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Brain-derived neurotrophic factor (BDNF) has been shown to influence monoamine transmitter synthesis, metabolism and release. We investigated possible relationships between four BDNF gene polymorphisms and cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) in healthy volunteers (n = 132). All BDNF polymorphisms (270 C/T, -633 T/A, Val66Met, and 11757 G/C) were associated with MHPG (P < 0.02), but not with 5-HIAA and HVA concentrations. At a second clinical investigation 8-20 years after CSF sampling 30% of the subjects had experienced various psychiatric disorders. Development of a psychiatric disorder was predicted by low 5-HIAA concentrations (P = 0.01). The results suggest that BDNF gene variation participates in regulation of norepinephrine turnover rates in the central nervous system of human subjects.

Objectives: The present study investigates the effects of injections of a specific N-methyl-D-aspartic acid (NMDA) antagonist 3-[(R)-2-carboxypiperazin-4-yl]-propyl-1-phophonic acid (CPP) into the prefrontal cortex (PFC) on the extracellular concentrations of dopamine and acetylcholine in the nucleus accumbens (NAc) and on motor activity in the freely moving rat., Materials and Methods: Sprague-Dawley male rats were implanted with guide cannulas into the medial PFC and NAc to perform bilateral microinjections and microdialysis experiments. Spontaneous motor activity was monitored in the open field., Results: Injections of CPP (1 microg/0.5 microL) into the PFC produced a significant increase of the baseline extracellular concentrations of dopamine (up to 130%), dihydroxyphenylacetic acid (DOPAC; up to 120%), homovanillic acid (HVA; up to 130%), and acetylcholine (up to 190%) in the NAc as well as motor hyperactivity. In the NAc, perfusion of the NMDA and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate antagonists CPP (50 microM)+6,7-dinitroquinoxaline-2,3-dione (DNQX; 50 microM) through the microdialysis probe blocked acetylcholine release, but not DOPAC and HVA increases produced by CPP injections into the PFC. Also, increases in motor activity produced by prefrontal injections of CPP were significantly reduced by bilateral injections into the NAc of a mixed D1/D2 antagonist, flupenthixol (5 and 25 microg/0.5 microL). Injections into the NAc of the muscarinic antagonist scopolamine (1 and 10 microg/0.5 microL) further increased, and of the nicotinic antagonist mecamylamine (1 and 10 microg/0.5 microL) did not change, the increases in motor activity produced by prefrontal CPP injections., Conclusions: These results suggest that the dysfunction of NMDA receptors in the PFC could be a key factor in the neurochemical and motor effects associated with corticolimbic hyperactivity.

Rationale: Tardive dyskinesia is a syndrome of abnormal and involuntary movements which occurs as a complication of long-term neuroleptic therapy especially classical neuroleptics such as haloperidol and chlorpromazine. Dysfunction of GABA receptor mediated inhibition, and increased glutamatergic neurotransmission has been implicated in the development of orofacial dyskinesia in rats and tardive dyskinesia in humans. Neurosteroids modulate both GABAergic as well as glutamatergic neurotransmission in various brain areas., Objective: The objective of the present study was to elucidate the role of various neurosteroids in neuroleptic-induced vacuous chewing movements and related behaviors in rats by using behavioral, biochemical, and neurochemical parameters., Materials and Methods: Animals chronically treated with haloperidol (1 mg/kg i.p.) for a period of 21 days exhibited marked increase in vacuous chewing movements, tongue protrusions, and facial jerkings as compared to vehicle-treated controls. It also resulted in increased superoxide anion levels and lipid peroxidation, whereas decreased levels of endogenous antioxidant enzymes (catalase and superoxide dismutase) in rat brain striatum homogenates. Neurochemical studies revealed that chronic administration of haloperidol resulted in significant decrease in the levels of dopamine, serotonin, and norepinephrine in rat brain striatum homogenates, whereas urine biogenic amines metabolite levels were increased. In a series of experiments, rats co-administered with allopregnanolone (0.5, 1, and 2 mg/kg i.p.) and progesterone (5, 10, and 20 mg/kg i.p.), both positive GABA-modulating [negative N-methyl-D-aspartate (NMDA)-modulating] neurosteroids prevented, whereas pregnenolone (0.5, 1, and 2 mg/kg i.p.) and dihydroxyepiandrosterone sulfate (0.5, 1, and 2 mg/kg i.p.) both negative GABA-modulating (positive NMDA-modulating) neurosteroids aggravated all the behavioral, biochemical, and neurochemical parameters., Conclusions: These results suggest that neurosteroids may play a significant role in the pathophysiology of vacuous chewing movements and related behaviors by virtue of their action on either the GABA or NMDA modulation. Furthermore, neurosteroids showing selectivity for positive GABA modulation and/or negative NMDA modulation may be particularly efficacious as novel therapeutic agents for the treatment of tardive dyskinesia and deserve further evaluation.

