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We aimed to investigate the roles of dopamine in regulating caste-specific behaviors in bumble bees and mating-related behaviors in bumble bee gynes. We examined caste differences in behaviors, biogenic amine levels, and expression levels of genes encoding dopamine receptors in the brains of bumble bees, and analyzed the effects of dopamine-related drugs on bumble bee behavior. Locomotor and flight activities were significantly higher in 8-day-old gynes and light avoidance was significantly lower in 4-8-day-old gynes than in same-aged workers. Brain levels of dopamine and octopamine were significantly higher in 8-day-old gynes than in same-aged workers, but tyramine and serotonin levels did not differ between the castes. Relative expression levels of the dopamine receptor gene BigDop1 were significantly lower in 8-day-old gynes than in same-aged workers, but expression levels of other dopamine receptor genes did not differ between castes. Dopamine significantly enhanced locomotor and flight activities in 7-9-day-old workers, whereas the dopamine receptor antagonist flupentixol inhibited flight activity and mating acceptance in same-aged gynes. These results suggest that dopamine plays important roles in gyne-specific behavior in bumble bees and has a common dopaminergic function in female eusocial bees., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Morigami, Sasaki. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Huntington's disease (HD) is a rare, autosomal neurodegenerative disease characterized by motor and cognitive impairments appearing in adults. The R6/1 mouse model of the disease recapitulates the adult onset of motor symptoms preceded by cognitive and affective deficits. The monoaminergic systems participate in the establishment of motor and cognitive loops and we postulated that their organization and interaction could be precociously altered. Using tissue measurement of dopamine (DA), serotonin (5-HT), noradrenaline, and some metabolites, we observed that DA and/or its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), but not 5-HT or noradrenaline tissue content was reduced in an age-dependent manner (from two to six months) in the striatum, substantia nigra and globus pallidus of R6/1 mice. The metabolite of 5-HT was also lower in R6/1 mice, mainly in the substantia nigra and hippocampus. We then addressed early disorganization of monoaminergic systems in 18 brain regions encompassing several neurobiological networks in 35 day-old animals. DA tissue content was not altered in the striatum or substantia nigra but was decreased in the nucleus accumbens and increased in the globus pallidus. The correlations of monoaminergic index in-between the 18 selected brain regions revealed distinct organizations of monoamines in R6/1 mice, notably marked by a loss of the number of correlations of the DOPAC/DA ratio. The neurochemical analyses show that each monoaminergic system is distinctly altered in the R6/1 mouse model. The early abnormal organization of these systems likely points out altered maturation of neurobiological networks at early stages of HD., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: There is ample evidence that retinal dopamine (DA) is involved in the biochemical signaling cascade that controls emmetropization, but it is unknown how its release depends on the spectral composition of ambient light. We have studied DA release, refractive development, and growth in chicken eyes that were exposed to light of different spectral bands, and had either normal vision or were covered by frosted diffusers to induce myopia., Methods: Experiment 1: After spending the night in the dark, chicks were exposed to white room light (spectral range, 430-630 nm) or kept in the dark. Additional chicks were unilaterally exposed to blue (peak at 470 nm), red (620 nm), or UV lighting (375 nm) for 30 minutes and their fellow eyes covered with black occluders to minimize light exposure. Experiment 2: In the second experiment, chicks wore diffusers over one eye to induce deprivation myopia and were raised for 5 days in either white room light or in lighting supplied by UV, blue, or red light-emitting diodes (LEDs). Refractive states were recorded daily with infrared photoretinoscopy, and ocular dimensions at the start and end of the experiment with A-scan ultrasonography. DA and its metabolites were measured in retina and vitreous by high pressure liquid chromatography-electrochemical detection (HPLC-ED) in all cases., Results: Compared to chicks kept in the dark, retinal DA and vitreal 3,4-dihydroxyphenylacetic acid (DOPAC) concentrations were clearly elevated after 30 minutes in white light. Vitreal DOPAC was also increased in red, blue, and UV lighting, compared to the fellow eyes covered with black occluders (black occluder versus blue light: 1.31 ± 0.32 vs. 1.70 ± 0.37; red: 1.26 ± 0.33 vs. 1.64 ± 0.38; UV: 1.13 ± 0.19 vs. 1.63 ± 0.21 ng/0.1 g wet weight). Chickens developed significantly less deprivation myopia, with shorter eyes, when raised under UV and blue lighting for 5 days, compared to under red and white light. Eyes with normal vision became more hyperopic in blue and UV lighting. Vitreal DOPAC levels were lowest after 5 days of exposure to UV lighting., Conclusions: Red, blue, and UV lighting all stimulated the release of retinal DA, but there were wavelength-dependent differences in DA release and metabolism. Less deprivation myopia developed in UV and blue lighting, compared to white and red light. The application of these findings to humans is limited by the fact that, different from chicks, humans have very low sensitivity in the near-UV region of the spectrum.

