Dopamine Metabolites Dihydroxyphenylacetic Acid Research Articles

Specificity of interleukin–1β-induced changes in monoamine concentrations in hypothalamic nuclei: blockade by interleukin-1 receptor antagonist

The purpose of this study was to examine specificity in the effects of interleukin-1β (IL-1β) on monoamines in various areas of the hypothalamus. Adult male rats were injected i.p. with saline or 2.5 or 5.0 μg of IL-1β or were pretreated with 500 μg of IL-1 receptor antagonist (IL-1ra) followed 5 min later by 5 μg of IL-1β. The paraventricular nucleus (PVN), arcuate nucleus (AN), median eminence (ME), and medial preoptic area (MPA) were microdissected and analyzed for neurotransmitter concentrations by high-performance liquid chromatography with electrochemical detection (HPLC-EC). In the PVN, IL treatment produced significant increases in the concentrations of norepinephrine (NE), dopamine (DA), DA metabolite dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT), and its metabolite 5-hydroxyindoleacetic acid (5-HIAA). IL-1 treatment increased the concentrations of NE and DA in the AN but only of NE in the ME, and it was without any effect in the MPA. Pretreatment with IL-1ra completely blocked the IL-1 effects. It is concluded that IL-1 induces highly specific changes in monoamine metabolism in the hypothalamus, and the nature of these changes depends on specific hypothalamic nuclei.

Opposing roles for dopamine D 1 and D 2 receptors in the regulation of hypothalamic tuberoinfundibular dopamine neurons

The purpose of the present study was to characterize pharmacologically dopamine D 1 receptor-mediated inhibition of tuberoinfundibular dopamine neurons in males rats, and to determine if inhibitory dopamine D 1 receptors oppose stimulatory dopamine D 2 receptors and account for the inability of mixed dopamine receptor agonists to alter the activity of these neurons. Tuberoinfundibular dopamine neuronal activity was estimated by measuring the concentrations of the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the median eminence, the region of the hypothalamus containing terminals of these neurons. Administration of the dopamine D 1 receptor agonist (±)-1 phenyl-2,3,4,5-tetrahydro-(1 H)-3-benzazepine-7,8-diol (SKF38393) decreased median eminence DOPAC and increased plasma prolactin concentrations, whereas administration of the dopamine D 1 receptor antagonist ((−)- trans,6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy- N-methyl-5 H-benzo[ d]naphtho-[2,1 b]azepine (SCH39166) increased median eminence DOPAC concentrations but had not effect on plasma prolactin. The inhibitory effect of SKF38393 on median eminence DOPAC concentrations was blocked by SCH39166. These results demonstrate that acute activation of dopamine D 1 receptors inhibits the activity of tuberoinfundibular dopamine neurons and thereby increases prolactin secretion, and that under basal conditions dopamine D 1 receptor-mediated inhibition of tuberoinfundibular dopamine neurons is tonically active. Administration of the dopamine D 2 receptor agonist (5a R- trans)-5,5a,6,7,8,9,9a,10-octahydro-6-propyl-pyridol[2,3- g]quinazolin-2-amine (quinelorane) increased median eminence DOPAC concentrations, and SKF38393 caused a dose-dependent reversal of this effect. Administration of the mixed dopamine D 1/D 2 receptor agonist R(−)-10,11-dihydroxy-apomorphine (apomorphine) had no effect per se, but blocked quinelorane-induced increases in DOPAC concentrations in the median eminence. These results reveal that concurrent activation of dopamine D 1 and D 2 receptors nullifies the actions of each of these receptors on tuberoinfundibular dopamine neurons, which likely accounts for the lack of an acute effect of mixed dopamine D 1/D 2 receptor agonists on these hypothalamic dopamine neurons.

