Dopamine Metabolites Dihydroxyphenylacetic Acid Research Articles

Striatal dopamine release in vivo following neurotoxic doses of methamphetamine and effect of the neuroprotective drugs, chlormethiazole and dizocilpine.

1. Administration to rats of methamphetamine (15 mg kg-1, i.p.) every 2 h to a total of 4 doses resulted in a neurotoxic loss of striatal dopamine of 36% and of 5-hydroxytryptamine (5-HT) in the cortex (43%) and hippocampus (47%) 3 days later. 2. Administration of chlormethiazole (50 mg kg-1, i.p.) 15 min before each dose of methamphetamine provided complete protection against the neurotoxic loss of monoamines while administration of dizocilpine (1 mg kg-1, i.p.) using the same dose schedule provided substantial protection. 3. Measurement of dopamine release in the striatum by in vivo microdialysis revealed that methamphetamine produced an approximate 7000% increase in dopamine release after the first injection. The enhanced release response was somewhat diminished after the third injection but still around 4000% above baseline. Dizocilpine (1 mg kg-1, i.p.) did not alter this response but chlormethiazole (50 mg kg-1, i.p.) attenuated the methamphetamine-induced release by approximately 40%. 4. Dizocilpine pretreatment did not influence the decrease in the dialysate concentration of the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) produced by administration of methamphetamine while chlormethiazole pretreatment decreased the dialysate concentration of these metabolites still further. 5. The concentration of dopamine in the dialysate during basal conditions increased modestly during the course of the experiment. This increase did not occur in chlormethiazole-treated rats. HVA concentrations were unaltered by chlormethiazole administration. 6. Chlormethiazole (100-1000 microM) did not alter methamphetamine (100 microM) or K+ (35 mM)-evoked release of endogenous dopamine from striatal prisms in vitro. 7. Several NMDA antagonists prevent methamphetamine-induced neurotoxicity; however chlormethiazole is not an NMDA antagonist. Inhibition of striatal dopamine function prevents methamphetamine-induced toxicity of both dopamine and 5-HT pathways. Therefore the attenuation of the enhanced dopamine release which occurs in animals given chlormethiazole may be associated with the protective action of this drug against methamphetamine-induced neurotoxicity.

Age-related changes in biogenic amines, opiate, and steroid receptors in the prepubertal bull calf.

Events leading to the increase in pulsatile LH secretion during prepubertal development in the bull calf may include removal of inhibitory or the development of stimulatory mechanisms affecting the hypothalamic release of GnRH. To examine possible contributing systems, serial blood samples were collected from Holstein bull calves at 2, 5, and 10 wk of age one day prior to receiving either no treatment (controls) or two injections of alpha-methyl-p-tyrosine (alpha-MPT), an inhibitor of catecholamine synthesis. Blood was sampled every 10 min for 5 h and serum was analyzed for LH by RIA. Following treatment, animals were killed and hypothalamic and pituitary tissues were removed for analysis of total opiate receptors, mu-opiate receptors, estrogen and androgen receptors and concentrations of monoamines: dopamine, the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DO-PAC), norepinephrine, serotonin, and its metabolite 5-hydroxyindole-3-acetic acid (5-HIAA). Pulses of LH increased from non-detectable at 2 wk to nearly 1.5 pulses per sampling period at 10 wk. Pulse height rose to 0.95 +/- 0.16 ng/ml at 10 wk. Total opiate receptor number as determined by binding to naloxone was unchanged in all tissues between 2 and 10 wk. In contrast, mu-opiate receptors (DAGO binding) increased 2-fold in the preoptic-anterior hypothalamic area between 5 and 10 wk. No age-related changes in estrogen receptor concentrations were observed in any tissue except the anterior pituitary in which binding increased 3.2-fold between 2 and 10 wk. A similar increase was not noted for androgen receptors in the pituitary; however, testosterone binding in the preoptic-anterior hypothalamic area was 4.6-fold higher at 5 wk compared to levels at 2 and 10 wk.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma and cerebrospinal fluid neurochemical pattern in Menkes disease.

