrin on Dopamine Neurochemistry and the Role of Augmented Neurotransmitter Release

Neurochemical analyses of dopamine, consistent with the development of parkinsonism, were performed in C57BL6 male mice. Mice were treated by intraperitoneal injection, three times over a 2-week period with 6 mg/kg deltamethrin alone or in combination with a single treatment of 20 mg/kg of the parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In ex vivo synaptosomes prepared from treated mice, deltamethrin caused a 70% increase in maximal dopamine uptake, which would be consistent with increased dopamine outflow in vivo and suggested an up-regulation in dopamine transporter expression. In contrast, MPTP treatment had little effect on dopamine transport but it reversed the deltamethrin-induced increase in Vmax when given in combination. Potent effects of deltamethrin on dopamine release were confirmed in vitro, where deltamethrin had an EC50 of 48 nM for enhancing veratridine-stimulated dopamine release from preloaded striatal synaptosomes. Under similar experimental conditions, deltamethrin had an EC50 for enhancing glutamate release of 412 nM and an EC50 for enhancing serotonin release of 117 nM. Thus, the dopaminergic nerve terminals of the striatum were more sensitive to pyrethroid than those of other neurotransmitter types, and loss of dopamine from striatal terminals is a cardinal sign of Parkinson's disease. The augmented release of dopamine and glutamate in vivo could underlie deltamethrin-induced neuronal insult, since elevated levels of these neurotransmitters are known to be neurotoxic. However, at the dose and assessment times used in this study, dopamine and DOPAC levels were not significantly affected by deltamethrin, although there was a small increase in the metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), consistent with increased turnover of dopamine in vivo. In accord with previous studies, MPTP alone decreased levels of both dopamine and DOPAC. When co-applied, MPTP reversed the small increase in DOPAC caused by deltamethrin, perhaps indicating greater toxicity in the double-treatment group. Higher doses or longer exposure times would be expected to yield greater effects of deltamethrin on dopamine content in the nigrostriatum.

Reproductive experience reduces striatal dopaminergic responses in freely moving female rats.

Reproductive experience influences basal and pregnancy profiles of circulating prolactin levels in women and female rats, respectively. Endocrine responses to dopaminergic antagonists are modified by reproductive experience as well. Striatal extracellular dopamine metabolites were measured in vivo by HPLC-ED in perfusates obtained by microdialysis in non-anaesthetized, freely moving, intact and ovariectomized, nulliparous and primiparous rats. Data were collected for at least 7 h. This period always included the light-dark shift at 18:00 h. In a second experiment, microdialysis was performed in ovariectomized nulliparous and primiparous rats treated with haloperidol (1.0 mg/kg s.c.). During the 1 h before and after the onset of the light-dark shift, HVA concentrations in the perfusates increased in nulliparous compared with primiparous rats. The haloperidol-induced increase in DOPAC and HVA was less intense in primiparous rats than that in nulliparous ovariectomized rats. These data revealed a different pattern of striatal dopaminergic anticipation and response to the shift in the light-dark cycle in nulliparous as compared with primiparous intact females. In addition, a distinct striatal dopaminergic response to haloperidol was observed in primiparous as compared to nulliparous ovariectomized rats. The results suggest that reproductive experience can modulate the activity of dopaminergic terminals in the striatum.

Declines in stimulated striatal dopamine release over the first 32 h following microdialysis probe insertion: generalization across releasing mechanisms