NMDA receptor antagonists block stress-induced prolactin release in female rats at estrus

In order to evaluate the role of glutamate in prolactin secretion, we examined the effects of N-methyl- d, l-aspartic acid (NMDA) receptor antagonists on serum prolactin levels at both resting and restraint-stress conditions in female rats at estrus. NMDA increased basal serum prolactin levels. Administration of the selective NMDA receptor antagonist, cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS 19755) (5 and 10 mg/kg i.p.), to rats under resting conditions enhanced basal prolactin levels. A low dose of CGS 19755 (3 mg/kg) was unable to modify the hormone serum level. Under stress conditions the pretreatment with CGS 19755 (3 and 5 mg/kg) prevented the increase in serum prolactin levels. This effect was reversed by NMDA (60 mg/kg s.c.). The NMDA receptor antagonist (5 mg/kg) decreased the median eminence concentration of the dopamine metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), without modifying dopamine content. To examine the probable link between serotonin (5-HT) and glutamate in prolactin release, the 5-HT 2A/5-HT 2C receptor antagonist, ritanserin, was used. Under resting conditions, a dose of 5 mg/kg s.c. blocked the NMDA-induced prolactin release. In rats submitted to restraint, ritanserin decreased the prolactin response and NMDA was unable to correct the stress serum prolactin levels. The 5-HT 1A receptor agonist, 8-hidroxypropyl-amino tetralin (8-OH-DPAT) (3 mg/kg s.c.), increased basal serum prolactin levels and restored serum prolactin in stressed animals pretreated with CGS 19755 (5 mg/kg). The present data strongly suggest that the glutamatergic system participates in the regulation of prolactin secretion. A stimulation tone seems to be exerted via the tuberoinfundibular dopaminergic system, and the prolactin release evoked by restraint apparently involves glutamate/NMDA receptors linked to a serotoninergic pathway.

Role of Nitric Oxide in Modulating the Release of Dopamine, Glutamate, and GABA in Striatum of the Freely Moving Rat

This study investigated the role of nitric oxide (NO) in modulating the basal and N-methyl- d-aspartate (NMDA)-induced release of dopamine (DA), glutamate (GLU), and γ-aminobutiric acid (GABA) in striatum of the freely moving rat using microdialysis. Intrastriatal infusion of NMDA (5 mM) for 15 min increased extracellular concentrations of DA, GLU, and GABA. NMDA also decreased extracellular concentrations of DA metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC), and 4-hydroxy-3-methoxyphenylacetic acid (HVA), and of the GLU and GABA precursor, glutamine (GLN). Perfusion of N-nitroarginine (1–5 mM), an inhibitor of the synthesis of NO, potentiated NMDA-induced increases in extracellular concentrations of DA and attenuated increases of extracellular GLU. NMDA-induced decreases of extracellular concentrations of DOPAC were also attenuated by N-nitroarginine. N-nitroarginine had no effect on NMDA-induced changes of extracellular concentrations of GABA, HVA, and GLN. N-nitroarginine decreased basal concentrations of DOPAC and HVA, and increase basal concentrations of GLN, but had no effect on basal DA, GLU, and GABA. These results suggest a role for NO in modulating the NMDA-induced release of DA and GLU in striatum. They also suggest that NO could be regulating the basal metabolism of DA, GLU, and GABA.

Degeneration of pre-labelled nigral neurons induced by intrastriatal 6-hydroxydopamine in the rat: behavioural and biochemical changes and pretreatment with the calcium-entry blocker nimodipine.