Menkes disease is a neurodegenerative disorder of copper metabolism. Because the enzyme dopamine-beta-hydroxylase requires copper to catalyze the conversion of dopamine to norepinephrine, we reasoned that patients with Menkes disease would have a neurochemical pattern similar to that seen in patients with congenital absence of dopamine-beta-hydroxylase, i.e., high levels of dopamine, the dopamine metabolite dihydroxyphenylacetic acid (DOPAC), and the catecholamine precursor dihydroxyphenylalanine (DOPA), and low levels of norepinephrine and its neuronal metabolite dihydroxyphenylglycol (DHPG). We measured plasma and cerebrospinal fluid (CSF) levels of catechols in 10 patients ranging in age from 9 days to 27 months. In contrast to patients with congenital absence of dopamine-beta-hydroxylase, norepinephrine levels were normal in plasma of 4 Menkes patients and in CSF of all 10 patients. However, the ratios of DOPA:DHPG and DOPAC:DHPG in plasma and CSF of Menkes patients were invariably increased beyond the ranges of control values. These neurochemical findings indicate partial deficiency of dopamine-beta-hydroxylase in Menkes patients, with compensatory increases in catecholamine biosynthesis in sympathetic nerves and in the brain. Increased tyrosine hydroxylation and increased exocytotic release of norepinephrine may be responsible for preservation of plasma and CSF norepinephrine levels in Menkes patients. The abnormal neurochemical pattern, including high ratios of DOPA:DHPG and DOPAC:DHPG, may serve as a biochemical marker for Menkes disease and provide a baseline against which the influence of proposed therapies can be judged.

Effects of postnatal stress on dopamine mesolimbic system responses to aversive experiences in adult life

The effects of postnatal stress on mesolimbic dopamine (DA) functioning in 90-day-old mice were investigated. Postnatal stress consisted of 15 min daily exposure to clean bedding (CB) in the absence of the mother for the first two weeks of life. Controls were daily exposed to home cage bedding (HCB) in the absence of the mother. A single brief (5–10 min) exposure to restraint produced a clear-cut increase in DA metabolites (3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 3-methoxytyramine (3-MT)) in the nucleus accumbens septi (NAS) of adult HCB but not CB mice. Moreover, when tested in an elevated plus maze, CB mice showed more exploration and reduced fearfulness in comparison with HCB mice. Taken together, these results indicate reduced emotional reactivity in adult mice repeatedly stressed during postnatal development. Moreover, HCB mice but not CB mice showed altered behavioral responsiveness to apomorphine following repeated restraint stress (10 daily 120 min) in adult life, although no difference in the behavioral response to either a low or a high dose of apomorphine was observed in adult unstressed mice of the CB and HCB groups. These results indicate that the effects of early experiences on brain DA functioning may not be evident in basal conditions and be revealed only under environmental pressure. Finally, a single exposure to 120 min of restraint had similar effects on DA metabolism (decrease of 3-MT and increase of DOPAC and HVA levels) in the NAS of adult HCB and CB mice, suggesting that postnatal stress experiences do not affect the ability of the mesolimbic DA system to respond to unavoidable aversive experiences.

Effects of single or repeated immobilization on release of norepinephrine and its metabolites in the central nucleus of the amygdala in conscious rats.

