Dopamine Metabolite Concentrations Research Articles

Relationship between circadian changes in spontaneous motor activity and dorsal versus ventral striatal dopamine neurotransmission assessed with on-line microdialysis.

The relationship between circadian changes in spontaneous motor activity in rats and dopamine (DA) neurotransmission in the dorsal or ventral striatum was assessed with on-line in vivo microdialysis. The concentration of DA and DA metabolites in the dorsolateral caudate nucleus increased significantly at night. In contrast, DA in the nucleus accumbens did not change significantly across the light-dark cycle. The concentration of DA metabolites in the nucleus accumbens did show circadian variation, however, which was comparable with that seen in the dorsolateral caudate nucleus. Although there was a significant positive correlation between the concentration of DA in both the dorsal and ventral striatum and spontaneous nocturnal motor activity, the relationship was very weak, especially for the accumbens. This suggest that regulating the level of spontaneous motor activity per se is not a primary function of the mesostriatal DA system.

Mesolimbic dopamine neurotransmission is increased by administration of μ-opioid receptor antagonists

Microdialysis and high pressure liquid chromatography were used to assess the effects of ventral tegmental area microinjections of the μ-opioid receptor antagonists D-Pen-Cys-Tyr- D-Trp-Orn-Thr-Pen-Thr-NH 2 (CTOP) and β-funaltrexamine (β-FNA) on extracellular ventral striatal dopamine and metabolite concentrations. While CTOP is known to antagonize the increases in extracellular ventral striatal dopamine and dopamine metabolite concentrations induced by ventral tegmental area microinjections of a μ-opioid receptor agonist, it produced dose-orderly increases in ventral striatal dopamine and dopamine metabolite concentrations when administered by itself. β-FNA also elevated dopamine and metabolite concentrations. These μ-agonist-like effects of the μ-opioid receptor antagonists were unexpected and suggest that a complex local circuitry mediates opioid-dopamine interactions in the ventral tegmental area. Since μ-opioids are known to act on ventral tegmental neurons that contain γ-aminobutyric acid (GABA), a model of interactions between GABAergic afferents to the ventral tegmental area and ventral tegmental GABAergic interneurons is proposed.

Low and high dose bromocriptine have different effects on striatal dopamine release: an in vivo study.

We wished to determine if low and high doses of bromocriptine produce distinct patterns of dopamine release and metabolism. Accordingly, we administered bromocriptine (0, 2.5, 5, and 10 mg/kg, IP) to rats and monitored extracellular concentrations of dopamine and dopamine metabolites in the corpus striatum with the technique of cerebral microdialysis. Extracellular dopamine levels increased following administration of 2.5 and 5 mg/kg bromocriptine. In contrast, dopamine levels decreased following 10 mg/kg bromocriptine. Dopamine metabolite levels decreased 45 minutes following all doses of bromocriptine. Bromocriptine administration had no effect on the levels of 5HIAA, the major serotonin metabolite. These findings with high dose bromocriptine fit the predicted profile of a dopamine D2 receptor agonist. The delayed decrease in dopamine metabolites at all bromocriptine doses is consistent with the known dopamine synthesis inhibiting action of bromocriptine. In contrast, the increased dopamine release observed following low and medium doses of bromocriptine is not readily explainable by current theories of bromocriptine action which predict decreased dopamine release and therefore decreased striatal extracellular dopamine levels with both high and low-doses of bromocriptine. Our findings indicate that bromocriptine has a complex pharmacological action that extends beyond simple agonism at dopamine D2 receptors.

Effect of repeated electroconvulsive shock on striatal L-dopa and dopamine metabolism: an in vivo study.