Neurotransmitter:sodium symporters (NSSs) are integral membrane proteins responsible for the sodium-dependent reuptake of small-molecule neurotransmitters from the synaptic cleft. The symporters for the biogenic amines serotonin (SERT), dopamine (DAT), and norepinephrine (NET) are targets of multiple psychoactive agents, and their dysfunction has been implicated in numerous neuropsychiatric ailments. LeuT, a thermostable eubacterial NSS homolog, has been exploited as a model protein for NSS members to canvass the conformational mechanism of transport with a combination of X-ray crystallography, cysteine accessibility, and solution spectroscopy. Despite yielding remarkable insights, these studies have primarily been conducted with protein in the detergent-solubilized state rather than embedded in a membrane mimic. In addition, solution spectroscopy has required site-specific labeling of nonnative cysteines, a labor-intensive process occasionally resulting in diminished transport and/or binding activity. Here, we overcome these limitations by reconstituting unlabeled LeuT in phospholipid bilayer nanodiscs, subjecting them to hydrogen-deuterium exchange coupled with mass spectrometry (HDX-MS), and facilitating interpretation of the data with molecular dynamics simulations. The data point to changes of accessibility and dynamics of structural elements previously implicated in the transport mechanism, in particular transmembrane helices (TMs) 1a and 7 as well as extracellular loops (ELs) 2 and 4. The results therefore illuminate the value of this strategy for interrogating the conformational mechanism of the more clinically significant mammalian membrane proteins including SERT and DAT, neither of which tolerates complete removal of endogenous cysteines, and whose activity is heavily influenced by neighboring lipids.

We developed a method to detect biogenic amines and their metabolites in rat brain tissue using simultaneous high-performance liquid chromatography and a photodiode array detection. Measurements were made using a Hypersil Gold C-18 column (250 × 2.1 mm, 5 µm). The mobile phase was 5 mM perchloric acid containing 5 % acetonitrile. The correlation coefficient was 0.9995-0.9999. LODs (S/N = 3) and LOQs (S/N = 10) were as follows: dopamine 0.4 and 1.3 pg, 3, 4-dihydroxyphenylacetic acid 8.4 and 28.0 pg, serotonin 0.4 and 1.3 pg, 5-hydroxyindolacetic acid 3.4 and 11.3 pg, and homovanillic acid 8.4 and 28.0 pg. This method does not require derivatization steps, and is more sensitive than the widely used HPLC-UV method.

The content of biogenic amines and their metabolism in the ancient part of the amygdala (paleoamygdala) differ in male and female rats and depended on the phase of the estrous cycle.