The release of norepinephrine (NE) and its metabolites in the central nucleus of the amygdala was measured using in vivo microdialysis during immobilization (IMMO) stress in conscious rats. Animals underwent 2-hour periods of IMMO either once or daily for 7 days. Extracellular fluid concentrations of NE, dihydroxyphenylglycol (DHPG), methoxyhydroxyphenylglycol (MHPG), and the dopamine metabolite dihydroxyphenylacetic acid (DOPAC) were measured before, during, and after IMMO. Microdialysate levels of NE and DHPG attained 2- to 3-fold increments during the 1 h of IMMO and declined thereafter, whereas MHPG and DOPAC levels attained maximal levels of about twice basal concentrations during the 2- or 3-h after initiation of IMMO. After the sixth IMMO basal levels of NE, DHPG, MHPG, and DOPAC were decreased, and NE, DHPG, and DOPAC responses during the seventh IMMO failed to attain levels found during the first IMMO, although the absolute changes during IMMO were similar between animals subjected to IMMO once or seven times. The results indicate that acute IMMO increases synthesis, release, and metabolism of NE in the central nucleus of the amygdala and that repetition of IMMO decreases basal catecholamine synthesis and noradrenergic turnover in this brain region, without inhibiting acute noradrenergic responses.

Stress-induced norepinephrine release in the paraventricular nucleus of rats with brainstem hemisections: a microdialysis study.

Immobilization (IMMO) of conscious rats evokes marked increases in release of norepinephrine (NE) in the paraventricular nucleus (PVN) of the hypothalamus, consistent with a role of NE in the PVN release of corticotropin-releasing hormone and therefore in pituitary-adrenocortical activation during stress. The present study examined the effects of surgical hemisection of the brainstem between the locus ceruleus and rostral portion of the medulla on release of NE in the PVN of the hypothalamus in vivo in conscious rats, at baseline and during IMMO. Concentrations of NE, the intraneuronal NE metabolite dihydroxyphenylglycol (DHPG), and the dopamine metabolite dihydroxyphenylacetic acid (DOPAC) were measured in microdialysate samples obtained beginning 24 h after implantation of a microdialysis probe in the PVN either ipsilateral or contralateral to the hemisection. On the lesioned side, baseline levels of NE, DHPG, and DOPAC were significantly lower and IMMO-induced increases were smaller than in sham-operated rats. Contralateral to the hemisection, DOPAC levels were significantly reduced. Neither baseline levels nor IMMO-induced increases in plasma corticosterone levels differed between lesioned and sham-operated animals. The present results indicate that: (1) NE release in the PVN at baseline and during IMMO depends mainly on ascending medullary tracts from ipsilateral brainstem A1 and A2 catecholaminergic areas, with small contributions from the locus ceruleus and from contralateral medullary cells, and (2) brainstem hemisection does not influence IMMO-induced activation of the hypothalamic-pituitary-adrenocortical axis as indicated by plasma corticosterone levels in conscious rats.

Sexual differences in the stimulatory effects of bombesin on tuberoinfundibular dopaminergic neurons

The purpose of this study was to (1) examine the effects of central administration of bombesin on the activity of tuberoinfundibular dopaminergic (DA) neurons in male and female rats, and (2) determine if sexual differences in the responsiveness of these neurons to bombesin were due to the presence of prolactin or gonadal steroids. The activity of tuberoinfundibular DA neurons was estimated by measuring the concentrations of the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in terminals of these neurons in the median eminence. The effects of bombesin on the secretion of prolactin and α-melanocyte stimulating hormone (αMSH), and the activities of nigrostriatal, mesolimbic, and periventricular-hypophysial Da neurons were also determined in gonadally intact male and female rats. Central administration of bombesin (10 ng/rat; i.c.v.) decreased prolactin secretion in gonadally intact male and female rats, but only in males was this associated with an increase in the activity of tuberoinfundibular DA neurons. In contrast, bombesin increased the activity of periventricular-hypophysial DA neurons terminating in the intermediate lobe of both male and female rats, and this was associated with a decrease in αMSH secretion in both sexes. Bombesin had no effect on the activities of nigrostriatal, mesolimbic, or periventricular-hypophysial DA neurons terminating in the neural lobe in either sex. The loss of endogenous gonadal hormones following ovariectomy rendered tuberoinfundibular DA neurons responsive to the stimulatory effects of bombesin, whereas immunoneutralization of endogenous prolactin following administration of prolactin antiserum had no effect on the inability of bombesin to alter the activity of these neurons in female rats. Estrogen administration to both ovariectomized and ovariectomized + prolactin antiserum-treated rats reinstated the lack of responsiveness of tuberoinfundebular DA neurons to bombesin, whereas neither orchidectomy nor testosterone administration to orchidectomized male rats altered the stimulatory effects of bombesin on the activity of tuberoinfundibular DA neurons. Taken together, these results reveal that sexual differences in the responsiveness of tuberoinfundibular DA neurons to the stimulatory effects of bombesin are due, at least in part, to the prolactin-independent effects of estrogen.

