Exposure of a 'witness rat' to one treated with beta-carboline FG 7142 does not increase dopamine turnover in the medial prefrontal cortex of the 'witness rat'.

A method for selectively activating the dopaminergic field of the prefrontal cortex would be highly useful for studies of mesocortical dopamine systems. When a rat ('witness' rat) is exposed to a rat that is undergoing footshock, prefrontocortical dopamine metabolism is selectively increased in the witness rat. Since the anxiogenic beta-carboline FG 7142 mimics many of the effects of footshock, we hypothesized that exposure of a witness-rat to a rat treated with FG 7142 would also increase dopamine metabolism in the prefrontal cortex. We found that while as expected, FG 7142 itself increased prefrontal cortex dopamine metabolism, there was no significant change in dopamine metabolism in the witness rat. Thus exposure to a rat treated with FG 7142 does not selectively activate the mesocortical dopamine system.

GC/MS analysis of anandamide and quantification of N-arachidonoylphosphatidylethanolamides in various brain regions, spinal cord, testis, and spleen of the rat.

Anandamide [N-arachidonoylethanolamide (NAE)] was initially isolated from porcine brain and proposed as an endogenous ligand for cannabinoid receptors in 1992. Accumulating evidence has now suggested that, in the tissue, NAE is generated from N-arachidonoylphosphatidylethanolamides (N-ArPEs) by phosphodiesterase. In this study a sensitive and specific procedure was developed to quantify NAE and N-ArPE, including organic solvent extraction, reverse-phase C-18 cartridge separation, derivatization, and gas chromatography/mass spectrometry (GC/MS) analysis. NAE is converted by a two-step derivatization procedure to a pentafluorobenzoyl ester followed by pentafluoropropionyl acylation. Quantification was performed by isotope dilution GC/MS using deuterium-labeled NAE (NAE-2H8) as an internal standard. The same chemical derivatization was applicable to N-ArPE quantification. The separated N-ArPE fractions were converted by a two-step cleavage/derivatization procedure into the pentafluorobenzoyl ester of NAE and then to its pentafluoropropionyl amide. The derivative was quantified by GC/MS using deuterium-labeled 1,2-[2H8]dioleoyl-sn-glycero-3-phospho(arachidonoyl)ethanolamid e as an internal standard. Using these methods, we have found that endogenous NAE levels in rat brain, spleen, testis, liver, lung, and heart were below the level of quantification achievable (0.1 pmol/mg of protein) but that N-ArPE is readily quantifiable and is widely distributed in the rat CNS with the highest level in the spinal cord. The striatum, hippocampus, and accumbens contain intermediate concentrations of N-ArPE, whereas the value is lowest in the cerebellum.

SR 141716A, a CB1 cannabinoid receptor antagonist, potentiates the locomotor stimulant effects of amphetamine and apomorphine.

The intraperitoneal (i.p.) injection of apomorphine or d-amphetamine significantly increased locomotor activity in Sprague-Dawley rats. Prior administration of the cannabinoid receptor antagonist, SR 141716A, significantly enhanced the stimulant effect of both d-amphetamine and apomorphine in a dose-dependent manner. Administration of SR 141716A alone had no effect on locomotor activity. These data indicate that endogenous cannabinoids exert an inhibitory action on the increase in locomotor activity produced by amphetamine and apomorphine.

Effects of antipsychotics, vitamin E, and MK-801 on dopamine dynamics in the rat brain following discontinuation of cocaine.

Cocaine, 10 mg/kg, I.P., twice daily, was given to rats for 1 week. At 1 and 4 weeks following discontinuation of cocaine, the initial rate of 3,4-dihydroxyphenylacetic acid (DOPAC) formation was assessed. The initial rate of DOPAC formation was found to be decreased in the frontal and cingulate cortices at 1 week, but was only decreased in the frontal cortex at 4 weeks. When administered in conjunction with cocaine, haloperidol, clozapine, and vitamin E, but not MK-801, were found to prevent cocaine's effects. In addition to the potential value these findings have for further understanding cocaine abuse, it is proposed that the alteration in dopamine metabolism produced by cocaine, and the ability of haloperidol, clozapine and vitamin E to decrease cocaine's effects, model some biochemical aspects of schizophrenia.