In a recent paper [R.R. Holson, J.F. Bowyer, P. Clausing, B. Gough, Methamphetamine-stimulated striatal dopamine release declines rapidly over time following microdialysis probe insertion, Brain Res. 739 (1996) 301–307] we reported that methamphetamine-stimulated striatal dopamine release declined rapidly over the first eight hours following microdialysis probe insertion. This decline was strictly a function of time post-probe implantation, and not due to tolerance or desensitization. To further examine this phenomenon, we subjected rats to three brief pulses of several DA-releasing compounds at 2, 4 and 6 h post-probe insertion, and compared these results to those caused by a single pulse 6 h post-insertion, or in some cases to pulses given more than 24 h post-insertion. We found that when buproprion, a dopamine reuptake blocker, was infused briefly into the striatum via the microdialysis probe, there was a pronounced drop in the amount of dopamine released at 6 h vs. 2 h post-insertion; this drop was not due to repeated exposure, since dopamine release at 6 h post-insertion was the same for a single pulse, or when preceded by two earlier pulses. Twenty-four hours later, buproprion-stimulated dopamine release was still lower, but did not appear to drop further thereafter. Potassium-stimulated dopamine release, on the other hand, dropped rapidly over the first 8 h post-insertion, and this decline continued throughout the 24–32 h interval post-insertion. Similarly, a single i.p. injection of 0.5 mg/kg haloperidol released three times as much dopamine when given two compared to six hours post-implantation. Both bupropion- and potassium-stimulated dopamine release were accompanied by declines in extracellular DOPAC concentrations, and these declines were the same 2 or 26 h post-insertion. In contrast, haloperidol exposure increased extracellular DOPAC, and this haloperidol-stimulated DOPAC increase was also greatly attenuated at 6 compared to 2 h post-insertion. We conclude that there is a general decline over time post-probe implantation in the ability of the striatal dopamine system to release dopamine, and perhaps to increase dopamine synthesis, in response to pharmacological challenges.

Effect of reserpine on 3-methoxy-4-hydroxyphenylethyleneglycol and 3,4-dihydroxyphenylacetic acid in the hippocampus of depression-model rats: An in vivo microdialysis study

Using in vivo microdialysis, we examined the effect of intraperitoneal injection of reserpine (2 mg/kg) on hippocampal 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) and 3,4-dihydroxy-phenylacetic acid (DOPAC), two major metabolites of catecholamine. Responses were examined serially for 12 h in the hippocampus of walking-stress-induced depression-model rats, recovery rats and control rats. Control rats showed a rapid rise followed by a gradual fall of free and total MHPG and a delayed increase of DOPAC in response to reserpine. Depression-model rats showed a significantly blunted biphasic response of free and total MHPG as well as blunted monophasic response of DOPAC compared with control rats. Recovery rats also exhibited a blunted fall response of MHPG. Our findings suggest that the vesicle membrane in the central noradrenaline (NA) neurons could be hyposensitive to reserpine in the depression-model rats.

Androgen inhibits neurotransmitter turnover in the medial prefrontal cortex of the rat following exposure to a novel environment

Previous studies have demonstrated that gonadal steroid hormones affect the neuroendocrine response to a novel environment and other stressors. Introduction to a novel environment also increases neurotransmitter turnover in the medial prefrontal cortex (MPFC). In this study, we examined the possibility that gonadal steroid hormones could similarly modulate the neurotransmitter response to a novel environment in the MPFC of the male rat. Male Fischer 344 rats at 3 months of age were gonadectomized (GDX'd) and implanted with Silastic capsules containing dihydrotestosterone propionate (DHTP, a non-aromatizable form of androgen), 17 β-estradiol (E), or placebo. Control animals were left intact. Each of these groups was further divided into a group introduced to a novel environment or a home cage control group. Animals exposed to a novel environment were killed after spending 20 min in a novel open field, whereas control animals were killed immediately upon removal from their home cage. Using high performance liquid chromatography, the MPFC was assayed for tissue levels of dopamine (DA) and its metabolites, 3,4-dihydroxyphenylalanine (DOPAC) and homovanillic acid (HVA); norepinephrine (NE) and its metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG); or serotonin (5-HT) and its metabolite 5-hydroxyindole acetic acid (5-HIAA). The introduction to a novel environment caused significant increases in turnover of all three neurochemicals examined as estimated by metabolite/precursor ratios. These increases were characterized by increases in DOPAC, HVA, MHPG and 5-HIAA coupled with decreases in DA, NE and 5-HT. There was no effect of GDX on neurotransmitter turnover, however, treatment of GDX animals with DHTP prevented the open field induced increase in DOPAC/DA, MHPG/NE, and 5-HIAA/5-HT ratio. Treatment of GDX animals with estrogen had the opposite effect of DHTP, DOPAC/DA and MHPG/NE ratios increased to a greater level following the introduction to a novel environment than in GDX or intact animals. Examination of behavior in the open field showed significant decreases in activity in the DHTP-treated group but not in any other behavioral parameter (rears, nose pokes). Since the non-aromatizable androgen, DHTP, is presumably acting via androgen receptors, and E is presumably acting via estrogen receptors, these data suggest that, in the MPFC of male rats, androgen and estrogen receptors act in an opposing fashion to modify neurotransmitter turnover. This suggests that local changes in the relative levels of androgen and estrogen can have profound effects on the neurobiological response of the medial prefrontal cortex to stimuli.© 1997 Elsevier Science B.V. All rights reserved.