Acetyl-L-carnitine releases dopamine in rat corpus striatum: an in vivo microdialysis study

The effect of acetyl-L-carnitine, a compound reported to be beneficial for senile patients, on the release of dopamine (DA) from the striatum was studied by using in vivo brain dialysis in anesthetized rats coupled with HPLC-electrochemical detection. Striatal infusion of acetyl-L-carnitine increased the efflux of DA with no apparent changes in efflux of DA metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and 4-hydroxy-3-methoxyphenylacetic acid (HVA). The DA-releasing effect of acetyl-L-carnitine was concentration- and Ca 2+-dependent, and was abolished by ω-conotoxin fraction GVIA and tetrodotoxin, inhibitors of the voltage-dependent Ca 2+ and Na + channels, respectively. Nomifensine, an inhibitor of DA reuptake did not alter the DA-releasing property of acetyl-L-carnitine. DA released from the striatum by acetyl-L-carnitine was decreased by reserpine pretreatment whereas the d-amphetamine-evoked DA outflow was not affected. In contrast to acetyl-L-carnitine, d-amphetamine reduced the extracellular concentrations of DOPAC and HVA. We conclude from the present data that acetyl-L-carnitine evokes DA release from the vesicular pools of the nigrostriatal dopaminergic neurons by a Ca 2+-dependent, exocytotic process.

Neurochemical predisposition to self-administer morphine in rats

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

Evidence for different sites of monoamine oxidase and catechol- O-methyltransferase in the striatum

Wistar rats were implanted with a probe for brain microdialysis in the striatum, and measured for two major dopamine metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). Intraperitoneal chlorpromazine (5 mg/kg) increased the concentrations of both metabolites in the dialysate when the determinations were carried out before 90 min after the administration. An apparent difference between the declines in concentrations of DOPAC and HVA was observed. Although the concentration of HVA maintained higher levels for over 6 h after the administration, DOPAC underwent a decrease in its concentration after the maximum level, which occurred at 90 min after the administration. These results are discussed in terms of the different distributions of two enzymes related to the metabolism of dopamine, catechol- O-methyltransferase and monoamine oxidase.

Differential effect of self-stimulation on dopamine release and metabolism in the rat medial frontal cortex, nucleus accumbens and striatum studied by in vivo microdialysis

Changes in the extracellular levels of dopamine (DA) and its metabolites in the dopaminergic terminal regions, the medial frontal cortex (MFC), nucleus accumbens (NAC), and striatum (STR), were measured by microdialysis during self-stimulation of the medial forebrain bundle (MFB) in rats pretreated with the DA uptake inhibitor, nomifensine (1 mg/kg, i.p.).Self-stimulation of the MFB in nomifensine-pretreated rats caused an increase in the extracellular DA level in the MFC and NAC but not in the STR. Self-stimulation also increased the extracellular concentrations of the main DA metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) to a similar extent in the MFC and NAC and to a lesser extent in the STR. Thus, there was a regional difference in the neurochemical changes following self-stimulation with either the MFC or the NAC showing larger extracellular levels of DA, DOPAC, and HVA than the STR. Furthermore, these changes were observed on both hemispheres ipsilateral and contralateral to the stimulation. The results indicate that self-stimulation of the MFB preferentially activates the mesocorticolimbic DA systems, thereby bilateral increases in the release of DA and its metabolism being produced in their terminal regions, the MFC and NAC.