A higher prevalence and incidence of Parkinson's disease is observed in men, and beneficial motor effects of estrogens are observed in parkinsonian women. In rodents, an effect of estradiol on dopamine systems is documented, whereas much less is known in monkeys. Enkephalin was shown to exert a compensatory modulatory effect on the denervated dopamine nigrostriatal pathway in monkeys and in humans. Moreover in rodents, striatal preproenkephalin mRNA is increased by estrogen treatment. Hence, we investigated the responsiveness of striatal dopamine to estradiol in long-term ovariectomized monkeys bearing a unilateral lesion with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to mimic parkinsonian postmenopausal women. Seven ovariectomized female monkeys received a unilateral MPTP lesion; 4 years after ovariectomy, three received 1-month treatment with 17beta-estradiol and the others received vehicle. The lesioned striata showed extensive denervation in all monkeys as measured with dopamine and metabolite concentrations assayed by high-performance liquid chromatography and by autoradiography of the dopamine transporter. The lesioned and intact striata of estradiol-treated monkeys had increased 3-methoxytyramine, and lesioned putamen increased dopamine concentrations compared with vehicle-treated monkeys. Estradiol treatment increased the dopamine transporter in subregions of the intact caudate and putamen compared with the intact striata of vehicle-treated monkeys, but not in the lesioned striata. Preproenkephalin mRNA levels measured by in situ hybridization were increased in the lesioned striata of vehicle treated monkeys and were not further enhanced in estradiol-treated monkeys. These results show that long after ovariectomy, modeling postmenopausal hormonal conditions, brain dopamine metabolism, and transporter are still responsive to estradiol., (Copyright 2008 Wiley-Liss, Inc.)

In social insects, biogenic amines are thought to play regulatory roles in the transition between reproductive states in females. To determine the effect of dopamine on the reproductive development of workers in primitively eusocial societies, isolated workers of the paper wasp Polistes chinensis were supplied with oral dopamine. Ovarian development was accelerated in dopamine-fed workers as compared to control workers of the same age fed only sucrose solution. Oral dopamine increased brain levels of dopamine and its metabolite (N-acetyldopamine). Brain levels of tyramine or octopamine were also increased by dopamine application in one of two colonies; levels of the tyramine metabolite N-acetyltyramine were unchanged. These results indicate that dopamine plays a gonadotropic role in isolated workers in the primitively eusocial wasp, similar to the gonadotropic role previously reported for juvenile hormone. This is the first study to report effects of dopamine on ovarian development in workers of the paper wasp.

The effect of zonisamide, an antiepileptic agent with anti-parkinsonian effects, was studied on dopamine neurons of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated C57 mice and common marmosets. Groups of mice (n = 8 - 9) were treated with: MPTP (15 mg/kg every 2 h x4); MPTP plus zonisamide (40 mg/kg administered 1 h before each MPTP dose); MPTP plus selegiline (2 mg/kg administered 1 h before the first MPTP dose); zonisamide (40 mg/kg x4); and saline controls. Groups of common marmosets (n = 4 - 6) were treated with: MPTP (2.5 mg/kg every 24 h x3); MPTP plus zonisamide (40 mg/kg administered 1 h before each MPTP dose); MPTP plus selegiline (2 mg/kg administered 1 h before the first MPTP dose); and saline controls. Brain dopamine and its metabolites were determined by HPLC. Dopamine content decreased in the striatum of MPTP-treated mice and monkeys. Co-administration of selegiline inhibited the effect of MPTP and dopamine contents were similar to those of the controls. Co-administration of zonisamide did not inhibit the effect of MPTP on dopamine content, but increased striatal dopamine turnover of animals treated with MPTP plus zonisamide more than in those treated with MPTP alone. MPTP treatment caused a compensatory increase of dopamine turnover in the striatum by remaining neurons. Zonisamide may help dopaminergic neurons by increasing striatal dopamine turnover following MPTP treatment.