Intrastriatal application of 6-hydroxydopamine (6-OHDA) initiates a delayed and progressive loss of nigral dopaminergic neurons and therefore may better resemble the slowly developing neuropathology of Parkinson's disease. We investigated the anatomical, behavioural and biochemical consequences of intrastriatal 6-OHDA after prior labelling of nigral dopaminergic neurons in rats and whether the dihydropyridine L-type calcium channel blocker nimodipine protected from the induced deficits. Adult rats received bilateral intrastriatal injections of the retrograde fluorescence tracer fluorogold and nimodipine (n=12) or placebo (n=9) pellets implanted subcutaneously. One week later all rats were injected unilaterally with 6-OHDA (20 microg) at the same intrastriatal site. Placebo-treated rats displayed relatively few d-amphetamine-induced ipsilateral net rotations (R) (1.3+/-1.4 R/min; mean+/-SEM) 1 week after the lesion with a slight but non-significant decline thereafter (after 2, 3 and 4 weeks). In nimodipine-treated rats the rotation behaviour after 1 week was more prominent (3.5+/-0.8 R/min; mean+/-SEM) with a similar slight decline until week 4. Fluorescent and immunocytochemical analysis of the midbrain after 4 weeks revealed a 35% and 39% loss of tyrosine hydroxylase positive cells and a 62% and 56% (placebo and nimodipine, respectively) loss of fluorogold-labelled cells in the ipsilateral substantia nigra pars compacta. Striatal dopamine levels were reduced to 47% (placebo) and 43% (nimodipine) of the control side and the dopamine metabolites dihydroxyphenylacetic acid and homovanillic acid to about 50%. Pretreatment with nimodipine failed to antagonize or to ameliorate any of the lesion-induced deficits. We conclude that pretreatment with 80 mg nimodipine pellets does not prevent nigrostriatal damage induced by intrastriatal 6-OHDA.

Endogenous glutamate increases extracellular concentrations of dopamine, GABA, and taurine through NMDA and AMPA/kainate receptors in striatum of the freely moving rat: a microdialysis study.

Interactions between glutamate (Glu), dopamine (DA), GABA, and taurine (Tau) were investigated in striatum of the freely moving rat by using microdialysis. Intrastriatal infusions of the selective Glu uptake inhibitor L-trans-pyrrolidine-3,4-dicarboxylic acid (PDC) were used to increase the endogenous extracellular [Glu]. Correlations between extracellular [Glu] and extracellular [DA], [GABA], and [Tau], and the effects of a selective blockade of ionotropic Glu receptors, were studied. PDC (1, 2, and 4 mM) produced a dose-related increase in extracellular [Glu]. At the highest dose of PDC, [Glu] increased from 1.55 +/- 0.35 to 6.11 +/- 0.88 microM. PDC also increased extracellular [DA], [GABA], and [Tau]. The increasing [Glu] was correlated significantly with increasing [DA], [GABA], and [Tau]. PDC also decreased extracellular concentrations of DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and 4-hydroxy-3-methoxyphenylacetic acid (HVA). Perfusion with the NMDA-receptor antagonist 3-[(R)-2-carboxypiperazin-4-yl]-propyl-1-phosphonic acid (1 mM) or the AMPA/kainate-receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) (1 mM) attenuated the increases produced by PDC (4 mM) on [DA], [GABA], and [Tau], and decreases in [DOPAC] and [HVA]. DNQX also attenuated the increases in [Glu] induced by PDC. These data show that endogenous Glu plays a role in modulating the extracellular concentrations of DA, GABA, and Tau in striatum of the freely moving rat.

Deprenyl induces the tyrosine hydroxylase enzyme in the rat dopaminergic nigrostriatal system

Chronic treatment of aged rats with deprenyl prevents age-induced protein oxidation in substantia nigra and protects tyrosine hydroxylase (TH) enzyme against inactivation [11]. With these precedents, we treated adult rats with deprenyl for 3 weeks in order to get further insight in the mechanism by which deprenyl exerts such actions. After completing the treatment, dopamine (DA) levels markedly increased in both striatum and substantia nigra while levels of the acid DA metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), decreased in the two brain areas, thus proving MAO-inhibiting properties of the treatment. We then studied the cellular expression of TH mRNA by in situ hybridization. Following treatment with deprenyl, levels of TH mRNA were significantly higher in individual dopaminergic nigral cell bodies than in those of control rats (+74%). Western blotting analysis of TH enzyme amount revealed a positive effect of the treatment in both the terminal field (+44%) and the cell body region (+31%). This correlation between TH mRNA and amount was also extended to TH enzyme activity in the two brain areas studied, which significantly increased in striatum (+57%) and substantia nigra (+35%) following deprenyl treatment. Taken together, our results clearly suggest a TH-inducing effect of deprenyl in the dopaminergic nigrostriatal system, which seems to be independent of its protective action against oxidative stress described previously. These results expand our knowledge about the beneficial effect of deprenyl in the therapy of Parkinson's disease.