Rationale and Objectives: Flinders sensitive line (FSL) rats, an animal model of depression, display a different pattern of maternal behavior compared to Sprague-Dawley (SD) controls. In this study, we examined the rewarding value of mother-infant interaction for FSL dams., Materials and Methods: In the main study, we measured monoamine levels in the nucleus accumbens (NAc) of early postpartum FSL and SD dams during an interaction with pups, using the microdialysis technique. In addition, we compared the preference patterns of FSL and SD rats using the conditioned place preference paradigm, with pups as the unconditioned stimuli., Results: Dopamine (DA) levels in dialysates from the NAc of SD dams but not FSL dams were elevated while interacting with pups but the metabolism of DA to dihydroxyphenylacetic acid was greater in FSL than in SD dams. While SD dams showed a conditioned preference for a region that was associated with SD pups, FSL dams did not show a preference for regions associated either with SD or FSL pups, but water deprived FSL rats demonstrated a preference to a region associated with water, eliminating an alternative explanation of learning deficit in FSL rats., Conclusions: Taken together, these results suggest that FSL dams are less rewarded by pups, compared to control dams.

Rationale: Methamphetamine (METH) and amphetamine (AMPH) are both abused psychostimulants. Although METH is generally accepted to be more addictive and potent than its analogue AMPH, there are no known neurobiological differences in action between the two drugs that may account for such differences., Objective: METH and AMPH were compared to determine potential mechanisms for such differences between the two drugs in order to provide new targets for the treatment of METH addiction., Methods: Using in vivo microdialysis on rats, dopamine (DA), DA metabolites, and glutamate (GLU) release in the nucleus accumbens (NAC) and prefrontal cortex (PFC) were measured after administration of 2 mg/kg, IP, of METH or AMPH. Based on the neurochemical differences between METH and AMPH, a locomotor activity study was designed to assess differences in locomotor activation for a range of doses (1-4 mg/kg, IP) of METH and AMPH and after pretreatment with intra-accumbens GLU antagonists., Results: METH and AMPH raised NAC DA levels to a similar degree. In the PFC, both METH and AMPH raised DA levels, but METH was less effective than AMPH. In the NAC, AMPH raised GLU levels but METH did not. In the PFC, METH raised GLU levels but AMPH did not. The locomotor activity dose response curve for METH had a lower peak than that of AMPH. This difference was blocked by pretreatment with either the GLU NMDA antagonist AP5 or the GLU AMPA antagonist DNQX locally in the NAC., Conclusions: This study reveals several previously unknown neurochemical and behavioral differences between METH and AMPH. Based on these results, it is suggested that new pharmacotherapeutic agents that produce augmentations of NAC GLU or PFC DA activity, or perhaps inhibition of PFC GLU activity, may someday be useful for the treatment of METH addiction.

Fifteen days after a striatal kainic acid (KA) injection, we have examined presynaptic modifications of dopamine and serotonin terminals in the striatum through (i) autoradiographic labeling of dopamine, serotonin and vesicular monoamine transporters respectively with 3H-mazindol, 3H-citalopram and 3H-dihydrotetrabenazine, and (ii) determination of the contents in dopamine, serotonin and their metabolites. Acetylcholinesterase histochemical labeling enabled the definition of severely and moderately KA-lesioned subregions within the striatum. A significant decrease of the three transporters labeling density was observed only in the severely lesioned subregions. The strong decrease in serotonin transporter labeling revealed here has not been described until now. Besides, the striatal contents of homovanillic acid (dopamine metabolite) and 5-hydroxyindolacetic acid (serotonin metabolite) were significantly increased in the lesioned striatum. The whole data evidence an incomplete sparing of dopamine and serotonin terminals in the striatum 15 days after a KA injection, especially in the areas where the degeneration of postsynaptic neurons was the most extensive.