Evidence that D 2 receptor-mediated activation of hypothalamic tuberoinfundibular dopaminergic neurons in the male rat occurs via inhibition of tonically active afferent dynorphinergic neurons

The purpose of the present study was to determine if D 2 receptor-mediated activation of hypothalamic tuberoinfundibular dopaminergic (TIDA) neurons occurs via afferent neuronal inhibition of tonically active inhibitory dynorphinergic neurons in the male rat. To this end, the effects of either surgical deafferentation of the mediobasal hypothalamus or administration of a κ opioid receptor agonist (U-50,488) or antagonist (nor-binaltorphimine (NOR-BNI)) on D 2 receptor-mediated activation of TIDA neurons were assessed. For comparison, the activity of mesolimbic DA neurons was also determined in these studies. TIDA and mesolimbic DA neuronal activities were estimated by measuring dopamine synthesis (accumulation of 3,4-dihydroxyphenylalanine (DOPA) following decarboxylase inhibition) and metabolism (concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC)) in terminals of these neurons in the median eminence and nucleus accumbens, respectively. Intraperitoneal administration of the D 2 receptor agonist quinelorane caused a dose-dependent increase in DOPAC in the median eminence and a decrease in DOPAC in the nucleus accumbens; surgical deafferentation of the mediobasal hypothalamus prevented the effect of quinelorane in the median eminence, but not the nucleus accumbens. Activation of κ opioid receptors with U-50,488 had no effect per se, but blocked quinelorane-induced increases in median eminence DOPA. In contrast, U-50,488 had no effect on DOPA in the nucleus accumbens of either vehicle- or quinelorane-treated rats. Blockade of κ opioid receptors with NOR-BNI increased median eminence DOPA, and prevented the stimulatory effects of quinelorane on dopamine synthesis. Administration of prolactin also increased median eminence DOPA, but did not alter the ability of quinelorane to stimulate dopamine synthesis. Neither NOR-BNI nor prolactin had any effect on DOPA in the nucleus accumbens of vehicle- or quinelorane-treated rats. These results suggest that D 2 receptor-mediated activation of TIDA neurons occurs via an afferent neuronal mechanism involving, at least in part, inhibition of tonically active inhibitory dynorphinergic neurons in the male rat.

The effects of ethanol in combination with the α2-adrenoceptor agonist dexmedetomidine and the α2-adrenoceptor antagonist atipamezole on brain monoamine metabolites and motor performance of mice