Differential trace amine alterations in individuals receiving acetylenic inhibitors of MAO-A (clorgyline) or MAO-B (selegiline and pargyline).

Marked, dose-dependent elevations in the urinary excretion of phenylethylamine, para-tyramine, and meta-tyramine were observed in depressed patients treated for three or more weeks with 10, 30, or 60 mg/day of the partially-selective inhibitor of MAO-B, selegiline (l-deprenyl). In comparative studies with other, structurally similar acetylenic inhibitors of MAO, pargyline, an MAO-B > MAO-A inhibitor used in doses of 90 mg/day for three or more weeks, produced elevations in these trace amines which were similar to those found with the highest dose of selegiline studied. Clorgyline, a selective inhibitor of MAO-A used in doses of 30 mg/day for three or more weeks (a dose/time regimen previously reported to reduce urinary, plasma, and cerebrospinal fluid 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) > 80%, indicating a marked inhibitory effect on MAO-A in humans in vivo) produced negligible changes in trace amine excretion. In comparison to recent studies of individuals lacking the genes for MAO-A, MAO-B, or both MAO-A and MAO-B, the lack of change in trace amine excretion in individuals with a mutation affecting only MAO-A is in agreement with the observed lack of effect of clorgyline in the present study. Selegiline produced larger changes in trace amines--at least at the higher doses studied--than found in individuals lacking the gene for MAO-B, in agreement with other data suggesting a lesser selectivity for MAO-B inhibition when selegiline was given in doses higher than 10 mg/day. Overall, trace amine elevations in individuals receiving the highest dose of deprenyl or receiving pargyline were approximately three to five-fold lower than the elevations observed in individuals lacking the genes for both MAO-A and MAO-B, suggesting that these drug doses yield incomplete inhibition of MAO-A and MAO-B.

Increased stress response and beta-phenylethylamine in MAOB-deficient mice.

MAOA and MAOB are key iso-enzymes that degrade biogenic and dietary amines. MAOA preferentially oxidizes serotonin (5-hydroxytryptamine, or 5-HT) and norepinephrine (NE), whereas MAOB preferentially oxidizes beta-phenylethylamine (PEA). Both forms can oxidize dopamine (DA). A mutation in MAOA results in a clinical phenotype characterized by borderline mental retardation and impaired impulse control. X-chromosomal deletions which include MAOB were found in patients suffering from atypical Norrie's disease, which is characterized by blindness and impaired hearing. Reduced MAOB activity has been found in type-II alcoholism and in cigarette smokers. Because most alcoholics smoke, the effects of alcohol on MAOB activity remain to be determined. Here we show that targetted inactivation of MAOB in mice increases levels of PEA but not those of 5-HT, NE and DA, demonstrating a primary role for MAOB in the metabolism of PEA. PEA has been implicated in modulating mood and affect. Indeed, MAOB-deficient mice showed an increased reactivity to stress. In addition, mutant mice were resistant to the neurodegenerative effects of MPTP, a toxin that induces a condition reminiscent of Parkinson's disease.

Cerebrospinal fluid monoamine metabolites in childhood-onset schizophrenia.

OBJECTIVE: Pediatric studies of cerebrospinal fluid (CSF) monoamine metabolites in childhood-onset schizophrenia may help to elucidate both pathophysiology and treatment response in early-onset psychosis. METHOD: CSF homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) and serum prolactin were measured during drug-free and antipsychotic medication conditions in 18 patients (mean age = 14.2 years, SD = 1.7) who had onset of schizophrenia by age 12 (mean age at onset = 9.9 years, SD = 1.8). Relationships between changes in CSF monoamines and serum prolactin and clinical outcome were examined, and the degree of change in CSF monoamines in response to clozapine treatment was compared with that for 16 patients with later-onset schizophrenia. RESULTS: Despite patients' significant clinical improvement with treatment, CSF monoamine concentrations and ratios of HVA/5-HIAA and HVA/MHPG did not significantly change with 6 weeks of either haloperidol or clozapine treatment. Serum prolactin levels increased during haloperidol treatment. Clozapine had similar effects on CSF monoamines in patients with childhood- and later-onset schizophrenia. CONCLUSIONS: While these data are compatible with continuity between childhood- and later-onset schizophrenia, they also highlight the complexity of the biochemical events mediating clinical changes in schizophrenia.