To determine the effect of prenatal lead exposure on brain monoaminergic systems, pregnant rats were given tap water containing 250 ppm lead acetate, for the duration of pregnancy, while tap water without lead (Pb(2+)) was substituted at birth. Control rats were derived from dams that consumed tap water during pregnancy, and had no exposure to lead afterwards. At 12 weeks after birth, Pb(2+) content of brain cortex was increased 3- to 4-fold (P < 0.05). At this time the endogenous striatal levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid were 19% lower in Pb(2+) exposed rats (P < 0.05), while there was no change in the striatal level of dopamine (DA), noradrenaline, 3,4-dihydroxyphenylglycol, serotonin (5-HT) and 5-hydroxyindoleacetic acid (HPLC/ED). Also there was no change in these monoamines and metabolites in the prefrontal cortex of Pb(2+) exposed rats. However, turnover of 5-HT in prefrontal cortex, as indicated by 5-hydroxytryptophan accumulation 30 min after acute treatment with the decarboxylase inhibitor NSD-1015 (100 mg/kg IP), was lower in the Pb(2+) exposed rats. In the striatum AMPH-induced (1 mg/kg IP) turnover of DA, evidenced as L-DOPA accumulation after NSD-1015, was increased to a lesser extent in the Pb(2+) exposed rats (P < 0.05). The nitric oxide synthase inhibitor 7-nitroindazole (10 mg/kg IP) attenuated the latter effect, indicating that neuronal NO mediates this AMPH effect, at least in part. Moreover, DA D(2) receptor sensitivity developed in Pb(2+) exposed rats, as evidenced by enhanced quinpirole-induced yawning activity and enhanced quinpirole-induced locomotor activity (each, P < 0.05). These findings indicate that ontogenetic exposure to lead can have consequences on monoaminergic neuronal function at an adult stage of life, generally promoting accentuated behavioral effects of direct and indirect monoaminergic agonists, and related to increased dopamine turnover in basal ganglia.

Proline-rich-polypeptides (PRPs) isolated from bovine hypothalamus have been shown to render protection against neuronal injury of the brain and spinal cord. We examined two PRPs containing 15 and 10 amino acid residues (PRP-1 and PRP-4 synthetic polypeptide) for their effect, if any, on dopaminergic neuronal damage caused by the parkinsonian neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Effects of these PRPs on hydroxyl radical ((*)OH) generation in a Fenton-like reaction as well as from isolated mitochondria were monitored, employing a sensitive salicylate hydroxylation procedure. Balb/c mice treated (i.p., twice, 16 h apart) with MPTP (30 mg/kg) or PRP-1 (1.6 mg/kg), but not PRP-4 (1.6 mg/kg) showed significant loss of striatal dopamine and norepinephrine as assayed by an HPLC-electrochemical procedure. Pretreatment with the PRPs, 30 min prior to the neurotoxin administration failed to attenuate MPTP-induced striatal dopamine or norepinephrine depletion, but significantly attenuated the MPTP-induced decrease in dopamine turnover. A significant increase in the generation of (*)OH by the PRPs in a Fenton-like reaction or from isolated mitochondria suggests their pro-oxidant action, and explains their failure to protect against MPTP-induced parkinsonism in mice.

Rasagiline [N-propargyl-1R(+)-aminoindan; TVP1012] is a potent irreversible monoamine oxidase (MAO) inhibitor with selectivity for type B of the enzyme, which is being developed for treatment of Parkinson's disease. In this study we examined effects of rasagiline on CNS monoamine levels, modification of behavioural response to L-tryptophan, fluoxetine and L-DOPA, and reversal of reserpine syndrome. Reserpine-induced ptosis was reversed by rasagiline at doses above 2 mg x kg(-1) i.p., which inhibit MAO-A as well as MAO-B, but not at MAO-B-selective doses. However, combination of rasagiline (10 mg x kg(-1) i.p.) with L-DOPA or L-tryptophan (50 mg x kg(-1) i.p.), or rasagiline (10 mg x kg(-1) p.o.) with fluoxetine (10 mg x kg(-1) p.o.), did not induce the behavioural hyperactivity syndrome which is seen following inhibition of both MAO-A and MAO-B by tranylcypromine together with the monoamine precursors. Following oral administration, levels of noradrenaline (NA), 5-hydroxytryptamine (5-HT) and dopamine (DA) were unaffected in hippocampus and striatum after single doses of rasagiline up to 2 mg x kg(-1). Following chronic oral administration (21 days, one dose daily), levels of NA, 5-HT and DA in hippocampus and striatum were unaffected by rasagiline at doses up to 1 mg x kg(-1). Rasagiline does not modify CNS monoamine tissue levels or monoamine-induced behavioural syndromes at doses which selectively inhibit MAO-B but not MAO-A.