The time course of the effects of ethanol alone and in combination with the selective α 2-adrenoceptor agonist dexmedetomidine and the α-adrenoceptor antagonist atipamezole was studied in NIH-Swiss mice. Core body temperature, rotarod performance, motility and changes in the noradrenaline, dopamine, and 5-hydroxytryptamine (5-HT) metabolite contents of different brain parts (limbic forebrain, striatum, lower brainstem, the rest of the forebrain + midbrain and hypothalamus) were measured. Atipamezole (3 mg/kg) attenuated the hypothermia induced by either ethanol (3 g/kg) alone or ethanol in combination with dexmedetomidine (0.3 mg/kg). Atipamezole shortened the duration of the ethanol-impaired and ethanol + dexmedetomidine-impaired rotarod performance. Further, atipamezole prevented the decreased motility due to the combined treatment with ethanol and dexmedetomidine. Ethanol increased 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) values. Dexmedetomidine alone decreased MHPG and 5-hydroxyindoleacetic acid (5-HIAA) concentrations and increased DOPAC and HVA values. Dexmedetomidine combined with ethanol resulted in a further increase in DOPAC and HVA values. Pharmacokinetic parameters did not contribute to this antagonism of ethanol's effects by atipamezole, nor did the antagonism observed in rotarod performance or hypothermia seem to correlate with the changes seen in the brain noradrenaline and dopamine or 5-HT metabolism. In conclusion, these findings suggest that several ethanol effects are not mediated via direct activation of α 2-adrenoceptors, even though some of ethanol's behavioral and physiological effects may be antagonized by coadministration of α 2-adrenoceptor antagonists.

Effects of kainic acid, quisqualic acid, and their antagonist, pCB-PzDA, on rat electrocorticograms and monoamine metabolite levels in rat striatum.

The action of kainic acid (KA), quisqualic acid (QA), and 1-(4-chlorobenzoyl)-piperazine-2,3-dicarboxylic acid (pCB-PzDA) was investigated in the central nervous system of male Sprague Dawley rats. Intracerebroventricularly injected KA and QA (100 nmol) induced spike discharges, and pCB-PzDA (100 nmol) suppressed electrocorticograms for one hour. pCB-PzDA enhanced the KA-induced spike discharges and inhibited those induced by QA. 2,3-Di-hydroxyphenylacetic acid(DOPAC) and homovanillic acid (HVA) levels were increased transiently by 10 nmol and continuously by 100 nmol of KA. KA dose-dependently increased 5-hydroxyindoleacetic acid (5-HIAA) levels 2 hours after administration. While 10 nmol of QA slightly increased the HVA level, 100 nmol of QA significantly increased DOPAC, HVA, and 5-HIAA levels. DOPAC and HVA levels were increased by 100 nmol of pCB-PzDA, although this agent inhibited KA-induced increases in DOPAC, HVA, and 5-HIAA levels. On the other hand, while pCB-PzDA first inhibited QA-induced increases in DOPAC, HVA and 5-HIAA levels for one hour, DOPAC and HVA levels thereafter increased additively. These findings suggest that pCB-PzDA may act not only as a NMDA antagonist, but that it may also act directly on dopaminergic neurons.

Striatal dopamine turnover during treadmill running in the rat: Relation to the speed of running

HATTORI, S., M. NAOI AND H. NISHINO. Striatal dopamine turnover during treadmill running in the rat: Relation to the speed of running. BRAIN RES BULL 35(1) 41–49, 1994.—To evaluate the physiological action of Striatal dopamine (DA) in exercise, rats were trained to run on a straight treadmill. Extracellular DA and its metabolites, dihydroxyphenylacetic acid (DO-PAC), and homovanillic acid (HVA) were measured by in vivo microdialysis, and striatal tissue tyrosine hydroxylase (TH) activity and monoamine oxidase (MAO) activity were measured using high performance liquid chromatography (HPLC) and spectrophotometer. DA turnover was increased by running, and the increase in DOPAC and HVA was closely related to the speed of running, while the increase in DA had no relationship to the speed. The threshold for the increase in DA, DOPAC, and HVA was between 300 and 660 cm/min. Striatal tissue TH activity was elevated up to 135% of basal values after the rats were trained for 7 days to run at 1800 cm/min. Just after running for 20 min, there was a further increase to 180%. These values became 150% and 90% of basal values at 2 h and 6 h, showing a similar time course as DA detected by microdialysis. MAO-B activity increased up to 160% of basal values after 7 days training but decreased to 130% and 110% just after and 2 h after running, then increased to 145% 6 h after running. MAO-A showed a similar variation as MAO-B. These data suggest that both the synthesis and metabolism of DA have a close relationship with physical exercise and might contribute to adjusting extracellular DA levels within an adequate range in response to exercise intensity.