Effects of the administration of amphetamine, either alone or in combination with reserpine or cocaine, on regional brain beta-phenylethylamine and dopamine release.

The effect of amphetamine sulfate (AMPH) on beta-phenylethylamine (PEA) and 3-methoxytyramine (3MT) levels in the rat frontal and cingulate cortices, the nucleus accumbens, and the striatum were evaluated after the administration of either cocaine or reserpine alone and in combination with AMPH. The purpose of this study was to evaluate the neuromodulator properties of PEA on dopamine (DA) release as reflected by 3MT steady-state concentrations. The highest concentration of PEA was found in the nucleus accumbens, followed by the cingulate and frontal cortices, and then the striatum. Time-course effects of the intraperitoneal administration of 5 mg/kg AMPH on PEA and 3MT concentrations were similar but not identical. AMPH at a dosage of 1 mg/kg significantly increased PEA concentration only in the striatum. A dosage of 2.5 mg/kg reserpine, which markedly depressed 3MT levels in all brain regions studied except the striatum, significantly reduced PEA concentrations only in the nucleus accumbens. This dosage of reserpine reduced DA concentrations by more than 80% in all regions examined, but its effects on norepinephrine were less marked. Pretreatment with cocaine (10 mg/kg) or reserpine (2.5 mg/kg) potentiated the effects of 1 mg/kg AMPH on PEA and 3MT levels in the frontal cortex and of 3MT in the striatum. Pretreatment with either 1 mg/kg reserpine (specifically used to partially mobilize DA storage) or cocaine (10 mg/kg) produced quantitative changes in the effects of 5 mg/kg AMPH on PEA and 3MT levels that were region-specific. For example, in contrast to the cortical regions and the nucleus accumbens, the AMPH-induced increase in 3MT was potentiated in the striatum. On the other hand, the increase in brain PEA produced by AMPH (5 mg/kg) was not influenced by either increased cytoplasmic DA (as deduced from the effects of 1 mg/kg reserpine pretreatment) or DA uptake inhibition (as deduced from the effect of cocaine pretreatment) in the frontal cortex or the nucleus accumbens. Furthermore, the increase in PEA produced by AMPH (5 mg/kg) in the cingulate cortex and the striatum were abolished and potentiated, respectively, by these drug pretreatments. Our results suggest that although DA release and PEA formation are stimulated by AMPH, these effects appear to involve mechanisms that are not directly related and hence suggest a dissociation between 3MT and PEA formation in the brain. Our work also suggests that PEA is most likely not to be co-released with DA following the administration of AMPH. Therefore, it is concluded that whatever physiological role PEA may play in central synaptic transmission, its effects do not appear to be dependent on DA release.

The effects of acute and chronic haloperidol treatment on dopamine release mediated by the medial forebrain bundle in the striatum and nucleus accumbens.