Duration of catalepsy correlates with increased intrastriatal sulpiride

To investigate the mechanism underlying sulpiride-induced catalepsy, we simultaneously examined cataleptic behavior and the kinetics of the dopamine receptor antagonist, sulpiride of dopamine, and the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), using in vivo voltammetry. After intrastriatal administration of sulpiride to freely moving rats, the levels increased, peaked at 20 min, and remained elevated for more than 3 h. Sulpiride-induced cataleptic behavior also continued for 3 h. Levels of DOPAC peaked 180 min after the injection and did not return to baseline within the experimental period. Thus, the time-course of cataleptic behavior correlated better with elevated extracellular levels of sulpiride than with that of DOPAC. These findings suggest that sulpiride induces catalepsy via a direct action.

A Kinetic Analysis of the Effects of β-Phenylethylamine on the Concentrations of Dopamine and Its Metabolites in the Rat Striatum

The purpose of this investigation was to determine whether the increase in the dopamine (DA) concentration in the rat striatum after a rapid iv injection of β-phenylethylamine (PEA) can be quantitatively explained by the alteration of the striatum PEA concentration using a constructed DA metabolism model and to examine whether the time courses of the striatum DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) concentration can be described by this DA metabolism model. The time courses of PEA concentration in plasma and the striatum were determined by gas chromatography–mass spectrometry. The plasma PEA concentration was described by a two-compartment model with nonlinear elimination kinetics. The striatum PEA concentration was about 10 times higher than the plasma PEA concentration. The time course of the striatum PEA concentration was described by a diffusion-limited model including a Michaelis–Menten type transport system from plasma to the striatum and nonlinear elimination from the striatum. The DA concentration in the striatum increased immediately after PEA injection. In contrast, the DOPAC concentration in the striatum decreased immediately. HVA concentration in the striatum increased gradually. Assuming that the enhancement of DA concentration in the striatum after PEA injection is caused by the competitive inhibition of PEA on the reuptake of DA into DA neuronal terminals (and the metabolism from DA to DOPAC is then competitively inhibited by PEA in the DA neuronal terminals), the relationship between the enhancement of DA concentration and PEA concentration in the striatum was analyzed using a constructed DA metabolism model. The enhancement of the DA concentration in the striatum was described quantitatively by this model. Thus, it was clarified that a quantitative relationship between PEA concentration and the enhancement of DA concentration in the striatum is present after PEA injection. However, the time courses of the striatum DOPAC (lower dose) and HVA (time delay) concentrations could not be described by this model. These results indicated that other factors might be necessary to explain the time courses of the DOPAC and HVA concentrations in the striatum after PEA injection, such as the separate evaluation of the effect of PEA on the reuptake of DA into DA neuronal terminals and on the monoamine oxidase-B (MAO-B) activity in the DA neuronal terminals, and the metabolic pathway from DOPAC to HVA.

Paw Preference, Rotation, and Dopamine Function in Collins HI and LO Mouse Strains