A course of treatments with electroconvulsive shock (ECS) has been reported to reestablish L-dopa efficacy in patients with advanced Parkinson's disease. We wished to determine if ECS could modify L-dopa and dopamine metabolism in an animal model of Parkinson's disease. Therefore, we administered repeated ECS (8 ECS at 48 hr intervals) to rats with partial destruction of the nigrostriatal dopamine pathway and used the cerebral microdialysis technique to monitor extracellular concentrations of dopamine and dopamine metabolites (DOPAC and HVA) in the corpus striatum. The control group of animals received sham-ECS treatments. Basal dopamine levels were decreased by 20% in animals receiving repeated-ECS versus sham-ECS. DOPAC levels, on the other hand, were increased by 84% in animals receiving repeated-ECS. HVA levels were equal in the two groups. Following L-dopa administration, dopamine and HVA levels increased equally in control animals and animals which had previously received repeated-ECS. DOPAC concentrations were uniformly greater in rats receiving repeated-ECS. When ECS was administered acutely, dopamine levels increased 390% and returned to baseline values in 75 minutes, DOPAC and HVA were unchanged, and 5HIAA levels decreased 30%. We conclude that 1) acute ECS administration produces a transient, marked release of striatal dopamine and 2) repeated ECS can reset the level of basal dopamine release, a finding compatible with ECS-induced dopamine receptor supersensitivity, and 3) neither single nor repeated administration of ECS has a major effect on the formation of dopamine or HVA from exogenously administered L-dopa although there was a strong tendency for increased DOPAC formation. ECS may exert its putative antiparkinsonian effect by enhancing dopamine receptor sensitivity.

Peripherally administered substance P affects extracellular dopamine concentrations in the neostriatum but not in the nucleus accumbens under anesthesia

The in situ microdialysis technique was used in urethane-anesthetized rats to monitor changes in the extracellular concentrations of dopamine and its metabolites in neostriatum and nucleus accumbens after the peripheral administration of substance P (50 or 250 μg/kg, IP). Four to five hours after urethane anesthesia a decrease of extracellular dopamine and its metabolites was observed which continued in the nucleus accumbens in the following 3 h. The administration of substance P induced a decrease in extracellular concentration of dopamine in neostriatum. This neurochemical change after substance P was not accompanied by parallel alterations in extracellular concentrations of dopamine metabolites. No effects of substance P were observed on dopamine or its metabolites in nucleus accumbens. These data are discussed in relation with the contrasting effects of substance P on awake rats and the possible changes in striatal dopamine activity induced by anesthetics.

Neurotensin increases extracellular striatal dopamine levels in vivo

This study employed intracranial microdialysis to assess the effects of neurotensin (NT) infusion on extracellular dopamine (DA) and DA metabolite concentrations in the rat striatum and nucleus accumbens, and the effects of NT on alterations in extracellular DA levels induced by cocaine and the DA D-2 receptor agonist, quinpirole. Direct NT infusion (.10, 1.0, 10.0 μM) did not significantly affect extracellular DA in the nucleus accumbens, but did produce a significant increase in the DA metabolite homovanillic acid (HVA). In contrast, direct NT infusion produced an increase in striatal DA levels, without altering DA metabolites. Neurotensin infusion (.10 μM) into the striatum significantly attenuated the peak DA increase induced by an intraperitoneal (IP) injection of a low dose (10.0 mg/kg) but not a high dose (30.0 mg/kg) of cocaine. Neurotensin infusion (.10 μM) did not affect the decrease in DA and its metabolites induced by an IP injection of a low dose of quinpirole (.03 mg/kg), but did alter the decrease in HVA induced by a high dose of quinpirole (.10 mg/kg). These results suggest that NT differentially affects in vivo DA release in the striatum and nucleus accumbens, and further strengthens the assertion that NT is an important modulator of dopaminergic function.

Prenatal stress alters brain catecholaminergic activity and potentiates stress-induced behavior in adult rats