An evolutionarily conserved feature of neural systems is that they can be modified by neuromodulators. These modulatory chemical signals include the biogenic amines, octopamine (OA), serotonin (5-HT) and dopamine (DA). Such modulation effectively broadens the operational range in which specific neural circuits can function adaptively. This report discusses how these amines are themselves modulated; for example, by the steroid hormone 20-hydroxyecdysone (20-E) or by the addition of a second biogenic amine. Such second-order neuromodulation, termed metamodulation, is discussed in the context of two well-studied invertebrate systems: the tobacco hornworm moth Manduca sexta, a model of neurodevelopment and plasticity, and the medicinal leech Hirudo medicinalis, a long-favored preparation used to study neural circuits at the level of identified neurons. A portion of this article reviews our previous research of M. sexta that shows that the 'preadult' rise in 20-E is both necessary and sufficient for the increased levels of octopamine observed in the adult. Such elevated levels likely play an important role in the production and modulation of adult behaviors. The somatic growth of median octopaminergic neurons and the late expression of OA-immunoreactivity by novel lateral neurons are also demonstrated to be dependent on 20-E. New immunocytochemical results of stained dopaminergic neurons in the larval and adult moth brain are provided as well, and the potential influence of 20-E on the developmental expression of this neuromodulator is presented. Turning attention to the leech, data indicate that the actions of OA are dramatically altered when 5-HT is combined with OA in the bath surrounding the isolated nervous system. Although either OA or 5-HT alone induces fictive swimming behavior, a cocktail of these two amines strongly inhibits the generation of swimming. Subsequent removal of such a mixture induces nearly continuous swimming and constitutes the best swim-inducing stimulus encountered to date. To understand better how these nonadditive effects are achieved, new results are discussed that indicate that the leech brain is the target of metamodulation by the two amines. Both the arthropod and annelid systems presented here highlight the multiple levels of metamodulation that can exist in nervous systems, and the diverse ways that a modulator's actions can become altered over short or long time periods., (Copyright 2003 S. Karger AG, Basel)

5-Hydroxytryptamine (5-HT) plays a role in the regulation of 3, 4-dihydroxyphenylethylamine (dopamine) neurons in the brain, but the precise mechanism of regulation by 5-HT(1A) receptors of dopamine release has not been defined. The present study describes the effect of 5-¿3-[[(2S)-1,4-benzodioxan-2ylmethyl]amino]propoxy¿-1, 3-benzodioxole HCl (MKC-242), a highly potent and selective 5-HT(1A) receptor agonist, on dopamine release in the prefrontal cortex using microdialysis in the freely moving rat. Subcutaneous injection of MKC-242 (0.3 - 1.0 mg kg(-1)) increased extracellular levels of dopamine in the prefrontal cortex. The effect of MKC-242 in the prefrontal cortex was antagonized by pretreatment with the selective 5-HT(1A) receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohe xanecarboxamide (WAY100635; 1 mg kg(-1), i.p.). Local application of WAY100635 (10 microM) via a microdialysis probe antagonized the effect of systemic MKC-242 in an increasing dopamine release, and locally infused 8-hydroxy-2-(di-n-propylamino)tetralin (10 microM) increased dopamine release in the prefrontal cortex. MKC-242 increased cortical dopamine release in the rats pretreated with 5, 7-dihydroxytryptamine (150 microgram, i.c.v.) that caused an almost complete reduction in cortical 5-HT content. The effect of MKC-242 to increase dopamine release was also observed in the hippocampus, but not in the striatum or nucleus accumbens. Fluoxetine, a selective serotonin reuptake inhibitor, increased dopamine release in the prefrontal cortex, but not in the nucleus accumbens, while buspirone, a 5-HT(1A) receptor agonist, increased dopamine release in both brain regions. The present results indicate that activation of postsynaptic 5-HT(1A) receptors increases dopamine release in a brain region-specific manner.