The delayed therapeutic effects of neuroleptics have been attributed to D2-mediated depolarization inactivation (DI) of mesolimbic dopaminergic neurons and concomitant reduction in dopamine release. Several studies have suggested, however, that DI may not reduce dopamine release and have hypothesized that this is due to increased impulse independent release. To examine the mechanisms that modulate dopamine release during DI, tetrodotoxin (TTX) was infused into the left medial forebrain bundle (MFB) of Sprague Dawley rats. Three-methoxytyramine (3-MT) levels 10 minutes after pargyline (75 mg/kg) were used as a measure of dopamine release. A dose response study showed that infusions of 10(-5) mol/L and 10(-4) mol/L TTX reduced 3-MT levels on the infused side by 70% in the striatum and 50% to 60% in the nucleus accumbens. In a time course study, 10(-5) mol/L TTX reduced striatal 3-MT at 30, 90, and 120 minutes. After intraperitoneal injections of haloperidol (0.4 mg/kg) for 1 or 21 days, TTX infusions again reduced 3-MT levels by approximately 70% in the striatum and 53% to 59% in the nucleus accumbens on the infused side. Acute and chronic haloperidol treatment did not alter the percent of TTX-induced reductions. These data suggest that dopaminergic neuronal impulse flow modulates similar amounts of total transmitter release after both acute and chronic haloperidol treatment. The results do not support the notion that DI mediates the antipsychotic effects of neuroleptics by markedly reducing total basal dopamine release or increasing impulse independent release. Alternatively, DI could reduce psychotic symptoms by changing the responsiveness of the dopamine system to external stimuli or by reducing synaptic dopamine levels that have been hypothesized to be elevated in psychotic patients.

Specific genetic deficiencies of the A and B isoenzymes of monoamine oxidase are characterized by distinct neurochemical and clinical phenotypes.

Monoamine oxidase (MAO) exists as two isoenzymes and plays a central role in the metabolism of monoamine neurotransmitters. In this study we compared the neurochemical phenotypes of previously described subjects with genetically determined selective lack of MAO-A or a lack of both MAO-A and MAO-B with those of two subjects with a previously described X chromosome microdeletion in whom we now demonstrate selective MAO-B deficiency. Mapping of the distal deletion breakpoint demonstrates its location in intron 5 of the MAO-B gene, with the deletion extending proximally into the Norrie disease gene. In contrast to the borderline mental retardation and abnormal behavioral phenotype in subjects with selective MAO-A deficiency and the severe mental retardation in patients with combined MAO-A/MAO-B deficiency and Norrie disease, the MAO-B-deficient subjects exhibit neither abnormal behavior nor mental retardation. Distinct neurochemical profiles characterize the three groups of MAO-deficient patients. In MAO-A-deficient subjects, there is a marked decrease in deaminated catecholamine metabolites and a concomitant marked elevation of O-methylated amine metabolites. These neurochemical changes are only slightly exaggerated in patients with combined lack of MAO-A and MAO-B. In contrast, the only biochemical abnormalities detected in subjects with the MAO-B gene deletion are a complete absence of platelet MAO-B activity and an increased urinary excretion of phenylethylamine. The differences in neurochemical profiles indicate that, under normal conditions, MAO-A is considerably more important than MAO-B in the metabolism of biogenic amines, a factor likely to contribute to the different clinical phenotypes.

Effects of chronic neuroleptic treatment on dopamine release: insights from studies using 3-methoxytyramine.

Antipsychotic medications appear to exert their therapeutic effects by blocking D2 receptors. While D2 blockade occurs rapidly, reduction in psychotic symptoms is often delayed. This time discrepancy has been attributed to the relatively slow development of depolarization inactivation (DI) of dopaminergic neurons. The reduced firing rates associated with DI has been hypothesized to reduce dopamine release and thus psychotic symptoms. Studies assessing changes in dopamine release during chronic neuroleptic treatment, using microdialysis and voltammetry, have been inconsistent. This may be due to methodological differences between studies, the invasive nature of these procedures, or other confounds. To investigate the effects of DI on dopamine release, 3-MT accumulation, an index of dopamine release that does not involve disruption of brain tissue, was measured during acute and chronic neuroleptic treatment. These results are compared with those using other techniques. 3-MT levels remained elevated after chronic treatment, suggesting that DI does not markedly reduce release. Regulation of dopamine release during DI was examined using two techniques known to block dopamine neuronal impulse flow. 3-MT levels were markedly reduced by both, implying that DI does not alter the portion of dopamine release mediated by neuronal impulse flow. Overall, studies to date suggest that the delayed therapeutic effects of neuroleptics are not due to reductions in impulse dependent dopamine release. Recent studies using a neurodevelopmental animal model of schizophrenia have pointed to altered pre- and post-synaptic indices of dopamine neurotransmission. The results suggest that neuroleptics may exert their therapeutic effects, in part, by limiting the fluctuations in dopamine release, and raise new issues for future research.