Previous studies demonstrated that throughout the preweaning period prenatally stressed rats have an overactive hypothalamic-pituitary-adrenal (HPA) system. This increased HPA activity was accompanied by an increase in defensive behavior. This study examined whether these alterations in HPA activity and defensive behavior continued into adulthood. Brain catecholamines in the cerebral cortex and locus coeruleus were also measured in prenatally stressed and control rats. Shock-induced levels of defensive freezing were significantly higher in prenatally stressed rats than in controls. However, plasma ACTH and corticosterone concentrations did not differ between groups either in the basal state or after exposure to foot shock. Concentrations of norepinephrine (NE) in the cerebral cortex and locus coeruleus region were significantly reduced in prenatally stressed rats. In addition, concentration of NE metabolites were significantly elevated in prenatally stressed rats, suggesting an increased turnover of brain NE. Prenatally stressed rats also had, in the locus coeruleus region, significantly reduced dopamine (DA) levels but elevated concentration of DA metabolites. Results indicate that prenatal stress produces an increased behavioral responsiveness to stress that is evident in early life and continues into adulthood. The early hyperactivity of the HPA system in prenatally stressed rats, however, appears to normalize in adulthood. The increased turnover in brain catecholamines measure in the cerebral cortex and locus coeruleus region of prenatally stressed rats may be associated with the heightened expression of stress-induced behavior.

Low serotonin and dopamine metabolite concentrations in cerebrospinal fluid from bulimic patients with frequent binge episodes.

Cerebrospinal fluid neurotransmitter metabolite levels were studied to assess whether measures of central serotonin, dopamine, or norepinephrine function are associated with severity of abnormal eating patterns in patients with bulimia nervosa. In comparison with healthy controls (N = 17), hospitalized bulimic patients with a history of binge eating more frequently than twice daily (N = 11) had significantly lower CSF concentrations of 5-hydroxyindoleacetic acid and homovanillic acid. For the total patient group (N = 29), levels of both metabolites were significantly inversely correlated with binge frequency. On the basis of preclinical studies, these results were examined in the context of speculative models in which low central serotonin function might contribute to blunted satiety responses in bulimic patients, while low central dopamine activity might play a role in abnormal hedonic responses to food.

Chronic l-DOPA treatment in the unilateral 6-OHDA rat: evidence for behavioral sensitization and biochemical tolerance

Two separate experiments were conducted to assess the behavioral and biochemical effects of chronic l-dihydroxyphenylalanine ( l-DOPA) treatment in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions. In this animal model, contralateral rotation provides the behavioral indicator response for l-DOPA activation of the dopamine denervated striatum. Following 30 daily l-DOPA treatments, a subthreshold dose (10 mg/kg) for rotation became suprathreshold and the contralateral rotation induced by a suprathreshold dose (20 mg/kg) became exaggerated. This motoric sensitization to l-DOPA was not reversed by a three-day period of l-DOPA withdrawal. In contrast with the emergence of behavioral sensitization to l-DOPA, biochemical measurements showed that the increase of dopamine metabolite concentrations (DOPAC and HVA) induced by acute l-DOPA treatment became attenuated with chronic treatment. This finding suggests that chronic l-DOPA treatment produces a partial tolerance in the conversion of l-DOPA to extracellular dopamine. The emergence of l-DOPA sensitization-overstimulation effects was hypothesized to reflect the combined effects of dopamine receptor priming and Pavlovian drug conditioning and to contribute to the emergence of dyskinetic effects of l-DOPA therapy. The partial tolerance observed for dopamine metabolites was hypothesized to represent a decreased conversion of l-DOPA to dopamine which with long-term treatment could progress to an eventual wearing-off effect of l-DOPA therapy.

Changes in Extracellular Concentrations of Glutamate, Aspartate, Glycine, Dopamine, Serotonin, and Dopamine Metabolites After Transient Global Ischemia in the Rabbit Brain

Although considerable evidence supports a role for excitatory amino acids in the pathogenesis of ischemic neuronal injury, few in vivo studies have examined the effect of increasing durations of ischemia on the extracellular concentrations of these agents. Recently, other neurotransmitters (e.g., glycine and dopamine) have been implicated in the mechanism of ischemic neuronal injury. Accordingly, this study was undertaken to examine the patterns of changes of extracellular glutamate, aspartate, glycine concentrations in the hippocampus, and dopamine, serotonin, and dopamine metabolites in the caudate nucleus with varying durations (5, 10, or 15 minutes) of transient global cerebral ischemia as evidence to support their pathogenetic roles. Microdialysis was used to sample the brain's extracellular space before, during, and after the ischemic period. Glutamate and aspartate concentrations in the dialysate increased from baseline by 1-, 5-, and 13-fold and by 4-, 9-, and 31-fold, respectively, for the three ischemic durations. The concentrations returned to baseline rapidly after reperfusion. The peak concentrations of glutamate and aspartate were significantly higher with increasing ischemic duration. Dopamine concentrations increased by approximately 700-fold in response to all three ischemic durations and returned to baseline within 10 min of reperfusion. Glycine, in contrast, increased during ischemia by a mean of 4-fold, but remained elevated throughout the 80-min period of reperfusion. The final concentrations of glycine were significantly higher than baseline levels (p = 0.0002, Mann-Whitney test). That glutamate and aspartate concentrations in the hippocampus co-vary with the duration of global ischemia is taken as supportive evidence of their pathogenetic role in ischemic neuronal injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamine, cocaine, and fencamfamine: relationship between locomotor and stereotypy response profiles and caudate and accumbens dopamine dynamics