Nielsen, D. M., K. E. Visker, M. J. Cunningham, R. W. Keller, Jr., S. D. Glick and J. N. Carlson. Paw preference, rotation, and dopamine function in Collins HI and LO mouse strains. Physiol Behav 61(4) 525–535, 1997.—Mice have paw preferences that are consistent upon repeated measurement. The Collins HI and LO strains are two populations of mice that have been selectively bred to differ markedly in the degree of paw preference. They represent a unique genetic model of functional cerebral lateralization. Rotation (or circling) behavior in normal unlesioned animals reflects an endogenous lateralization of the functioning brain dopamine (DA) systems. In the present study, rotational behavior and lateralized brain DA neurochemistry were assessed in the Collins HI and LO strain mice. Confirming Collins findings, HI strain mice exhibited stronger paw preferences than LO strain mice. HI strain mice also showed stronger percent directional preferences during nocturnal tests of spontaneous rotation. Neurochemical differences were also apparent between the strains. DA and its metabolites were measured in the medial prefrontal cortex (PFC), nucleus accumbens (NAS), and striatum. Degrees of rotational and paw preference in HI, but not LO, mice were correlated with PFC asymmetries in DA and the DA metabolite dihydroxyphenyl acetic acid (DOPAC), respectively. Hemisphere, paw preference, turning preference, and strain interacted in a complex way to determine measures of DA utilization in the NAS and striatum. Even though the directions of paw preference and rotation were not correlated, HI and LO mice of differing paw and rotational directional preferences showed differences in DA neurochemistry in the NAS and striatum.

Decreased hypothalamic serotonin levels in adult rats treated neonatally with clomipramine

Early postnatal treatment with the antidepressant drug clomipramine has repeatedly been shown to lead to behavioural and physiological changes in adult rats. To provide some neurochemical correlates to these studies we have measured a number of monoaminergic parameters in the brains of adult (one year old) rats that were treated twice daily with 15 mg/kg clomipramine from postnatal day 2–14. The most consistent finding was that the hypothalamic levels of serotonin (5-HT) were decreased and those of the dopamine metabolite dihydroxyphenylacetic acid (DOPAC) were increased in rats irrespectively whether they went through a range of behavioural and physiological tests or not. The numbers of β-adrenoceptors in the frontal cortex and of α 2-adrenoceptors in the amygdala/piriform cortex were not changed. The decrease in hypothalamic 5-HT concentrations appears to be up to now the most consistent neurochemical alteration in adult rats that were neonatally treated with antidepressant drugs. It is, however, not clear what the relation is with the functional changes in these rats, that are proposed by some authors as an animal model for depression.

Behavioural and neurochemical sensitization of morphine-withdrawn rats to quinpirole

The sensitivity of dopamine D 2-like receptors in morphine-withdrawn rats was studied using the selective agonist quinpirole. Morphine was administered twice daily increasing the daily dose from 20 to 50 mg/kg during 7 days. Twenty-four hours after the last morphine administration the rats were given quinpirole (0.01–1 mg/kg), and their behaviour was assessed. Withdrawal from repeated morphine treatment enhanced yawning behaviour and penile erections induced by small doses (0.01–0.1 mg/kg) as well as the intensity of stereotypy induced by a large dose (1.0 mg/kg) of quinpirole. In the morphine-withdrawn rats the dose of 1 mg/kg of quinpirole caused less yawning than in the control rats, whereas the number of erections induced by this dose was enhanced as compared with the control animals. In the control rats the striatal and limbic concentrations of dopamine metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA), were not clearly affected by the smallest dose of quinpirole. However, the small dose of quinpirole (0.01 mg/kg) significantly reduced the levels of DOPAC and HVA in the striatum and limbic forebrain of the rats withdrawn from morphine either for 24 or 48 h. These findings indicate that withdrawal from repeated morphine treatment enhances the sensitivity of dopamine D 2-like receptors.

Prevention by (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin of both catalepsy and the rises in rat striatal dopamine metabolism caused by haloperidol.