Decreased DOPAC in the anterior cingulate cortex of individuals with schizophrenia.

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

Regional effects of amphetamine, cocaine, nomifensine and GBR 12909 on the dynamics of dopamine release and metabolism in the rat brain.

1. The effects of single-dose regimens of amphetamine, cocaine, nomifensine and GBR 12909 on the dynamics of dopamine (DA) release and metabolism were evaluated in the frontal cortex, hypothalamus, nucleus accumbens and striatum. The regimens selected are known to produce substantial behavioural effects. 2. 3-Methoxytyramine (3MT) and 3,4-dihydroxyphenylacetic acid (DOPAC) rates of formation were used to assess DA metabolism by catechol-O-methyltransferase and monoamine oxidase respectively. The rate of formation of 3MT was used as an index of synaptic DA. The ratio and sum, respectively, of 3MT and DOPAC rates of formation were used to assess DA reuptake inhibition and turnover. 3. The effects of amphetamine on 3MT production and DOPAC steady-state levels were similar in all regions, suggesting similar pharmacodynamic actions. Amphetamine increased 3MT formation and steady-state levels, and reduced DOPAC steady-state levels. DOPAC formation was significantly reduced only in the nucleus accumbens and striatum. Total DA turnover remained unchanged except in the nucleus accumbens. Apparently, the amphetamine-induced increase in DA release occurred at the expense of intraneuronal DA metabolism and did not require stimulation of synthesis. 4. Nomifensine elevated 3MT formation in all regions. A similar effect was produced by cocaine except in the nucleus accumbens. GBR 12909 elevated 3MT production only in the hypothalamus, the striatum and the nucleus accumbens. 5. Cocaine selectively reduced DOPAC formation in the frontal cortex. Nomifensine increased and reduced, respectively, DOPAC formation in striatum and hypothalamus. GBR 12909 elevated DOPAC formation in all regions except the cortex, where pargyline did not reduce DOPAC levels in GBR 12909-treated rats. 6. Ratios and sum of 3MT and DOPAC rates of formation also exhibited wide regional variations for each drug. In contrast to the other drugs, the ratio was not increased after GBR 12909. Apparently, the DA uptake properties of this drug are poorly related to its in vivo effects on the ratio of 3MTproduction to that of DOPAC, which should increase when DA reuptake is inhibited.7. Total DA turnover was increased by GBR 12909 in the hypothalamus, nucleus accumbens and striatum, while cocaine and nomifensine increased it only in the nucleus accumbens and striatum respectively.8. It is concluded that:(a) 3MT and DOPAC rates of formation provide better indices of DA release and metabolism than do their steady-state concentrations.(b) Some effects of DA uptake blockers on DA transmission, especially those of nomifensine and cocaine, may be attributed to increased DA release.(c) Patterns of regional effects of psychostimulants on the dynamics of DA release and metabolism may be better biochemical correlates of stimulant-induced behaviours than would changes in any single region.

3-Methoxytyramine is the major metabolite of released dopamine in the rat frontal cortex: reassessment of the effects of antipsychotics on the dynamics of dopamine release and metabolism in the frontal cortex, nucleus accumbens, and striatum by a simple two pool model.

3-Methoxytyramine (3-MT) and 3,4-dihydroxyphenylacetic acid (DOPAC) rates of formation were used, respectively, to assess the dynamics of dopamine (DA) release and turnover in the rat frontal cortex, nucleus accumbens, and striatum. Assuming total (re)uptake and metabolism of released DA are relatively uniform among the three brain regions, a simplified two pool model was used to assess the metabolic fate of released DA. Under basal conditions, 3-MT formation was found to comprise > 60% of total DA turnover (sum of 3-MT plus DOPAC rates of formation) in the frontal cortex, and not more than 15% in the nucleus accumbens and striatum. Haloperidol increased the 3-MT rate of formation to a greater extent in the frontal cortex than in the two other regions. Clozapine increased the 3-MT rate of formation in the frontal cortex and decreased it in the striatum. Both drugs increased DOPAC rate of formation in the frontal cortex and nucleus accumbens. It was elevated by haloperidol but not clozapine in the striatum. It is concluded that (1) O-methylation is a prominent step in the catabolism of DA in the frontal cortex under both physiological conditions and after acute treatment with antipsychotics, (2) 3-MT is the major metabolite of released DA in the frontal cortex and possibly also in the nucleus accumbens and striatum, (3) in contrast to the frontal cortex, most of the DOPAC in the nucleus accumbens and striatum appear to originate from intraneuronal deamination of DA that has not been released, (4) because presynaptic uptake and metabolism of DA give rise to DOPAC, whereas postsynaptic uptake and metabolism produced both DOPAC and 3-MT, the ratio of 3-MT to DOPAC rates of formation can be a useful index of reuptake inhibition.