The finding that endogenous tetrahydroisoquinolines may be involved in the etiology of Parkinson's disease suggests that their administration may cause changes resembling those observed in parkinsonian brain. We tested, using a high-performance liquid chromatography method, how single and chronic administration of 1,2, 3,4-tetrahydroisoquinoline and salsolinol affects dopamine and serotonin metabolism in the neurons of extrapyramidal and mesolimbic dopaminergic systems. We report that chronic administration of tetrahydroisoquinoline and salsolinol causes a decrease in a dopamine metabolism: the effect of tetrahydroisoquinoline was limited to the striatum, while salsolinol caused also a dramatic decline of dopamine level in the substantia nigra. The effect of both compounds on serotonin metabolism was small or absent. The tetrahydroisoquinolines produced no changes in the nucleus accumbens. The results indicate that tetrahydroisoquinoline and salsolinol specifically affect the nigrostriatal dopamine system, but only when administered chronically, and thus are compatible with the view that endogenous tetrahydroisoquinolines may participate in pathogenesis of Parkinson's disease.

Following amphetamine administration, the DSIP aggravated behavioural patterns but the EEG remained unaltered in the visual and motor cortex, and in the caudate nucleus. The findings suggest that the peptides modulating action depends on the way of dopamine hyperfunction initiation.

Iron is known to induce lipid peroxidation and recent evidence indicates that both iron and lipid peroxidation are elevated in the substantia nigra in Parkinson's disease (PD). To test whether excess intranigral iron induces lipid peroxidation, we infused an iron citrate solution (0.63 nmol in 0.25 microL) into the rat substantia nigra and measured nigral thiobarbituric acid reactive products at 1-h, 1-d, 1-wk, and 1-mo postinfusion. In a separate group of iron-infused animals, histologic analysis within the substantia nigra through 1-mo postinfusion was accomplished by thionine- and iron-staining, with concurrent assessment of striatal neurochemical markers. Concentrations of nigral thiobarbituric acid reactive products were significantly elevated at 1 h and 1 d in iron-infused animals compared to vehicle-infused and unoperated animals, with a return to control values by 1 wk. Similarly, striatal dopamine turnover was acutely elevated, suggesting damage to dopaminergic neurons, which was confirmed histologically. Although iron-staining within the iron diffusionary area was increased through the postinfusion month, there was an apparent progression of the cellular character of staining from predominantly neuronal to reactive glial and finally to oligodendroglial by 1 mo postinfusion. This progression of cellular iron-staining may indicate a shifting of infused iron to a more bound unreactive form, thus explaining only an acute elevation in lipid peroxidation through 1 d following intranigral iron infusion. The data indicate that damage to nigral neurons induced by iron infusion is transciently associated with a marker of oxidative damage and supports the possibility that iron-induced oxidative stress contributes to the pathogenesis of PD.

We investigated the relationship between the concentration of pyridoxal-5'-phosphate (PLP) and biogenic amine in mouse brain. The production of PLP from pyridoxal (PL) by pyridoxal kinase (PLK) was inhibited by the addition of dopamine (DA), norepinephrine (NE) and 5-hydroxytryptamine (5-HT), but not by that of epinephrine and N-acetyl-serotonin. DA and NE were combined with PLP by a non-enzymatic reaction, whereas 5-HT was bound only slightly with PLP. The conjugated product of PLP with DA was also detected by HPLC analysis when PLK activity was assayed using PL as a substrate in the presence of DA. In an in vivo investigation, the depletion of DA and 5-HT in mouse brain after an intraperitoneal injection of 5 mg/kg reserpine, led to slight elevation of the PLP level to 120% of the control level. By contrast, the increase in DA in the brain caused by intraperitoneal administration of 150 mg/kg L-DOPA caused the PLP concentration to decrease to 70% of the control level. However, no change in PLK activity in the brain was observed when the mice were treated with either reserpine or L-DOPA. These results suggested that the level of PLP in mouse brain was partly regulated by the concentration of biogenic amines, such as DA, NE and 5-HT, without apparent induction of PLK.