1. The influence of (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on haloperidol-induced increases in the dopamine metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and 4-hydroxy-3-methoxyphenylacetic acid (HVA), was measured in three microdissected brain regions of the rat following a quantitative assessment of catalepsy. 2. Haloperidol alone (2.66 mumol kg-1, i.p.) caused a robust cataleptic response. Given 30 min after haloperidol, 8-OH-DPAT (76 or 760 nmol kg-1, s.c.) prevented catalepsy in 30% and 100% of rats, respectively. 3. Haloperidol significantly increased the DOPAC (by 2 to 4 fold) and HVA (by 3 to 7 fold) contents of the caudate-putamen, nucleus accumbens and medial prefrontal cortex. Given alone, only the lower dose of 8-OH-DPAT caused a significant biochemical change, a doubling of cortical DOPAC. 4. In the cases where catalepsy was prevented by either dose of 8-OH-DPAT, the haloperidol-induced increases in DOPAC and HVA were consistently lower in the caudate-putamen. This pattern was true for the rise in cortical HVA but only in response to the lower dose of 8-OH-DPAT. In contrast, neither dose of 8-OH-DPAT was able to influence the haloperidol-induced rises in cortical DOPAC. In the nucleus accumbens, 8-OH-DPAT did not affect the haloperidol-induced increases in the dopamine metabolites, irrespective of the dose employed or the resulting behaviour. When catalepsy was not prevented, 8-OH-DPAT did not alter the neurochemical responses to haloperidol in any region. 5. These results suggest that part of the mechanism by which 8-OH-DPAT prevents haloperidol-induced catalepsy is reflected by a reversal of the compensatory increase in meso-striatal and/or meso-cortical dopamine neuronal activity that normally accompanies postsynaptic dopamine receptor blockade with haloperidol.

5-HT3 receptor antagonist MDL 72222 dose-dependently attenuates cocaine- and amphetamine-induced elevations of extracellular dopamine in the nucleus accumbens and the dorsal striatum.

The effects of a 5-HT3 receptor antagonist MDL 72222 on cocaine- and amphetamine-induced increases in extracellular dopamine in the nucleus accumbens and the dorsal striatum were studied with microdialysis technique using halothane anaesthesized rats. Dopamine and its metabolites were measured by HPLC with electrochemical detection. Cocaine elevated extracellular dopamine in the nucleus accumbens and to a lesser extent in the dorsal striatum, but it did not affect dopamine metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid. Pretreatment with MDL 72222 (25-100 micrograms/kg) dose-dependently attenuated cocaine-induced elevation of dopamine in both of the nuclei studied. Amphetamine elevated extracellular dopamine and reduced DOPAC and homovanillic acid equally in the nucleus accumbens and in the dorsal striatum. MDL 72222 also attenuated the amphetamine-induced elevation of extracellular dopamine concentration in both brain areas studied, but first at a dose of 100 micrograms/kg. The different potencies of the interactions of the 5-HT3 receptor antagonist with cocaine and amphetamine could be related to the different mechanisms by which these drugs primarily elevate extracellular dopamine.

Effect of subcutaneous administration of levodopa ethyl ester, a soluble prodrug of levodopa, on dopamine metabolism in rodent striatum: implication for treatment of Parkinson's disease.

Levodopa ethyl ester (LDEE), a highly soluble prodrug of levodopa, was synthesized and administered to mice and rats subcutaneously or intraperitoneally. Striatal levels of levodopa, dopamine, and the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were determined using high-performance liquid chromatography with electrochemical detection and compared with those obtained after intraperitoneal injections of levodopa. LDEE injections produced significant and rapid elevations of striatal levodopa, dopamine, and DOPAC, which were similar to those achieved after levodopa administration, with similar dose-response curves. The elevations achieved by LDEE given s.c. were higher than those achieved after i.p. administration and lasted for longer periods. In addition, intraperitoneal administration of levodopa or LDEE to rats with unilateral 6-hydroxydopamine (6-OHDA) nigral lesions produced similar contraversive circling responses. We suggest that LDEE may be a beneficial antiparkinsonian agent. It has potential pharmacokinetic advantages that are superior to those of levodopa itself, and its subcutaneous administration may become an effective rescue strategy to overcome "off" situations in patients with Parkinson's disease and response fluctuations.

Aging is associated in the 344/N Fischer rat with decreased stress responsivity of central and peripheral catecholaminergic systems and impairment of the hypothalamic-pituitary-adrenal axis.