Increase of extracellular acetylcholine level in rat frontal cortex induced by (+) N-allylnormetazocine as measured by brain microdialysis

Acute administration of (+)N-allylnormetazocine ((+) SKF-10,047) was found to increase the extracellular acetylcholine (ACh) level in rat frontal cortex, as measured by brain microdialysis in freely-moving rats. The increase elicited by (+)SKF-10,047 was dose-dependent and the increase was significant at a dose of 5.0 mg/kg, compared with the saline-treated group. On the other hand, the extracellular dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) level in the frontal cortex was not changed by (+)SKF-10,047 at 5.0 mg/kg, whereas extracellular ACh level increased markedly in this area. These results suggest that (+)SKF-10,047 can affect some central nervous system (CNS) functions through the increment of extracellular ACh level in rat frontal cortex at lower doses.

Neurotensin-induced activation of hypothalamic dopaminergic neurons is accompanied by a decrease in pituitary secretion of prolactin and α-melanocyte-stimulating hormone

The effects of neurotensin on the activity of hypothalamic tuberoinfundibular and periventricular-hypophysial dopaminergic (DA) neurons, and on the secretion of pituitary hormones that are tonically regulated by these neurons (i.e. prolactin and α-melanocyte-stimulating hormone [αMSH], respectively) were examined in estrogen-primed ovariectomized rats. The activity of tuberoinfundibular and periventricular-hypophysial DA neurons was estimated by measuring concentrations of the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the terminals of these neurons in the median eminence and intermediate lobe of the posterior pituitary, respectively. Intracerebroventricular administration of neurotensin caused a dose- and time-related increase in DOPAC concentrations in both the median eminence and intermediate lobe, and a concurrent decrease in plasma levels of prolactin and αMSH. These results suggest that neurotensin-induced inhibition of secretion of prolactin and αMSH from the pituitary may be due to the stimulatory action of this neuropeptide on the release of dopamine from tuberoinfundibular and periventricular-hypophysial neurons.

Activation of tuberoinfundibular and tuberohypophysial dopamine neurons following intracerebroventricular administration of bombesin

The effect of bombesin on the activity of dopamine (DA) neurons comprising the nigrostriatal, mesolimbic, tuberoinfundibular and tuberohypophysial systems in the male rat was determined by measuring: (1) the accumulation of 3,4-dihydroxyphenylalanine (DOPA) after administration of a decarboxylase inhibitor, and (2) the concentration of the DA metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in brain (striatum, nucleus accumbens, median eminence) and pituitary regions (intermediate and neural lobes) containing terminals of these neurons. Intracerebroventricular (i.c.v.) injection of bombesin caused a dose- and time-related increase in the activity of DA neurons projecting to the median eminence and intermediate lobe of the pituitary, and a corresponding decrease in the concentrations of prolactin and α-melanocyte-stimulating hormone (αMSH) in the plasma. In contrast, doses of bombesin up to 10 ng i.c.v. failed to alter the activity of DA neurons terminating in the striatum, nucleus accumbens or neural lobe of the pituitary gland. Equimolar doses of bombesin and gastrin-releasing peptide (GRP), a bombesin-like peptide, increased the concentrations of DOPAC in the median eminence and intermediate lobe of the pituitary, suggesting that GRP-preferring receptors may be responsible for the stimulatory effects of bombesin on DA neuronal activity in these regions. The results of these studies suggest that bombesin increases the activity of tuberoinfundibular and tuberohypophysial DA neurons projecting to the median eminence and intermediate lobe of the pituitary, respectively, and thereby inhibits the secretion of prolactin and αMSH.