Using in vivo microdialysis, the caudate and nucleus accumbens dopamine (DA) responses to the psychomotor stimulants amphetamine (AMPH), cocaine (COC), and fencamfamine (FCF) were evaluated in rats concurrent with characterization of their behavioral response profiles. Doses of each stimulant that produced either enhanced locomotion or a prolonged period of intense focused stereotypies were examined to evaluate the quantitative relationships between stimulant-induced behaviors and changes in DA dynamics and to test the hypothesis that a balance between mesostriatal and mesolimbic DA activity contributes to the appearance of specific stimulant-induced behaviors. Although 10 mg/kg COC and 1.7 mg/kg FCF promoted levels of locomotor activity substantially greater than 0.5 mg/kg AMPH, the magnitude of the DA increases in both caudate and accumbens were markedly less than was obtained following AMPH. Thus, stimulant-induced locomotion appears to be dissociated from the quantitative DA response in both brain regions. This behavioral/DA dissociation was also apparent at higher doses of AMPH (2.5 mg/kg), COC (40 mg/kg), and FCF (6 mg/kg), doses that promoted a behavioral pattern that included a prolonged period of intense stereotypy. Indeed, the regional DA responses to these high doses of COC and FCF were substantially less than the response to 0.5 mg/kg AMPH. Furthermore, there were no differences in the ratio of the caudate and accumbens DA responses as a function of dose for any of the three drugs. Thus, the balance between the regional DA activation does not appear to regulate the expression of the behavioral response. Additionally, the effects of these stimulants on regional DA metabolite concentrations were compared. The results indicate that AMPH promoted an identical pattern of effects on caudate and accumbens DA metabolites, suggesting that similar mechanisms govern the dynamics of DA in response to AMPH in both brain regions. In contrast, the DA uptake blockers promoted some region-specific effects on DA metabolites that may be due to regional differences in the DA metabolism and rates of impulse flow.

Effects of a secondary and a tertiary amine tricyclic antidepressant on cerebral biogenic amines as a function of mouse strain: A comparative neurotoxicological evaluation

The effect of equal-dose regimens of amitriptyline and nortriptyline on the concentrations of serotonin, dopamine and major acidic metabolites was compared in 5 distinct brain regions as a function of inbred mouse strain. Amitriptyline increased to a greater extent the regional brain serotonin levels in the albino BALB/c mouse than did nortriptyline. Both drugs increased serotonin levels but decreased cerebral 5-hydroxyindoleacetic acid levels in some distinct brain regions of the black C 57BL/6 mouse strain. The results suggest a strain-dependent differential increase in brain serotonin turnover in specific mouse strain brain regions which may account for the greater incidence of amitriptyline-induced sedation and Scizures. The BALB/c mouse was also found to be more sensitive than the C 57BL/6 strain to the action of both drugs on dopamine and major acidic metabolites with amitriptyline showing more regional brain potency than nortriptyline. The data suggest an increase in dopamine turnover particularly in brain areas associated with motor function and posture which may account for tricyclic-antidepressant-induced extrapyramidal disorders. The results also indicate that the C 57BL/6 mouse strain may be of experimental value for studying the mechanism underlying tricyclic-induced adverse reactions relevant to sedation and movement disorders as a function of genetic predisposition.