The effects of acute stress on various indices of sympatho-adrenal, sympathoneural functions and hypothalamic-pituitary-adrenal (HPA) axis were examined both at central and peripheral sites in healthy, intact male Fischer 344/N rats of increasing age. Extracellular fluid (ECF) levels of norepinephrine (NE), its metabolites dihydroxyphenylglycol (DHPG), and methoxyhydroxyphenylglycol (MHPG), and of the dopamine metabolite dihydroxyphenylacetic acid (DOPAC), were measured 24 h after implantation of a microdialysis probe in the paraventricular nucleus (PVN) of the hypothalamus, and samples collected at 30-min. intervals during immobilization (IMMO). ECF levels of NE, DHPG, MHPG, and DOPAC were at baseline similar in both age groups, and all increased significantly in response to IMMO. The IMMO-induced increases in ECF levels of NE and MHPG were, however, significantly smaller in old than in young rats. Plasma levels of the dihydroxyphenylalanine (DOPA), -NE, epinephrine (EPI), DHPG, MHPG, dopamine (DA), DOPAC and HVA, were determined in different groups of young and old rats, cannulated in the tail artery, at baseline, and after 5, 30, 60, and 120 min of IMMO. Basal levels of DOPA, DHPG, MHPG, DA, DOPAC, HVA, NE and EPI were significantly higher in old than in young rats, and increased in plasma during IMMO. However, the magnitude of the increase in the majority of these compounds was significantly smaller in old than in young rats. Basal plasma levels of ACTH were similar among age groups, and basal plasma levels of corticosterone showed a significant aging-associated decline. Two i.v. doses (2 and 20 micrograms/kg BW) of rat CRF elicited significantly greater and delayed ACTH, and greater corticosterone responses in older rats, consistent with the pattern encountered in hypothalamic CRF deficiency. An i.v. injection of ACTH evoked lower corticosterone responses in the older (18 and 24 month old) than in the younger (2 and 8 month old) groups of rats, consistent with secondary adrenocortical atrophy in older animals. Steady-state mRNA levels of mineralocorticoid and glucocorticoid receptors were significantly decreased in the hippocampus of the 8-, 18-, and 24-month-old rats, compatible with maturational rather than senescent changes. CRF mRNA levels in the paraventricular nucleus of the hypothalamus, and levels of POMC mRNA in the anterior pituitary were significantly reduced with age. In conclusion, in this strain of rats, aging is associated with diminished responsiveness of central, and peripheral catecholaminergic systems to acute stress, and progressive hypothalamic CRH deficiency.

Catecholaminergic inhibition by hypercortisolemia in the paraventricular nucleus of conscious rats.

Administration of glucocorticoids decreases the release of corticotropin-releasing hormone and in vitro turnover of norepinephrine (NE) in the paraventricular nucleus (PVN) of the hypothalamus, and immobilization (IMMO) markedly increases NE release and stimulates corticotropin-releasing hormone neurons in the PVN. This study assessed whether hypercortisolemia affects in vivo indexes of catecholaminergic activation in the PVN. Microdialysis was used to simultaneously measure PVN microdialysate concentrations of NE, the neuronal NE metabolite dihydroxyphenylglycol, the extraneuronal NE metabolite methoxyhydroxyphenylglycol, and the dopamine metabolite dihydroxyphenylacetic acid before, during, and after 2 h of IMMO. Catecholamine synthesis was examined based on elevations of 3,4-dihydroxyphenylalanine levels after local perfusion with NSD-1015, an inhibitor of L-aromatic acid decarboxylase. Cortisol (CORT; 25 mg/kg.day) or vehicle (VEH; saline) was infused sc for 7 days via an osmotic minipump. CORT-treated rats had lower basal NE, dihydroxyphenylglycol, methoxyhydroxyphenylglycol, and dihydroxyphenylacetic acid levels and significantly smaller levels of all these compounds during IMMO than VEH-treated rats. CORT-treated rats also had less NSD-1015-induced accumulation of microdialysate 3,4-dihydroxyphenylalanine at baseline and during IMMO than VEH-treated rats. Basal and IMMO-induced plasma ACTH and corticosterone responses were reduced in CORT-treated rats. The results indicate that chronic hypercortisolemia decreases basal levels and stress-induced increments in indexes of release, metabolism, turnover, and synthesis of catecholamines in the PVN and suggest that glucocorticoids restrain the limit of hypothalamo-pituitary-adrenocortical axis activation during stress by attenuating catecholamine synthesis and release in the PVN.