Lateralized changes in prefrontal cortical dopamine activity induced by controllable and uncontrollable stress in the rat

Exposure to stressors that are not controlled results in a variety of changes in behavior and in brain chemistry. Among these is the activation of dopamine-containing neuronal systems projecting to the medial prefrontal cortex (PFC), to a lesser extent the nucleus accumbens (NAC) and, in a few studies, the striatum. Previous data have shown that stressor evoked PFC activation is asymmetrical. The present experiments were designed to assess the effects of controlled and uncontrolled stressors on these DA systems using the procedures of the learned helplessness (LH) model. In a first experiment, 80 trials of either a controllable (ESC) or identical uncontrollable footshock stressor (YOK) caused an activation, as indiated by increased metabolite concentrations of DA in the PFC, NAC and striatum. In the PFC, YOK caused a bilateral DA depletion, relative to ESC and control animals, and a right > left increase in DOPAC/DA which was not seen in ESC animals. These findings suggested a preferential effect of YOK in the right PFC. A second experiment used rats that had been grouped according to their turning behavior, YOK right-biased rats showed an increase in DOPAC on the right side of the PFC and YOK left-biased rats displayed a similar increase on the left side in response to a brief (5 min) controllable footshock stressor. Since right-turning rats had been shown to be more sensitive to a LH behavioral phenomenon, the data suggested that right PFC activation is responsible for the greater LH sensitivity. A final experiment evaluated the neurochemical and behavioral responses to a prolonged footshock stressor 24 h after uncontrolled footshock. Right-biased YOK animals displayed depressed footshock escape behavior and a right > left depletion in PFC DA and HVA. Across-groups footshock escape performance was correlated with DA and HVA concentrations on the right but not on the left side of the PFC. Thus a disturbance of right PFC DA utilization was again associated with compromised coping behavior. The data suggest that the inability to control a stressor causes a lateralized alteration of PFC DA and this results in a disruption of the ability to respond to a new stressor. These findings indicate that the two sides of the PFC are differentially specialized for responding to a stressor.

Benzodiazepines preferentially affect mesolimbic dopamine turnover in rats

Withdrawal of benzodiazepines in man may induce hallucinatory symptoms and can evoke delusional depressions, which can be treated with dopamine-antagonistic drugs. Withdrawal of benzodiazepines in rats induces a strong hyperactivity during daytime, leaving the nighttime activity relatively undisturbed. This hyperactivity may be related to an enhanced dopaminergic activity in the mesolimbic area, especially in the nucleus accumbens. Mesolimbic dopaminergic activity may be specifically involved in the development of benzodiazepine withdrawal. Acute administration of benzodiazepines in otherwise non-treated rats, has been described not to affect the dopamine-turnover in the nucleus accumbens, measured by synthesis inhibition. However, activation by administration of haloperidol (feedback activation)_ can be suppressed by benzodiazepines effectively. Five different benzodiazepines viz. desmethyldiazepam (DMD), lorazepam (LRZ), brotizolam (BTZ), triazolam (TRZ) and flunitrazepam (FNZ) have been compared with respect to their acute effects. Using a 3-fold increase in dopamine turnover (determined by measuring the DOPAC-concentration), benzodiazepines were capable to reduce this increase maximally for 70–80% in the nucleus accumbens. The results point to a selective effect of benzodiazepines in the nucleus accumbens. The increase induced by haloperidol in the corpus striatum was found to be much less sensitive to benzodiazepines. In contrast to the other compounds lorazepam appeared to have no effect on haloperidol-induced increase in DOPAC concentration. Flunitrazepam and brotizolam did affect not only the haloperidol-induced DOPAC increase but also the basal DOPAC concentrations. Linear dose-response curves could not be obtained for the compounds, but minimal effective doses could be assessed. Flunitrazepam and triazolam appeared to be the most active compounds. The data indicate that benzodiazepines are capable to inhibit dopamine turnover when stimulated by haloperidol. The nucleus accumbens appeared to be more sensitive than the corpus striatum.