We studied in vivo the effects of locally infused taurine (50, 150, and 450 mM) on the striatal dopamine and its metabolites in comparison with those of GABA and homotaurine, a GABAA receptor agonist, in freely moving rats. The extracellular dopamine concentration was elevated maximally 2.5-, 2- and 4-fold by taurine, GABA and homotaurine, respectively. At 150 mM concentration, at which the maximum effects occurred, homotaurine increased the extracellular dopamine more than taurine or GABA. When taurine and GABA were infused simultaneously with tetrodotoxin the output of dopamine did not differ from that in the presence of tetrodotoxin alone. In comparison, tetrodotoxin did not inhibit the increase in extracellular dopamine caused by homotaurine. Furthermore, omission of calcium from the perfusion fluid inhibited the increase of extracellular dopamine caused by GABA. However, it did not block the increase of dopamine caused by taurine or homotaurine. The present study suggests that the effects of intrastriatal taurine, GABA and homotaurine on the striatal extracellular dopamine differ. Thus, these amino acids seem to affect the striatal dopaminergic neurons via more than one mechanism.

We investigated the relationships between methylphenidate (MPD) enantiomers and endogenous dopamine (DA) levels in striatal extracellular fluid, and that between DA level and locomotor activity, after intravenous administration of racemic MPD (2, 5 or 10 mg/kg dose) or the individual enantiomers (2.5 mg/kg dose) to rats. MPD and DA levels in the extracellular fluid were measured by in vivo brain microdialysis. The maximum levels of MPD enantiomers in the striatal extracellular fluid were obtained within 15 min after administration. On the other hand, the mean maximum DA levels after administration of 2-10 mg/kg dose of racemic MPD were obtained within 10 min with values in the range of 3.0- to 8.6-fold higher than the basal DA level. The maximum DA level (4.2-fold of the basal level) after administration of (+/-)-MPD was greater than that (2.2-fold) of the same dose of (-)-MPD. A clockwise hysteresis was observed between MPD concentration and DA level in the extracellular fluid after MPD administration. Locomotor activity after administration of (+)-MPD was also greater than (-)-MPD. From these results, it was shown that the locomotor activity induced by MPD may be related to the increase of DA level in the extracellular fluid, and the degree of increase of the DA level by (+)-MPD was greater than that of the (-)-isomer.

The effects of single and repeated (9 times) administration of two dihydropyridines (DHPs), nimodipine (NIM) and nifedipine (NIF) (5 mg/kg per 12 h and 2.5 mg/kg per 12 h, IP), on the behavior of male adult rats in the holeboard and in the plus-maze, were investigated. Besides, the effects of repeated administration of the drugs on the levels of dopamine (DA), serotonin (5-HT), and their respective major metabolites in several regions of the central nervous system (CNS) were also assessed. The effects of single and repeated administration of the drugs were similar. Both DHPs caused a significant decrease in general motor activity which was evident in both tests and more marked, with the higher doses. The two exploratory parameters measured in the holeboard, i.e. head-dipping frequency and duration, were dissociated under pharmacological treatment. The drug-treated animals did not show an increased emotionality in the holeboard. However, in the plus-maze, NIF (5 mg/kg) and to a lesser extent NIM, appeared to induce some anxiety-related responses which may be secondary, at least in part, to the depressing effect on activity and exploration. Repeated administration of NIM and NIF caused an increase in striatal DA and DOPAC levels, whilst no effects were found on serotonergic system in any of the regions of the CNS analyzed.

In vivo microdialysis was used to study the effects of systemically administered phencyclidine (PCP, 10 mg/kg) on the extracellular levels of dopamine, dihydroxyphenylacetate (DOPAC), homovanillate (HVA), 5-hydroxy-indolacetate (5-HIAA), gamma-aminobutyrate (GABA), glutamate, and aspartate in the rat dorsolateral striatum. In order to demarcate the effects of anesthesia, tissue trauma and gliosis, the effect of PCP was studied in both anesthetized rats with long and short probe implantation periods and in conscious rats with a long probe implantation period. PCP significantly increased the extracellular levels of dopamine in all experimental groups, though the post-implantation interval and anesthesia modulated the degree of increase. PCP increased 5-HIAA levels in both conscious and anesthetized rats after a long post-implantation period and HVA only in anesthetized rats after a long post-implantation period. Glutamate, aspartate, and DOPAC were not affected by PCP challenge but our study indicated for the first time that systemic PCP elevates extracellular GABA in conscious rats.

