Striatal dopamine nerve terminal markers in human, chronic methamphetamine users.

Methamphetamine is a drug that is significantly abused worldwide, Although long-lasting depletion of dopamine and other dopamine nerve terminal markers has been reported in striatum of nonhuman primates receiving very high doses of the psychostimulant, no information is available for humans. We found reduced levels of three dopamine nerve terminal markers (dopamine, tyrosine hydroxylase and the dopamine transporter) in post-mortem striatum (nucleus accumbens, caudate, putamen) of chronic methamphetamine users. However, levels of DOPA decarboxylase and the vesicular monoamine transporter, known to be reduced in Parkinson's disease, were normal. This suggests that chronic exposure to methamphetamine does not cause permanent degeneration of striatal dopamine nerve terminals at the doses used by the young subjects in our study. However, the dopamine reduction might explain some of the dysphoric effects of the drug, whereas the decreased dopamine transporter could provide the basis for dose escalation occurring in some methamphetamine users.

Reduced brain 5-HT and elevated NE turnover and metabolites in bipolar affective disorder.

Levels of norepinephrine (NE), serotonin (5-HT), dopamine (DA), and their major metabolites were determined in postmortem brain obtained from nine subjects with antemortem histories meeting DSM-III-R criteria for bipolar affective disorder. Compared with controls, no statistically significant differences were found in mean levels of NE, 5-HT, or DA in any brain area of bipolar subjects. NE turnover as estimated by the ratio of the major NE metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) to NE was increased in frontal (+107%), temporal (+103%), and occipital (+64%) cortex and thalamus (+83%). Significant decreases were found in the major 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA), in frontal (-54%) and parietal cortex (-64%), and in 5-HIAA/5-HT ratio in temporal cortex (-55%), with a trend for decreases in both measures in caudate nucleus. In addition, levels of the major DA metabolite, homovanillic acid (HVA) were significantly decreased (-46%) in parietal cortex and HVA/DA ratios were significantly reduced (-66%) in occipital cortex obtained from bipolar compared to control subjects. Our data, taken together with previous findings regarding monoamines in postmortem brain of depressed and suicide subjects, suggest that decreased 5-HT metabolite levels and turnover may be common to all mood disorders. Increased cortical NE turnover, however, may be a more important component in the pathophysiology of bipolar disorder.

Cerebellar norepinephrine in patients with Parkinson's disease and control subjects.

Norepinephrine was measured in postmortem cerebellar cortex of 22 non-neurological control subjects and nine patients with Parkinson's disease, using the high-performance liquid chromatography method with amperometric detection. In all control subjects, substantial amounts of norepinephrine was found in cerebellar cortex. There was a moderate negative correlation between age of control subjects and cerebellar norepinephrine concentration. In the patients with Parkinson's disease, the cerebellar cortical norepinephrine levels were significantly below normal. This is in accord with previously reported reduced norepinephrine levels in locus ceruleus and other regions of the parkinsonian brain. Although the main symptoms of Parkinson's disease are primarily caused by disturbed basal ganglia (dopamine) function, cerebellar dysfunction related to norepinephrine may contribute to some abnormalities of motor performance in this disorder.

Reversible drug-induced parkinsonism. Clinicopathologic study of two cases.

Parkinsonism developed in two patients who were received neuroleptic drugs. In each case the clinical manifestations remitted completely when the offending drug or drugs were discontinued. Histologic examination in each patient disclosed abnormalities characteristic of idiopathic paralysis agitans (IPA). Levels of homovanillic acid were low in both cases, and dopamine (DA) levels were measurably reduced in the striatum in one case. It is postulated that before administration of neuroleptic drugs, both patients had preclinical IPA, which predisposed them to parkinsonism when challenged with DA antagonists. Our observations suggest that some patients with irreversible drug-induced parkinsonism may suffer from IPA and that the reversibility of clinical features does not exclude the presence of subclinical IPA.

Brain neurotransmitter changes in human narcolepsy.

We measured the concentrations of the three major monoamine neurotransmitters noradrenaline, dopamine, and serotonin, their metabolites, and receptor binding sites in autopsied brain of three patients with narcolepsy. As compared with the controls, concentrations of the noradrenaline and serotonin metabolites MHPG and 5-HIAA, respectively, were markedly elevated in cerebral cortical subdivisions of the narcolepsy patients together with a trend for above-normal neurotransmitter/metabolite "turnover" ratio. A moderately reduced number of alpha 1-adrenoceptors, as judged by the reduced levels of 3H-prazosin binding, was observed in cerebral cortex of two of the three patients with narcolepsy. Mean striatal levels of dopamine and its metabolite homovanillic acid were normal, whereas the concentration of dopamine's second metabolite, dihydroxyphenylacetic acid, was markedly reduced by 50% or greater. This was accompanied by a marked increase (+125%) in mean 3H-spiperone binding to the D2 dopamine receptor in both caudate and putamen; in contrast, the levels of 3H-SCH 23390 binding to the striatal D1 dopamine receptor were in the normal range. Our data provide evidence for altered brain monoaminergic neurotransmitter function in human narcolepsy.