Microinjection of apomorphine into the prefrontal cortex of the rat reduces dopamine metabolite concentrations in microdialysate from the caudate nucleus

The effects of dopamine fDA) depletion within the medical prefrontal cortex (MPFC) suggest that mesocortical DA projections influence subcortical DA systems (Pycock et al 1980). This hypothesis has been weakened by negative reports (Joyce et al 1983) and by problems inherent to lesion studies. In vivo neurochemical techniques offer a more direct approach. In vivo voltammetry studies have shown that enhancement of DA release in the MPFC is followed by a reduction in DA turnover in the nucleus accumbens (Louilot et al 1989)o Using intracerebral microdialysis we have tested the analogous hypothesis, that stimulation of MPFC DA

Neurotensin and cholecystokinin microinjected into the ventral tegmental area modulate microdialysate concentrations of dopamine and metabolites in the posterior nucleus accumbens

Neurotensin and cholecystokinin, neuropeptides which coexist with dopamine in many ventral tegmental neurons, were microinjected into the ventral tegmental area during in vivo microdialysis in the posterior nucleus accumbens. Neurotensin significantly elevated concentrations of dopamine and its metabolites at doses of 10 pmol, 1 nmol, and 10 nmol, while cholecystokinin significantly elevated dopamine metabolite concentrations only at a dose of 10 nmol. These data suggest that neurotensin potently mediates the release of dopamine from the mesolimbic pathway via direct actions on the cell body.

Effect of chronic caffeine administration oh monoamine and monoamine metabolite concentratiows in rat brain

Caffeine was chronically administered in four doses (0, 10, 25, and 50 mg/kg/day) to rats via twice-daily intraperitoneal injections for 30 days. Concentrations of brain tissue monoamines, dopamine (DA), norepinephrine (NE), and serotonin (5HT), and monoamine metabolites, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5HIAA), were determined. At the 10 mg/kg/day dose, no significant changes were found compared with controls. At 25 mg/kg/day and 50 mg/kg/day significant changes were observed within each monoamine system. In striatum, DA and 5HT were increased, while DOPAC was decreased. In frontal cortex, NE was increased. In cerebellum, 5HT and MHPG were increased.

Dopamine depletion in neonatal rats: effects on behavior and striatal dopamine release assessed by intracerebral microdialysis during adulthood

Rats depleted of dopamine (DA) by intraventricular 6-hydroxydopamine (6-OHDA) in infancy show behavioral impairments as adults, but their basic sensory-motor functions and feeding abilities are intact; at least relative to the pronounced deficits seen in rats given similar v treatment in adulthood. Here we investigate whether presynaptic changes culminating in enhanced DA release are present in adult rats that received neonatal damage, and whether these are of a sufficient magnitude to contribute to the sparing of function. We used microdialysis in rats during the resting state, walking on a treadmill, and after a systemic injection of amphetamine. It was found that neonatal 6-OHDA produced a nearly complete (<1% of control) depletion of DA in postmortem tissue, but this was not accompanied by a comparable decline in the basal extracellular concentrations of DA, which were only reduced by 12–54% of control values. In contrast, the extracellular concentrations of DA metabolites were greatly reduced, reflecting the post-mortem tissue concentrations of DA. Nevertheless, neonatally depleted animals were markedly deficient in their ability to respond to an amphetamine challenge, both behaviorally and in their ability to further increase DA release. Thus, following neonatal DA depletion there appear to be extensive changes in the few remaining DA terminals that are sufficient to maintain relatively high extracellular (and presumably synaptic) concentrations of DA during the resting state, but the capacity of the remaining DA neurons to respond to increased demand is very limited. This presynaptic compensatory response may play a role in the sparing of behavioral function seen following neonatal damage.

Influence of maternal proximity on behavioral and physiological responses to separation in infant rhesus monkeys (Macaca mulatta).