Alterations in dopamine metabolism by intraperitoneal ethanol in rats selected for high and low ethanol preference: a 3-methoxytyramine study.

Effects of an ethanol dose (1 g/kg, IP) on the metabolism of dopamine (DA) in the nucleus accumbens, striatum and hypothalamus of ethanol-naive alcohol-preferring (AA) and alcohol-avoiding (ANA) rats were studied. Rats were sacrificed by focused-beam microwave irradiation of the brain 20 minutes after ethanol administration, and the concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), assumed to reflect DA metabolism, and of 3-methoxytyramine (3-MT), assumed to reflect DA release, were measured using gas chromatography-mass spectrometry. Basal striatal DOPAC and HVA concentrations were higher in the AA rats in comparison with ANA rats. Ethanol increased HVA, but not DOPAC, concentration in the nucleus accumbens and striatum, but not in the hypothalamus. There was a significant rat line x ethanol treatment interaction with respect to HVA concentration in the nucleus accumbens. The increase in HVA was higher in the AA than ANA rats. Basal 3-MT concentration was not changed by ethanol, except in the nucleus accumbens, where a significant rat line x ethanol treatment interaction was found. A decrease in 3-MT concentration was only detected in the ANA rats. After inhibition of monoamine oxidase with pargyline hydrochloride (75 mg/kg, IP, 10 min before sacrifice), 3-MT accumulation was decreased by ethanol, especially in the nucleus accumbens of both AA and ANA rat lines as well as in that of nonselected Wistar rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Selective reduction in dopamine turnover in the rat frontal cortex and hypothalamus during withdrawal from repeated cocaine exposure.

The effects of 7 days repeated cocaine administration on the dynamics of dopamine release and metabolism in four rat brain regions (frontal cortex, hypothalamus, nucleus accumbens and striatum) were evaluated 1 week (long-term effects) after the final cocaine injection. 3-Methoxytyramine and 3,4-dihydroxyphenylacetic acid (DOPAC) rates of formation were respectively used to assess the dynamics of dopamine release and metabolism. Consistent with a previous report, cocaine withdrawal was associated with marked reductions in DOPAC rate of formation in the frontal cortex and hypothalamus but not in the nucleus accumbens or the striatum. Dopamine release as indicated by 3-methoxytyramine steady-state concentration and its rate of formation was normal in all four brain regions 1 week after repeated cocaine exposure. The ratios of 3-methoxytyramine rate of formation to that of DOPAC were calculated and found to be increased in the frontal cortex and hypothalamus suggesting dopamine reuptake inhibition, at least 1 week after cocaine withdrawal, continued to be depressed in these regions. It is concluded that repeated cocaine has no long-term effect on dopamine release but produces selective long-term reductions in dopamine turnover in frontal cortex and hypothalamus. Cocaine withdrawal is therefore better associated with changes in dopamine turnover than with its release.

Absence of 6-hydroxydopamine in the rat brain after treatment with stimulants and other dopaminergic agents: a mass fragmentographic study.