Dopamine release and metabolism in the corpus striatum increased markedly when the core body temperature of anesthetized rats was increased from 35 degrees to 41 degrees C while temperatures below 34 degrees were associated with a marked attenuation of dopamine release. These observations may have clinical relevance in cases where alterations in body temperature are associated with extrapyramidal dysfunction.

Significant concentrations of carbidopa (CD) were found in rat hypothalamus, striatum, and in striatal microdialysis efflux after intraperitoneal administration of the drug. Efflux levels peaked one hour after administration of 100 mg/kg at 0.37 micrograms/ml, or about 2% of serum levels. Concurrent CD levels in hypothalamus and striatum were about 2.5% and 1.5%, respectively, of corresponding serum levels. Levels of dopamine and its principal metabolites in striatal efflux were unaffected. The removal of the brain blood by saline perfusion decreased the striatal and hypothalamic CD concentrations only by 33% and 16%, respectively. In other rats receiving both CD and levodopa (LD), brain L-dopa, dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels after one hour tended to be proportionate to LD dose. When the LD dose remained constant, increasing the CD dose dose-dependently enhanced L-dopa levels in the hypothalamus and striatum. However dopamine levels did not increase but, in contrast, decreased dose-dependently (although significantly only in the hypothalamus). CD also caused dose-dependent decrease in striatal 3-O-methyldopa (3-OMD) and in striatal and hypothalamic homovanillic acid (HVA), when the LD dose was 50 mg/kg. We conclude that, at doses exceeding 50 mg/kg, sufficient quantities of CD enter the brain to inhibit dopamine formation, especially in the hypothalamus. Moreover, high doses of LD/CD, both of which are themselves catechols, can inhibit the O-methylation of brain catecholamines formed from the LD.

In four human controls, four cases of Parkinson's disease and three cases of amyotrophic lateral sclerosis analysis of dopamine, noradrenaline, serotonin and the metabolites 3,4-dihydroxyphenylacetic acid, homovanillic acid and 5-hydroxyindoleacetic acid was performed in various segments of postmortem spinal cord. In controls the concentrations of dopamine are about 1/3 to 1/4 that of noradrenaline; the significantly highest content of noradrenaline was found in the lumbar, and dopamine in thoracic, lumbar and sacral segments of the spinal cord. Intersegmental distribution of monoamines was only present in spinal cord of controls, while in the spinal cord of parkinsonian patients such a difference was not found. Otherwise, biogenic amine and metabolite concentrations in spinal cord segments of parkinsonian patients did not differ significantly from those in the control subjects. However, it cannot be excluded that these segments are sensitive to drugs including neuroleptics and combined L-DOPA treatment. In subjects with amyotrophic lateral sclerosis significantly lower concentrations of noradrenaline in the cervical and thoracic, and of dopamine and homovanillic acid in the thoracic and lumbar segments were found in comparison with controls. The concentrations of serotonin and 5-hydroxyindoleacetic acid in the thoracic segments of amyotrophic lateral sclerosis were significantly lower than that of controls. Differences in the inter-segmental distribution of noradrenaline in lumbar, lumbar-sacral, and serotonin in lumbar segments of spinal cord were found in this group.

Acetyl-levo-carnitine (ALC) protects against 1-methyl, 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity in the nonhuman primate. ALC pretreated monkeys do not show signs of parkinsonism or electroretinographic changes typical of dopaminergic deficiency when given MPTP. In addition, pilot neurochemical and morphological data confirm a partial protection effect. While MAO-B inhibitors, like L-Deprenyl, are thought to protect dopaminergic neurons from MPTP-induced cell death by preventing the conversion of MPTP to its toxic metabolite MPP+, ALC is not known to have MAO-B affinity. Converging evidence suggests that ALC may affect directly mitochondrial respiration, which is known to be the target of MPP+ and affected in human neurodegenerative diseases, including Parkinson's disease. The results of this study point to new therapeutic avenues for the treatment of these nosologic entities.