Striatal monoamine neurotransmitters and metabolites in dominantly inherited olivopontocerebellar atrophy.

We measured the levels of the monoamine neurotransmitters and metabolites in striatum of 14 patients with end-stage dominantly inherited olivopontocerebellar atrophy (OPCA). On average, dopamine levels were reduced in putamen (-53%), caudate (-35%), and nucleus accumbens (-31%). However, individual patient values showed a wide variation, indicating that mild to moderate striatal dopamine loss is a common but not constant feature of OPCA. Seven patients had marked putamen dopamine loss (-62% to -81%) but without evidence of correspondingly severe substantia nigra cell damage; this suggests the possibility of a "dying-back" phenomenon in which nerve terminal loss precedes cell body degeneration. Severe substantia nigra cell loss with almost total (-95% to -99%) putamen and caudate dopamine depletion was present in two patients; however, none of the 14 patients had had a clinical diagnosis of parkinsonism or was receiving antiparkinsonian medication. Mean striatal serotonin levels were normal, whereas concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid were elevated by 47% to 63%; this suggests increased activity of raphe dorsalis serotonin neurons innervating the striatum, which might aggravate the functional consequences of the dopamine deficit.

Differential changes in neurochemical markers of striatal dopamine nerve terminals in idiopathic Parkinson's disease.

To determine the extent that different dopamine (DA) neuronal markers provide similar estimates of striatal (caudate and putamen) DA nerve terminal loss in idiopathic Parkinson's disease (PD), we compared, in postmortem striatum of 12 patients with PD and 10 matched controls, levels of five different DA neuronal markers. These markers included DA itself, three different estimates of the density of the DA transporter (DAT) ([3H])GBR 12,935 and [3H]WIN 35,428 binding; DAT protein immunoreactivity), and one estimate of the vesicular monoamine transporter (VMAT2; [3H]DTBZ binding). Striatal levels of all examined DA markers in PD were significantly intercorrelated. However, the magnitude of loss relative to controls was unequal (DAT protein = DA > [3H]WIN 35,428 > [3H]DTBZ > [3H]GBR 12, 935), with the differences more marked in the severely affected putamen. The less severe reduction of binding of the DAT/VMAT2 radioligands relative to DA and DAT protein could be explained by differential regulation/degeneration of different DA nerve terminal components or lack of specificity of the radioligands for the DA neuron. These postmortem data may help in interpretation of in vivo neuroimaging studies in PD in which only one radioligand is routinely employed.

The pallido-subthalamic projection in rat: anatomical and biochemical studies.

Horseradish peroxidase injected into the rat globus pallidus was transported retrogradely to subthalamic nucleus neuronal cell bodies and anterogradely to axon terminals in the subthalamic nucleus. Electron microscopic observations revealed that the labeled axon terminals made symmetrical axosomatic and axo-dendritic synaptic contacts with labeled subthalamic nucleus perikarya and dendrites. Injection of kainic acid in the globus pallidus several days prior to the horseradish peroxidase injection abolished the anterograde but not the retrograde transport of the tracer. This suggested the anterograde labeling observed in the subthalamic nucleus originated from neuronal cell bodies in the globus pallidus. Kainic acid lesions identical to those employed in the above anatomical studies resulted in a loss of neuronal cell bodies throughout the globus pallidus and caused a drop in glutamic acid decarboxsylase and choline acetyltransferase levels in the globus pallidus. Levels of these two enzymes were not changed in the subthalamic nucleus after the globus pallidus kainic acid lesions, but both showed small, statistically significant decreases in the substantia nigra. It was concluded that there is a massive pathway from the globus pallidus to the subthalamic nucleus, which terminates on subthalamic nucleus neurons projecting back to the globus pallidus. Neither gamma-aminobutyric acid nor acetylcholine is the major neurotransmitter in the massive pallido-subthalamic pathway.

Noradrenaline, dopamine and serotonin levels and metabolism in the human hypothalamus: observations in Parkinson's disease and normal subjects.