Formation of 6-hydroxydopamine (6-OHDA) from dopamine has been hypothesized to mediate neurodegeneration induced by some psychostimulants. Although the emergence of a 6-OHDA-like substance was reported in the striatum of methamphetamine-treated rats, this substance has not been identified by a direct approach. We used mass fragmentography to search for 6-OHDA in the rat frontal cortex and striatum after the administration of a number of drugs including 3,4-dihydroxyphenyl-L-alanine, methamphetamine, amphetamine, and cocaine, all of which increase synaptic dopamine. No 6-OHDA was detected after the acute systemic administration of these agents. Intraventricular administration of 6-OHDA (10 micrograms/rat) produced measurable concentrations of 6-OHDA that were higher in the striatum than in the frontal cortex. Intraventricular administration of 2,4,5-trihydroxyphenyl-D,L-alanine (6-OHDOPA; 10 micrograms/rat) produced similar concentrations of 6-OHDA in both regions. Pargyline, but not carbidopa (alpha-methyl-dopa-hydrazine), enhanced the effect of intraperitoneal 6-OHDOPA administration (80 mg/kg). We conclude that (1) 6-OHDOPA can cross the blood-brain barrier and is converted to 6-OHDA in the brain, (2) 6-OHDA is a substrate for monoamine oxidase(s) and therefore a search for its purported deaminated metabolite is warranted, and (3) acute treatment with the above stimulants either does not lead to the formation of 6-OHDA or produces concentrations below the detection limit of the assay (< 34 pg/mg of protein).

Haloperidol and clozapine increase intraneuronal dopamine metabolism, but not gamma-butyrolactone-resistant dopamine release.

In a previous study, two coexisting mechanisms of dopamine release were identified in dopamine neuron terminals. One can be blocked with gamma-butyrolactone, suggesting it is impulse flow-dependent, while the other one cannot and is apparently impulse flow-independent. The goal of this study was to further characterize the gamma-butyrolactone-resistant mechanism and its relation to dopamine metabolism. Following acute and chronic haloperidol or clozapine treatment, gamma-butyrolactone was given to block dopamine neuronal impulse flow. In all groups, 3-methoxytyramine levels after monoamine oxidase inhibition with pargyline (an index of dopamine release) were measured in the frontal cortex, nucleus accumbens and striatum. Regional steady-state levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were also measured in the rats treated acutely with neuroleptics. In all three regions, gamma-butyrolactone reduced the 3-methoxytyramine levels by over 50% after chronic neuroleptic treatment. This indicates that dopamine release from the terminals is primarily impulse flow-dependent during chronic neuroleptic treatment, both in the dopamine neurons which do undergo depolarization block, and in those that do not. No neuroleptic effect on the gamma-butyrolactone-resistant dopamine release was observed, while DOPAC and HVA were markedly elevated by the acute treatment, suggesting a predominant production of these metabolites from unreleased dopamine.

gamma-Butyrolactone-sensitive and -insensitive dopamine release, and their relationship to dopamine metabolism in three rat brain regions.

Some data suggest dopamine (DA) release from neuronal terminals is partially independent of impulse flow. We examined the changes in tissue DA and its major metabolite levels 30 and 90 min after treatment with y-butyrolactone (750 mg/kg). Accumulation of 3-methoxytyramine within 10 min of pargyline injection (75 mg/kg) was used as an index of DA release. Thirty minutes after gamma-butyrolactone injection, DA content was increased maximally in the frontal cortex, nucleus accumbens and striatum (by 91%, 80% and 73%, respectively). 3-Methoxytyramine rates of accumulation were reduced by 77%, 77%, and 92%, respectively. Ninety minutes after the treatment, DA levels remained high in all three areas, while DA release was persistently low in the striatum and nucleus accumbens, but had returned to baseline in the frontal cortex. Changes in 3,4-dihydroxyphenyl-acetic acid and homovanillic acid levels were not synchronized with changes in DA release in the striatum and nucleus accumbens, and were absent in the frontal cortex. The data suggest that an impulse flow-independent mechanism contributes to approximately one tenth and one fourth of the basal DA release in the terminals of DA neurons originating in the substantia nigra and ventral tegmental area, respectively. The acidic DA metabolite levels become at best poorly associated with DA release during blockade of the DA neuronal firing, probably because of the increased in situ metabolism of newly synthesized DA.