The effects of chronic ethanol consumption on the mesolimbic and nigrostriatal dopamine systems.

Both the mesolimbic dopamine system, which is involved with the rewarding properties of several drugs of abuse, and the nigrostriatal dopamine system, which is involved with motor function, appear to be sensitive to the effects of ethanol. In order to determine which components of the mesolimbic and nigrostriatal dopamine systems are adversely affected by chronic ethanol consumption, we assessed dopamine and DOPAC (3,4-dihydroxyphenylacetic acid) concentration and D1 and D2 receptors in several dopaminergic brain areas. These studies demonstrated that consumption of a 6.6% (v/v) ethanol-containing lipid diet for 1 month affected several components of the mesolimbic dopamine system in 3-month-old Fisher 344 rats and fewer components of the nigrostriatal dopamine system. Specifically, there was a 1.6- to 2.6-fold increase in the concentration of DOPAC in the nucleus accumbens (NA), frontal cortex (FCX), ventral tegmental area (VTA), and substantia nigra (SN). While the increase in DOPAC in the FCX and VTA was paralleled by a similar increase in dopamine, there was a significant deficiency of dopamine in the SN. These results suggest that there is an increase in dopamine turnover in the FCX, VTA, NA, and SN, which is accompanied by increased dopamine synthesis in the former two regions. Studies of dopamine receptors in control and ethanol-fed rats demonstrated a 25% loss of D1 receptors in the NA. No significant differences were found in D1 receptors in the striatum or globus pallidus. In addition, there were no differences in the number of total D2 receptors or in the conversion of the high to low affinity state of D2 receptors in the nucleus accumbens and striatum.(ABSTRACT TRUNCATED AT 250 WORDS)

Lack of Glucocorticoids Enhances the Early Activation of the Medullary Catecholaminergic Cell Groups Triggered by Restraint Stress

We have investigated whether the stress-induced activation of the medullary catecholaminergic neurons, that was shown previously to provide the main central activation input to the hypothalamo-pituitary-adrenocortical axis during an immobilization stress, is sensitive to circulating corticosteroids. Experiments were carried out on adrenalectomized rats that were first maintained on corticosterone in the drinking water for 5 days following surgery and then switched to corticosterone-free water 15 h before stress application. Some of the latter animals were injected with dexamethasone. Activation of the brainstem Catecholaminergic neurons was estimated by assaying 3,4-dihydroxyphenylacetic acid (DOPAC), a side metabolite of the noradrenaline and adrenaline biosynthesis pathway that was established previously as a reliable index of the activity of these neurons. In the so-called A(1) C(1) and A(2) C(2) Catecholaminergic groups of the medulla, lack of corticosterone under these experimental conditions did not modify the basal level of DOPAC but led to a further enhancement (+ 35% to 40%) of the approximately 2-fold increase in DOPAC content observed 15 min after the onset of the 5-min immobilization stress. No significant further enhancement of the stress-induced DOPAC increase was observed in the locus coeruleus. In these adrenalectomized rats, dexamethasone pretreatment prevented the enhancement of the stress-induced increase in DOPAC level observed in the medullary cell groups but did not abolish the response to stress. Lack of endogenous corticosteroids led to a 10-fold enhancement of the adrenocorticotropin increase following immobilization stress. Pretreatment with dexamethasone fully abolished the stress-induced increase in adrenocorticotropin plasma level. Our results show that circulating corticosteroids reduce the stress-induced activation of the medullary A(1) and A(2) C(2) groups i.e. those that contribute mainly to the catecholaminergic innervation of the hypothalamo-pituitary-adrenocortical axis within the hypothalamic paraventricular nuclei. However, since the feedback regulation of the central catecholaminergic systems is much less efficient than the feedback actually observed on the adrenocorticotropin secretion, we suggest that it is likely to play a minor physiological role in the overall feedback regulation exerted by circulating corticosteroids on the hypothalamo-pituitary-adrenocortical axis.