We examined whether pentobarbital (PB) inhibited the acute extracellular release of dopamine that occurs in the striatum following the onset of ischemic injury in the gerbil model of stroke. The cerebral dialysis technique was employed to monitor striatal extracellular dopamine concentrations before and after carotid artery occlusion while perfusing either a control solution of artificial cerebrospinal fluid (CSF) or a 1 mM solution of pentobarbital in CSF (PB/CSF). During perfusion with CSF, extracellular dopamine increased from a baseline concentration of 0.40 +/- 0.09 (SEM) pmoles/10 minute collection interval to 30.0 +/- 9.0 pmoles/10 minutes after carotid artery occlusion. In contrast, during perfusion with PB/CSF, dopamine levels increased from a baseline of 1.37 +/- 0.3 pmoles/10 minutes to 8.30 +/- 2.6 pmoles/10 minutes; this increase was significantly less than the increase in controls. In animals with established ischemia, repeatedly alternating the perfusion fluid between CSF and PB/CSF demonstrated that dopamine concentrations were significantly increased with CSF alone and decreased with PB/CSF. These findings demonstrate that pentobarbital perfusion either before or following the onset of ischemia inhibits extracellular release of dopamine in the striatum. Inhibition of neurotransmitter release may, in part, be responsible for the protective effect of pentobarbital in ischemic brain injury.

The post-mortem brain concentrations of dopamine (DA) and homovanillic acid (HVA) were determined in 16 parts of the brain from patients with no history of neurologic or psychiatric illness. Fifteen men and nine women, with a mean age of 61.0 +/- 18.7 years (range 23--92 years) were included. They had died from either ischaemic heart disease or cancer. In the post-mortem investigation several factors were controlled: age, time between death and autopsy, time between autopsy and chemical analysis and storage time (-20 degrees C). The DA concentrations in the different brain areas were found to be positively intercorrelated, especially those in the basal ganglia, hippocampus and the mesencephalon. The HVA concentrations measured in various cortical structures were also positively intercorrelated. In several regions of the brain there was a significant inverse correlation between the DA and HVA concentrations. The DA and HVA concentrations did not differ according to sex, but age had a marked influence on the DA concentration. Significant decrease with age was observed in the nucleus caudatus, globus pallidus, mesencephalon, hippocampus and in the cortex gyrus hippocampus. These findings are discussed in relation to the effect of aging neurons. A review of human post-mortem investigations on DA and HVA concentrations is also presented.

Quinpirole, (4 aR-trans)-4, 4a, 5, 6, 7, 8, 8a, 9-octahydro-5-propyl-1 H-pyrazolo [3, 4-g]quinoline, is a dopamine agonist selective for the D2 subtype of dopamine receptors. In rats, quinpirole at doses of 0.3 mg/kg i.p. and higher decreased hypothalamic epinephrine concentrations. The doses required for this effect are only slightly higher than the minimum doses that decreased the concentration of dopamine metabolites in cerebral hemispheres. At higher doses of quinpirole (2-3 mg/kg i.p.), dopamine concentration was increased and norepinephrine concentration was decreased in hypothalamus, and MHPG sulfate (the norepinephrine metabolite) concentration was increased in brain stem and in hypothalamus. All of these neurochemical effects of quinpirole were blocked by pretreatment with spiperone, a dopamine antagonist. The effects were not produced by SKF 38393, a selective D1 agonist, or by the dextrorotatory enantiomer of quinpirole, which lacks D2 agonist activity. The data support the interpretation that quinpirole, by activating D2 receptors, results in a decrease in dopamine metabolites, a decrease in hypothalamic epinephrine concentration, and an increased conversion of norepinephrine to MHPG sulfate in rat brain probably through enhanced norepinephrine release.

A mass fragmentographic method for the simultaneous determination of 4-hydroxy-3-methoxy-phenylacetic acid (HVA), 4-hydroxy-3-methoxy-phenylethylene glycol (MOPEG), and 5-hydroxyindole-3-acetic acid (5-HIAA) was described. Deuterated analogues of the compounds were used as internal standards. The specificity was proved by multiple ion analysis. The experimental error was below 7% when applied to the analysis of human lumbar cerebrospinal fluid, urine, or rat brain tissue. In cerebrospinal fluid the major part of the monoamine metabolites occurred in the free form. In rat brain and human urine considerable amounts of conjugated HVA was found.