In order to determine whether, besides the severe striatal dopamine (DA) loss, other brain neurotransmitter changes may be a constant biochemical feature of idiopathic Parkinson's disease (iPD), we measured the concentration of the three major brain monoamines noradrenaline (NA), DA, and serotonin (5-HT) and their metabolites in five rostro-caudal subdivisions of the hypothalamus of eight control patients and nine patients with morphologically confirmed iPD. In the whole hypothalamus of the iPD patients we found a mild to moderate mean reduction of NA (-52%, P < 0.05), DA (-25%), and 5-HT (-26%). At the subregional level, the most consistently affected area was the intermediate subdivision of the hypothalamus proper where all three monoamines were statistically significantly reduced. Evaluation of individual patient values indicated that, in contrast to the constant and severe DA reduction present in putamen of each of the iPD patients (DA loss ranging from 96% to 99%), several of these patients had whole (and subregional) hypothalamic monoamine values well within the range of controls. We conclude that, although possibly involved in autonomic and/or endocrine disturbances in some patients with iPD, none of the observed monoamine changes in the hypothalamus is an obligatory feature of iPD. Our study demonstrates the need for evaluation of individual patient values rather than mean differences in order to permit valid conclusions to be drawn as to whether an observed neurochemical change can be regarded as specific to a given brain disorder.

Amygdala dopamine levels are markedly elevated after self- but not passive-administration of cocaine.

The influence of cocaine on rat brain monoaminergic neurotransmitters (dopamine, serotonin, noradrenaline) and their metabolites, and on binding of [3H]WIN 35,428 and [3H]GBR 12,935 to the dopamine transporter was measured after 4 weeks of cocaine exposure. Cocaine (mean daily dose 9.25 +/- 0.48 mg/kg) was self-administered (responders) or passively received (yoked) during sessions which lasted for 1 h per day. As compared with the controls, mean dopamine and serotonin levels were significantly elevated (+ 107% and + 47%, respectively) in amygdala of responders, but not of yoked rats, sacrificed 1 h after the last cocaine session. Dopamine and metabolite levels were normal in all other brain areas examined, including striatum, nucleus accumbens and medial prefrontal cortex, at both 1 h and 4 weeks withdrawal from cocaine. [3H]WIN 35,428 and [3H]GBR 12,935 binding were unaltered after cocaine exposure. These data provide additional support for the involvement of the amygdala in the acquisition of drug seeking behavior associated with cocaine self-administration.

Normal serotonin but elevated 5-hydroxyindoleacetic acid concentration in cerebellar cortex of patients with dominantly-inherited olivopontocerebellar atrophy.

Beas-Zarate and coworkers (Eur. J. Pharmacol., 198 (1991) 7-14) recently reported markedly reduced concentration of presynaptic serotonin neurotransmitter markers in cerebellum of rodents which had suffered destruction of the inferior olivary-cerebellar (climbing fibre) projections by the neurotoxin 3-acetylpyridine; these experimental animal data suggested that serotonin might be one of the neurotransmitters released by climbing fibres. We measured the concentration of serotonin and its major metabolite 5-hydroxyindoleacetic acid (5-HIAA) in autopsied cerebellar cortex of 14 patients with dominantly-inherited olivopontocerebellar atrophy (OPCA) who all had near-total degeneration of the inferior olivary climbing fibres. As compared with the controls, mean concentration of serotonin in cerebellar cortex of the OPCA patients was normal whereas 5-HIAA levels (+79%, P less than 0.02) and 'turnover' ratio 5-HIAA/serotonin (+148%, P less than 0.05), on average, were significantly elevated. These data do not support the notion that serotonin is a predominant neurotransmitter of the human climbing fibre. However, the markedly elevated serotonin turnover ratio suggests the possibility of increased serotonergic neuronal activity, which might alter, and perhaps improve, the functioning of the preserved cerebellar cortical neurones in OPCA.

Brain monoamines in progressive supranuclear palsy--comparison with idiopathic Parkinson's disease.

Like idiopathic Parkinson's disease (iPD), Progressive Supranuclear Palsy (PSP) is characterized, inter alia, by a pronounced non-overlapping loss of dopamine (DA) in caudate, putamen and substantia nigra. Unlike iPD, in PSP the striatal DA loss is more severe in the caudate than in the putamen; this may contribute to the higher frequency of cognitive deficits in PSP. In contrast to iPD, in patients with PSP the serotonin (5-HT) levels in the basal ganglia are not significantly reduced, thus resulting in a relative predominance of the inhibitory serotonergic influences on the motor behaviour in these patients. It is suggested that combination of levodopa with a 5-HT receptor blocker may substantially improve the (poor) responsiveness of patients with PSP to DA substitution therapy.

Brain monoamines in the rhesus monkey during long-term neuroleptic administration.