Extracellular dopamine increases in the neonatal olfactory bulb during odor preference training

Young rats learn to approach an odor that has been paired with tactile stimulation. This attraction is accompanied by changes in the metabolism and anatomy within the olfactory bulb glomerular layer. In this study, we examined the changes that occur in the olfactory bulb during early olfactory learning, rather than after such pairings have occurred. Specifically, we determined whether the pairing of an odor with tactile stimulation would produce a modified response by olfactory bulb glomerular-layer neurons. To monitor one large subgroup of these neurons during early learning, we used in vivo microdialysis to assess the activity of dopaminergic neurons in the olfactory bulb of postnatal day (PND) 3 rats during simultaneuous presentation of odor and tactile stimulation, tactile stimulation alone, odor alone, or clean air alone. Clean air evokes no change in extracellular dopamine (DA), while both odor alone and stroking alone induce and prolonged increases in DA peaking at about 200% of baseline. The combination of odor and tactile stimulation, which allows an olfactory preference to be formed, induces a prolonged increase in DA which peaks at about 400% of baseline. The level of the DA metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) increases only in pups receiving both odor and tactile stimulation and peaks at about 200% of baseline. With the exception of the pups exposed to clean air, all groups show an increase in homovanillic acid (HVA) of between 150–200% following sitmulation. The large and prolonged increase in DA may be linked to the longer term anatomical and physiological changes in the glomerular layer of the bulb that form as a consequence of early olfactory preference training.

Biochemical Assessment of Preoperative Stress

Diazepam 5 mg or an inert placebo tablet was given as preoperative hypnotic on the night before operation to two groups (n = 18 in each of healthy women having elective Caesarean section under spinal analgesia. A third group (n = 18) received no hypnotic. The quality of the preoperative night's sleep assessed subjectively was significantly better in the diazepam-treated patients compared with those receiving no drug. The diazepam-treated patients had also smaller CSF concentrations of noradrenaline (NA) and of the dopamine metabolite, 3, 4-dihydroxy phenylacetic acid (DOPAC). In comparison with the two other patient groups, in the diazepan group there was no correlation between demo-graphic, physiological or subjectively estimated variables and CSF or plasma measurements of monoamine transmitters and their metabolites. Preoperative fear and apprehension correlated most strongly with preoperative heart rate and with the increase in heart rate from the previous day. The monoamine neurotransmitters or their metabolites were of limited use in monitoring the intensity of preoperative fear and anxiety.

Prolonged Alterations in Canine Striatal Dopamine Metabolism Following Subtoxic Doses of l‐Methyl‐4‐Phenyl‐ 1,2,3,6‐Tetrahydropyridine (MPTP) and 4′‐Amino‐MPTP Are Linked to the Persistence of Pyridinium Metabolites

Single toxic doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).HCl (2.5 mg/kg i.v.) and 4'-amino-MPTP.2HCl (22.5 mg/kg) induce loss of striatal dopamine (DA) and tyrosine hydroxylase (TH) activity and of nigral DA neurons in the dog. To examine the subacute neurochemical changes induced by low doses of MPTP and 4'-amino-MPTP, dose-response studies of these compounds were carried out in the dog, using 6- and 3-week survival times for these two compounds, respectively. Low single doses of MPTP (1.0, 0.5, and 0.1 mg/kg i.v.) and 4'-amino-MPTP (15, 7.5, and 3.75 mg/kg i.v.) did not cause depletion of canine striatal DA or TH or a loss of nigral neurons. However, levels of the DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were decreased in a dose-related fashion, with significant loss of DOPAC being evident 6 weeks after the lowest administered dose of MPTP and 3 weeks after 4'-amino-MPTP. This selective loss of DA metabolites following nontoxic doses of MPTP and 4'-amino-MPTP led to a shift in the ratio of DA to DOPAC or HVA, which was characteristic for each compound. The measurement of striatal 1-methyl-4-phenylpyridinium (MPP+) and 4'-amino-MPP+ levels revealed that high concentrations (up to 150 microM) persist in the striatum for weeks following administration of a single nontoxic dose of MPTP or 4'-amino-MPTP. A causal relationship between the striatal concentration of MPP+ or 4'-amino-MPP+ and the change in DA metabolism as reflected in the DA/DOPAC ratio is suggested by a significant correlation between these measures. It is suggested that presynaptic sequestration and retention of MPP+ and 4'-amino-MPP+ by striatal DA terminals result in the inhibition of the monoamine oxidase contained within these terminals.