Catecholaminergic inhibition by hypercortisolemia in the paraventricular nucleus of conscious rats

Administration of glucocorticoids decreases the release of corticotropin-releasing hormone and in vitro turnover of norepinephrine (NE) in the paraventricular nucleus (PVN) of the hypothalamus, and immobilization (IMMO) markedly increases NE release and stimulates corticotropin-releasing hormone neurons in the PVN. This study assessed whether hypercortisolemia affects in vivo indexes of catecholaminergic activation in the PVN. Microdialysis was used to simultaneously measure PVN microdialysate concentrations of NE, the neuronal NE metabolite dihydroxyphenylglycol, the extraneuronal NE metabolite methoxyhydroxyphenylglycol, and the dopamine metabolite dihydroxyphenylacetic acid before, during, and after 2 h of IMMO. Catecholamine synthesis was examined based on elevations of 3,4-dihydroxyphenylalanine levels after local perfusion with NSD-1015, an inhibitor of L-aromatic acid decarboxylase. Cortisol (CORT; 25 mg/kg.day) or vehicle (VEH; saline) was infused sc for 7 days via an osmotic minipump. CORT-treated rats had lower basal NE, dihydroxyphenylglycol, methoxyhydroxyphenylglycol, and dihydroxyphenylacetic acid levels and significantly smaller levels of all these compounds during IMMO than VEH-treated rats. CORT-treated rats also had less NSD-1015-induced accumulation of microdialysate 3,4-dihydroxyphenylalanine at baseline and during IMMO than VEH-treated rats. Basal and IMMO-induced plasma ACTH and corticosterone responses were reduced in CORT-treated rats. The results indicate that chronic hypercortisolemia decreases basal levels and stress-induced increments in indexes of release, metabolism, turnover, and synthesis of catecholamines in the PVN and suggest that glucocorticoids restrain the limit of hypothalamo-pituitary-adrenocortical axis activation during stress by attenuating catecholamine synthesis and release in the PVN.

Effects of selective opioid receptor antagonists on morphine-induced changes in striatal and limbic dopamine metabolism.

The effects of selective opioid receptor antagonists, beta-funaltrexamine (selective for mu receptor), naloxonazine (microliter) and naltrindole (delta) on morphine-induced changes in striatal and limbic dopamine (DA) metabolism were studied in rats. beta-Funaltrexamine (20 micrograms intracerebroventricularly) and naloxonazine (15 mg/kg intraperitoneally) were given 24 hr before morphine (15 mg/kg subcutaneously), and the rats were decapitated 60 min. after morphine. Naltrindole (1 mg/kg intraperitoneally) was given twice, 15 min. before and after morphine. Morphine significantly increased the concentrations of DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). This effect was significantly antagonized by pretreatment with beta-funaltrexamine but not by naloxonazine or naltrindole. However, naloxonazine attenuated the antinociceptive effect of morphine in the hot-plate test. The concentration of DA was not significantly altered by any of the drugs studied. These results show that selective blockade of mu-opioid receptors totally blocks the increase of striatal and limbic DA metabolism induced by morphine. It seems that mu 2-subtype of mu-opioid receptor predominantly mediates this effect. Blockade of delta-opioid receptor did not alter these effects of morphine.

Decreased DOPAC in the anterior cingulate cortex of individuals with schizophrenia

The dopamine metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), was found to be decreased in the anterior cingulate cortex of individuals with schizophrenia compared with normal controls. The finding does not appear to be solely related to the presence of antipsychotic medications, age, postmortem interval, or freezer time. No changes in norepinephrine and its metabolites were found.