Simultaneous plasma and cerebrospinal free and sulfoconjugated norepinephrine, epinephrine, dopamine and homovanillic acid determinations in 38 patients with various neurological disorders have shown consistently lower concentrations of dopamine sulfate, norepinephrine sulfate, and epinephrine sulfate in the cerebrospinal fluid than in plasma. An approximately three fold increase of plasma dopamine sulfate concentrations following banana ingestion did not result in increased dopamine sulfate concentrations in cerebrospinal fluid. There were positive correlations between plasma and cerebrospinal fluid concentrations of free norepinephrine and epinephrine as well as norepinephrine sulfate, dopamine sulfate and free homovanillic acid. Cerebrospinal fluid and plasma are apparently separated by the blood-brain barrier impermeable to catecholamine sulfates from the blood. Some other data and the observed positive correlation between cerebrospinal fluid and plasma dopamine and norepinephrine sulfates suggests however that catecholamine sulfates may pass from cerebrospinal fluid to the blood and reflect events in the brain.

Biochemical human post-mortem studies on depressed patients indicate an unspecific deficiency of neurotransmitters in several brain areas. The loss of drive of these patients could be correlated with a decrease of striatal dopamine concentration. Noradrenaline was significantly diminished in red nucleus, a fact which points to the characteristic posture of depressed patients. Serotonin was diminished in all brain areas. During remission all values trended to be normal. There also exists a circadian disrhythm in depressed patients resulting in lowered VMA- and HVA-levels in urines during the morning and a remission to normal values in the evening. This agrees with the findings of lowered blood tyrosine levels in the morning. The ratio of blood tyrosine and tryptophan is disturbed during depression and recovers during remission. Central and peripheral biochemical mechanisms seems to be involved in depression syndrom.

The acute effects of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (NMPTP) on mouse central monoaminergic neurons were investigated. In striatum, two hours after the injection of NMPTP (50 mg/kg s.c.) there was a seven-fold increase in 3-methoxytyramine that coincided with a 55% decrease in dopamine. In addition, the same dose of NMPTP caused an acute increase in mouse motor activity; this effect was antagonized by haloperidol or by pretreatment with reserpine. These data indicate that NMPTP initially causes a pronounced release of dopamine into the extraneuronal space.

The relationship of human brain levels of 3,4-dihydroxyphenylacetic acid (DOPAC) to cerebrospinal fluid levels of this domapine (DA) metabolite was studied. The effect of postmortem delay was evaluated in the rat. DOPAC was resistant to postmortem changes in brain kept in situ. The level of DOPAC (free and conjugated) determined in DA-rich areas of six human brains amounted to only a fraction of the homovanillic acid (HVA) found in the same regions. The DOPAC/HVA ratio in human brain was similar to that found in CSF. We conclude that HVA is the major DA metabolite in human brain and that DA metabolite levels in CSF reflect DA metabolite levels in brain.

BRL 20596 (N-(4-amino-5-chloro-2-methoxyphenyl)-1-phenylmethyl-4-piperidine-carbox amide) is a novel anilide related to clebopride (a gastric prokinetic benzamide) in which the sole change is reversal of the amide bond. Previous studies have shown conformational and electronic differences between these molecules which result in the anilide losing its gastric prokinetic activity, whilst retaining its central nervous system activity. Pharmacological and biochemical properties of BRL 20596 are compared here in animals with chlorpromazine, clebopride, haloperidol and sulpiride. BRL 20596 potently inhibited a number of behaviours, such as conditioned avoidance, amphetamine-induced stereotypy and turning, and apomorphine-induced climbing. Homovanillic acid (HVA) levels in the striatum and nucleus accumbens were raised at similar dose levels to those which inhibited these behaviours, whilst sedative activity was only exhibited at much higher dose levels. Haemodynamic changes were only observed with high IV doses of BRL 20596. Much lower doses of sulpiride were needed to raise prolactin levels than to raise HVA levels. This was not the case with BRL 20596 and the other drugs, where the doses needed for the two effects were similar. The results suggest that BRL 20596 is a central dopamine antagonist, with low sedative and haemodynamic activity.

The injection of reserpine [2.5 mg/kg, intraperitoneally (i.p.)] increased brain concentration of tyrosine and of the major catecholamine metabolites, 3-methoxy-4-hydroxy-phenylethylene--glycol-sulfate (MHPG-SO4) in the rat. In reserpine-treated animals, tyrosine administration (200 mg/kg, i.p.) caused further increases in brain tyrosine, DOPAC, and HVA, but not in brain MHPG-SO4. The increases in DOPAC and HVA levels were observed in a dopaminergic brain region (the corpus striatum) and a noradrenergic region (the cerebellum). These results support previous observations that catecholamine synthesis and release in both dopaminergic and noradrenergic neurons can depend in part upon brain tyrosine levels.