1. In this study, rhesus monkeys were given daly high doses of chlorpromazine (up to 40 mg/kg orally) or haloperidol (up to 1 mg/kg orally) for up to 17 months. After sacrifice the brains were analyzed for regional concentrations of DA, HVA, 5-HT, 5-HIAA, and NE. 2. The most prominent effects of this long-term administration of neuroleptics were (a) a widespread elevation of NE levels in the forebrain, including the hypothalamus, thalamus, olfactory area, and nucleus accumbens; (b) a decrease of 5-HT turnover (calculated from the ratio "5-HT/5-HIAA") in several limbic forebrain areas, including the amygdaloid nucleus, septum, and nucleus accumbens as well as thalamus; and (c) a mild but consistent increase of HVA concentration in all DA-containing forebrain regions; in the striatum, this effect was found in the CPZ but not the HAL group. 3. The possible involvement of these neurochemical changes in the clinical actions of neuroleptics characteristically requiring long-term medication, such as the production of persistent (tardive) dyskinesias as well as the antipsychotic effect, is discussed.

Reduction of noradrenaline in cerebellum of patients with olivopontocerebellar atrophy.

Noradrenaline (NA) was measured in postmortem cerebellar cortex of 15 patients with dominantly inherited olivopontocerebellar atrophy (OPCA). The mean cerebellar cortical NA level was significantly reduced (by 40%) in OPCA as compared with control values. The NA deficit most likely reflects a degeneration of the locus caeruleus noradrenergic system that is known to occur in some patients with OPCA. The relationship between the altered cerebellar NA levels and the clinical symptomatology of OPCA remains to be determined.

Elevated serotonin and reduced dopamine in subregionally divided Huntington's disease striatum.

We measured the rostrocaudal distribution of serotonin, dopamine, and their metabolites in Huntington's disease striatum (caudate and putamen). Mean levels of serotonin or 5-hydroxyindoleacetic acid were elevated in most striatal subdivisions, whereas concentrations of dopamine or its metabolite homovanillic acid were slightly to markedly reduced. Dopamine and serotonin were at control levels in the nucleus accumbens and substantia nigra. Whereas the above-normal serotonin can most likely be accounted for by striatal atrophy, the reduced dopamine suggests either a marked down-regulation of nigrostriatal dopamine neurons or an actual reduction in the arborization of the striatal dopamine neurons. As experimental animal data suggest, the relative excess of striatal serotonin or one of its metabolites may facilitate the neurodegenerative process in Huntington's disease striatum.

Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson's disease. Pathophysiologic and clinical implications.

Autografting of dopamine-producing adrenal medullary tissue to the striatal region of the brain is now being attempted in patients with Parkinson's disease. Since the success of this neurosurgical approach to dopamine-replacement therapy may depend on the selection of the most appropriate subregion of the striatum for implantation, we examined the pattern and degree of dopamine loss in striatum obtained at autopsy from eight patients with idiopathic Parkinson's disease. We found that in the putamen there was a nearly complete depletion of dopamine in all subdivisions, with the greatest reduction in the caudal portions (less than 1 percent of the dopamine remaining). In the caudate nucleus, the only subdivision with severe dopamine reduction was the most dorsal rostral part (4 percent of the dopamine remaining); the other subdivisions still had substantial levels of dopamine (up to approximately 40 percent of control levels). We propose that the motor deficits that are a constant and characteristic feature of idiopathic Parkinson's disease are for the most part a consequence of dopamine loss in the putamen, and that the dopamine-related caudate deficits (in "higher" cognitive functions) are, if present, less marked or restricted to discrete functions only. We conclude that the putamen--particularly its caudal portions--may be the most appropriate site for intrastriatal application of dopamine-producing autografts in patients with idiopathic Parkinson's disease.

Neuronal [3H]benzodiazepine binding and levels of GABA, glutamate, and taurine are normal in Huntington's disease cerebellum.

Alterations in one subunit of the proposed GABA receptor complex, namely, the GABA receptor, have been observed in Huntington's disease cerebellum. We measured binding to a second subunit, the benzodiazepine binding site, in the autopsied cerebellum of 12 patients dying with adult-onset Huntington's disease. Neuronal benzodiazepine ([3H]flunitrazepam) binding density (Bmax) and affinity in cerebellar cortex of the Huntington's disease patients were not significantly different from control values. Similarly, maximal GABA stimulation of benzodiazepine binding was normal in the Huntington's disease cerebellum. In addition, no significant changes were observed in the concentrations of GABA, glutamate, and taurine in cerebellar cortex, nor of GABA in the dentate nucleus.