Calcium mediation of cyanide-induced catecholamine release: Implications for neurotoxicity

Exposure of rat pheochromocytoma (PC12) cells to KCN (1.0-10 mM) over a 30-min period stimulated secretion of dopamine (DA) and decreased intracellular DA content. Addition of KCN (10 mM) to rat frontal cortex slices preloaded with 1-[7-3H]norepinephrine ([3H]NE) increased secretion of NE over a 10- to 30-min incubation period. In PC12 cells release of DA by KCN was nearly abolished in calcium-free media or by prior addition of diltiazem, a calcium channel antagonist. Release of [3H]NE from rat cortical slices by cyanide was only partly inhibited by diltiazem suggesting that intracellular calcium may be involved in this response. In PC12 cells KCN also produced a dose-related release of the DA precursor dihydroxyphenylalanine, without altering intracellular stores. Levels of the DA metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were enhanced at lower concentrations of KCN. These observations indicate cyanide elicits exocytotic release of neurotransmitters in a calcium-dependent manner and also show that cyanide alters catecholamine metabolism. These actions of cyanide may be important in CNS symptoms of intoxication.

Reserpine-insensitive dopamine release in the substantia nigra?

Dopamine (DA) is synthesized and released not only from the terminals of the nigrostriatal dopaminergic pathway, but also from the dendrites in the substantia nigra (SN). Whether the DA release in the SN is sensitive to reserpine treatment, as it is in the striatum, has however, not been clarified. We have determined the effects of reserpine on the concentrations of DA, serotonin and their metabolites in the SN and in the striatum and as an index of DA release in vivo we have assessed the accumulation of the DA metabolite 3-methoxytyramine (3-MT) following inhibition of monoamine oxidase by pargyline. The effects of reserpine on the concentrations of DA and its metabolites were different in the SN as compared to in the striatum. In the striatum there was a maximal depletion of DA to 2% of controls, but in the SN the DA concentration decreased only to 17% of controls. In the SN, the increases of the DA metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were less pronounced than in the striatum. In the striatum reserpine treatment (given 15 h, 3.75 h, or 1.75 h before pargyline) decreased the pargyline-induced 3-MT accumulation to 30% of pargyline-treated controls. However, in the SN no effects of reserpine were observed. The results indicate that DA in the SN partly is situated in a reserpine insensitive pool and that the release of DA might be insensitive to reserpine. These differences between the SN and the striatum could be due to different storage mechanisms. In the striatum DA is stored in classical storage granulas but in SN DA is partly stored in storage granulas and partly in smooth endoplasmatic reticulum.

A comparison between the non-competitive NMDA antagonist dizocilpine (MK-801) and the competitive NMDA antagonist D-CPPene with regard to dopamine turnover and locomotor-stimulatory properties in mice

Following intraperitoneal administration of the non-competitive N-methyl-D-aspartate (NMDA) antagonist dizocilpine (MK-801), levels of the dopamine (DA) metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) increased in mouse striatum and limbic forebrain. When dizocilpine was given to animals treated with NSD 1015, an inhibitor of 3,4-dihydroxyphenylalanine (DOPA) decarboxylase and monoamine oxidase, there was an increase in levels of DOPA and 3-methoxytyramine (3-MT). These findings suggest that dizocilpine stimulates DA synthesis and release in mouse brain. Following dizocilpine treatment a clear-cut increase in spontaneous locomotor activity was observed, probably partly due to enhanced dopaminergic tone. The competitive NMDA antagonist D-CPPene produced locomotor stimulation as well, but in contrast to following dizocilpine treatment levels of 3-MT decreased. Thus the stimulation of locomotor activity following D-CPPene treatment does not seem to be mediated through activation of central dopaminergic systems. However, haloperidol pretreatment antagonized this locomotor response, indicating that the dopaminergic system plays a permissive role in this context.