Regional effects of DSP 4 on monoamine neurons have been analyzed by chemical assay of endogenous monoamines and their metabolites in rat CNS. The results confirmed that the neurotoxic action of DSP 4 is predominantly on noradrenaline nerve terminal projections originating from locus coeruleus, with the most marked effects on terminal fields localized most distant from the noradrenaline perikarya. DSP 4 treatment (10 days) caused no alteration of the regional DA levels, except in cingulate cortex, where a moderate increase (+40%) was observed, possibly at least partially related to a sprouting of dopamine nerve terminals following the noradrenaline denervation. 5-hydroxytryptamine levels were generally unaltered after DSP 4, except for an about 10-25% reduction in cerebral cortex and hippocampus. There was with time a certain noradrenaline recovery, most likely related to regeneration of noradrenaline nerve terminals, although this process was relatively slow (months). Analysis of catecholamine decline after tyrosine hydroxylase inhibition and metabolite/monoamine ratios, as indices for transmitter utilization rate, indicated an increased noradrenaline turnover in terminals spared by DSP 4, while dopamine turnover appeared to be reduced in many regions (i.a. cerebral cortex, striatum, accumbens, olfactory tubercle and spinal cord), most pronounced in cingulate cortex. The results indicate that noradrenaline neurons have a facilitatory action on dopamine neurons. The DSP 4 treatment did not cause any significant effect on 5-hydroxytryptamine turnover in any of the individual regions analyzed.

Fluperlapine has been reported to possess antischizophrenic and antidepressant properties, with low incidence of extrapyramidal side-effects. In order to get more information about the interactions of fluperlapine with rat brain dopaminergic systems, its binding to striatal D2 receptors, measured ex vivo, and its effects on DA metabolism in different brain areas were investigated. Clozapine and haloperidol served as reference compounds in these investigations. It was found that all three agents blocked D2 receptors and increased DA metabolism. Clozapine and fluperlapine differed from haloperidol in that their potency was much lower. Although occupation of striatal D2 receptors by the two dibenzo-epines developed rapidly, the duration was considerably shorter than that of haloperidol. There was no indication that the two dibenzo-epines had a stronger or longer-lasting effect on limbic or cortical DA metabolism compared to that on the striatum. Both drugs caused a weak increase in striatal DA, whereas haloperidol decreased it. It was concluded that the low incidence of extrapyramidal side-effects of fluperlapine, and also of clozapine, is probably due to their weak and relatively brief action on brain DA systems and not due to a selective action on A10 neurotransmission. The anticholinergic properties of the dibenzo-epines might even further reduce the consequences of their already weak effects on DA systems.

The striatal concentration of dopamine (DA), norepinephrine (NE), and homovanillic acid (HVA) was assessed in adult male rabbits exposed to styrene vapours or dosed with mandelic acid (MA), phenylglyoxylic acid (PGA) and phenylglycine (PG). Styrene exposure produced a marked and dose-dependent decrease in striatal DA, concomitant with a consistent increase in HVA. The same effects were caused by i.p. administration of PGA and PG, but not of MA. The increased catabolism of DA was concomitant with a normal turnover time after inhibition of tyrosine hydroxylase by the administration of methyl-p-tyrosine. The amination of PGA to PG with a subsequent competition of the latter with DA for the vesicular storage capacity is suggested as the possible mechanism for styrene-induced brain dysfunction.

The effect of acute ethanol on the levels of NE, DA and its metabolites DOPAC and HVA, as well as on the levels of GABA, in the corpus striatum and hypothalamus were investigated in mice in the first two hours after acute ethanol administration. There was a marked increase in the concentration of DOPAC and HVA in the corpus striatum from 30 to 120 minutes after a dose of 3.5 g/kg of ethanol even though the concentration of DA was only elevated at 60 minutes after ethanol. A dose of 1.75 g/kg of ethanol did not increase DA levels 60 minutes after administration although it did increase the concentration of DOPAC and HVA at this time. In the hypothalamus a dose of 3.5 g/kg of ethanol did not change the concentration of NE or DA but did produce a marked increase in the levels of DOPAC and HVA at 60 and 120 minutes post ethanol. A lower dose of ethanol, 1.75 g/kg, produced the same effect 60 minutes after ethanol. Ethanol caused a dose-dependent accumulation of DOPA in the corpus striatum after inhibition of DOPA-decarboxylase suggesting an increased synthesis of DA. These data suggest that the increased concentrations of DA metabolites after ethanol is secondary to enhanced DA synthesis and turnover. The concentration of NE and GABA in the hypothalamus and the corpus striatum was unchanged at any time period after ethanol.