The effects of maternal proximity on the behavioral and physiological responses of infant rhesus macaques during 4 days of total or adjacent separations from the mother were studied. The 6 infants tested showed behavioral responses that differentiated the two separation conditions. Major differences were found in the quantity and quality of vocalizations, the occurrence of cage-biting and cage-shaking behavior, object exploration, and hunched and freezing postures. In particular, the structure of coo vocalizations clearly discriminated between the presence or the absence of the mother during separation. Cerebrospinal fluid (CSF) concentrations of dopamine and serotonin metabolites did not discriminate between the two separation conditions but showed a transient elevation at 24 hr after separation and were not different from baseline by 96 hr after separation. In contrast, both the plasma cortisol and the CSF norepinephrine metabolite responses tended to be greater and to persist for a longer period of time when infants were totally isolated. The results are discussed within the context of attachment and coping theories.

Tyrosine loading increases dopamine metabolite concentrations in the brain

Administration of haloperidol (1.5 mg/kg) to rats increased concentrations of dopamine metabolites in the corpus striatum, nucleus accumbens, hypothalamus and amygdala. Treatment of similar rats with various doses (25, 100 or 400 mg/kg) of tyrosine methyl ester in combination with the haloperidol led to additional elevations of 3,4-dihydroxyphenylacetic acid (DOPAC) in the corpus striatum and hypothalamus at the lowest dose tested. Therefore, it is concluded that during periods of increased neuronal activity, as induced by haloperidol, tyrosine availability may become a rate-limiting factor in dopamine metabolism.

Effect of YM-09151-2, a putative D 2 dopamine receptor antagonist, on dopamine metabolism in the striatum of rats

YM-09151-2, a novel benzamide derivative, significantly increased the concentrations of dopamine (DA) metabolites, both 3,4-dihydroxyphenylacetic acid and 3-methoxy-4-hydroxyphenylacetic acid (honovanillic acid). The maximum increase in such metabolites was about 4-fold the concentration in control animals, and was observed at 2 hr after oral administration. 3-Methoxy-4-hydroxyphenylethylene glycol, a metabolite of noradrenaline, was slightly increased in its concentration exhibiting a transient effect, but 5-hydroxyindoleacetic acid was not. YM-09151-2 antagonized the decreasing effects of apomorphine, a nonselective DA agonist, and LY-171555, a selective D 2 DA receptor agonist, on the concentrations of DA metabolites in the brain. In contrast, SCH-23390, a selective D 1 DA receptor antagonist, did not antagonize the effects of DA agonist. These results strongly suggest that YM-09151-2 is a selective antagonist of D 2 DA receptor and a candidate as a new antipsychotic agent for clinical use.

Dynamics of extracellular metabolites in the striatum after middle cerebral artery occlusion in the rat monitored by intracerebral microdialysis.

The aim of this study was to measure changes in the extracellular fluid (ECF) concentration of lactate, pyruvate, purines, amino acids, dopamine, and dopamine metabolites in the striatum of rats subjected to focal cerebral ischemia, using intracerebral microdialysis as the sampling technique. Microdialysis probes were inserted into the lateral part of the caudate-putamen bilaterally 2 h before the experiment. Ischemia was induced by permanent middle cerebral artery occlusion (MCAO) on the left side. Microdialysis samples were analyzed by high performance liquid chromatography. Following MCAO, the concentration of lactate, adenosine, inosine, and hypoxanthine rose markedly in the ECF on the occluded side, while there was no significant change in pyruvate. These changes were accompanied by dramatically elevated levels of aspartate, glutamate, taurine, gamma-aminobutyric acid, and dopamine. There was also a marked increase in alanine/tyrosine, while minor or no changes occurred with other amino acids. Concomitantly, the ECF level of the dopamine metabolites 3,4-dihydroxyphenylacetate and homovanillic acid decreased. There was no significant increase in any of the metabolites measured on the right, nonoccluded side. In relation to the concept of excitotoxicity in brain ischemia, it is concluded that during the acute stage of focal cerebral ischemia, the ECF is flooded with both potentially harmful (e.g., aspartate, glutamate, and DA) and protective (e.g., taurine, GABA, and adenosine) agents. The relative importance of these events for the development of cell death in the ischemic penumbra needs to be elucidated. In addition, lactate, inosine, and hypoxanthine, measured in the ECF by intracerebral microdialysis, may prove to have diagnostic and/or prognostic value in neurometabolic monitoring of the ischemic brain.