Levels of free and conjugated monoamine metabolites were analysed in brain tissue of rat and man. In the rat the conjugates were mainly of the sulfate ester type. The levels of conjugated dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) constituted 40--50% of the total amount of the metabolites. 4-Hydroxy-3-methoxy-phenylglycol (HMPG) and 5-hydroxy-3-indoleacetic acid (5-HIAA) were present as conjugates in 90 and 10% of the total levels. Chlorpromazine treatment resulted in an elevation of both the free and the conjugated forms of the dopamine metabolites and HMPG. In a human caudate nucleus obtained at autopsy both DOPAC and HMPG were present in the free form and as sulfate and glucuronide conjugates. The major dopamine metabolite found in this human brain was HVA. This metabolite and 5-HIAA occurred predominantly as free metabolites.

Diphenylhydantoin (DPH) is known to induce reversible paroxysmal dyskinesias and paranoid psychosis in humans, but its interactions with dopamine (DA) metabolism are not clear. Single doses of DPH (60-100 mg kg-1), with serum levels over 10 micrograms ml-1, reduced homovanillic acid (HVA) levels in rat striatum. The DPH-induced HVA decrease was enhanced by supersensitivity of postsynaptic DA receptors following chronic haloperidol (Hal) administration. DPH 60 mg kg-1 given acutely enhanced the HVA decrease induced by apomorphine (Apo) and partially counteracted the HVA increase following acute Hal (0.1-0.5-2 mg kg-1). After chronic DPH treatment, Apo was ineffective in reducing striatal HVA levels. Concomitant chronic treatment with DPH and Hal counteracted the development of supersensitivity of postsynaptic DA receptors to Apo. Single doses of DPH (30-60-100 mg kg-1) increased cyclic AMP striatal content; this effect was blocked by Hal. A dopaminomimetic DPH action and a subsensitivity of postsynaptic DA receptors after chronic DPH seem to be suggested. These effects could be related to the dyskinetic and psychotic syndromes produced by the drug.

The dibutyryl analogues of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) were administered into the lateral ventricles and catecholamine metabolites were determined in brain 40 min later. Dibutyryl cAMP elevated the level of homovanillic acid in whole brain and dihydroxyphenyl acetic acid levels in striatum, the dopamine-rich part of the limbic system and hemispheres but neither affected the accumulation of 3-methoxytyramine following inhibition of MAO with pargyline nor dopamine and noradrenaline levels. Normetanephrine accumulating after MAO inhibition was elevated markedly by dibutyryl cAMP. Dibutyryl cGMP was without effect on the catecholamine metabolites investigated. Dibutyryl cAMP appears to stimulate dopamine metabolism within dopaminergic nerve endings but does not stimulate dopamine release. Dibutyryl cAMP-induced activation of noradrenaline metabolism, however, appears to coincide with a stimulation of noradrenaline release.

The effects of the Ca2+-antagonist nimodipine on central dopamine (DA) neurons in mice were investigated in vivo. Nimodipine caused a dose-dependent decrease in the DA metabolite 3-methoxytyramine (3-MT) in striatum and the limbic region. If the brains were microwave radiated immediately after decapitation in order to minimize post-mortal accumulation of 3-MT, the effect of nimodipine was less pronounced and statistically not significant. Nimodipine markedly decreased the accumulation of 3-MT induced by pargyline, an inhibitor of monoamine oxidase, a phenomenon that was not attenuated by microwave radiation. Furthermore, whereas nimodipine had no effect on mouse motor activity when given alone it readily blocked the pargyline-induced increase in activity. The concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) in striatum and the limbic region were also reduced by nimodipine as was the accumulation of 3,4-dihydroxyphenylalanine (DOPA) measured after inhibition of the aromatic amino acid decarboxylase by 3-hydroxybenzylhydrazine (NSD 1015). In addition, nimodipine caused decreased concentrations of DA and homovanillic acid (HVA) in the limbic region but not in striatum. Nimodipine caused an increase in the striatal concentrations of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA); these changes were not seen in the limbic region. In conclusion, nimodipine appears to reduce the release as well as the synthesis of DA in mouse brain. These effects are believed to be related to the Ca2+-antagonism of nimodipine.