We examined effects of a high dose of methamphetamine (MA) (4.02 mg free base/kg, s.c., at 2-h intervals, 4 injections) on extracellular concentrations of monoamines such as dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) and those of glutamate and other several amino acids in rat striatum (ST) and nucleus accumbens (NA) using in vivo microdialysis. Five days after the microdialysis, tissue concentrations of monoamines were measured. The toxic dose of MA markedly increased extracellular concentrations of DA, and decreased those of DOPAC, HVA and 5-HIAA in both ST and NA. Magnitude of the increase in DA release was not different between ST and NA. Extracellular concentrations of glutamate showed a gradual increase in ST, but not in NA, while other amino acids showed no changes in both ST and NA. Tissue concentrations of serotonin (5-HT) and 5-HIAA were decreased to 43-58% of control values in both ST and NA, whereas those of DA, DOPAC and HVA showed 43-54% decrease in ST but no changes in NA. These data suggest that the marked increase of DA release is not directly related to the MA-induced dopaminergic neurotoxicity. The increase in glutamate release found only in ST may be related to the dopaminergic damage in ST. It may be that enhanced release in DA and glutamate act synergistically to cause the dopaminergic neurotoxicity in ST. However, enhancement in glutamate release did not appear to be essential for the MA-induced serotonergic neurotoxicity.

To provide a neurochemical basis for the central nervous system actions of nitrous oxide, the changes of brain dopamine (DA), serotonin (5-HT), norepinephrine (NE), and metabolites of DA and 5-HT were studied in rats. Thirty male Wistar rats were assigned to one of five groups according to the type of gas and the duration of gas exposure. The rats in one group, which served as control, were exposed to air for 30 min, and the rats in four other groups were exposed to 75% nitrous oxide in oxygen for 0.5, 1, 2, and 4 h, respectively. Animals were killed with microwave irradiation, and the brains were divided into seven sections: the cerebral cortex, cerebellum, striatum, hippocampus, midbrain-thalamus, hypothalamus, and medulla-pons. The contents of NE, DA, 3,4-dihydroxyphenyl-alanine (DOPAC), homovanillic acid (HVA), 5-HT, and 5-hydroxyindoleacetic acid (5-HIAA) in each discrete area were measured with high-performance liquid chromatography. Nitrous oxide had no significant effect on the contents of NE, 5-HT, nor 5-HIAA, but decreased that of DA in the striatum and midbrain-thalamus after 4 h of exposure (P < 0.05). Levels of DOPAC, but not DA, in the cerebral cortex and medulla-pons were increased significantly at exposures up to 2 h (P < 0.05), but were not significant from control levels after a 4-h exposure. Increased levels of DOPAC indicate that nitrous oxide increases dopaminergic neuronal activities in the mesocortical projection and the medullary network.(ABSTRACT TRUNCATED AT 250 WORDS)

The reuptake of dopamine into nerve terminals is the primary mechanism of inactivation of this neurotransmitter in the synaptic cleft. We report sex differences and estrous cycle variations of rat striatal dopamine uptake sites. During the estrous cycle, peak density of striatal dopamine uptake sites labelled with [3H]GBR-12935 occurred in the morning of proestrus in coincidence with peak dopamine, serotonin, dihydroxyphenylacetic acid and 5-hydroxytryptophan levels pointing to a presynaptic effect of gonadal hormones. Striatal homovanillic acid and 5-hydroxyindoleacetic acid levels as well as [3H]GBR-12935 binding affinity remained unchanged throughout the estrous cycle. The density of [3H]GBR-12935 striatal binding sites was lower in ovariectomized rats compared to intact female rats during the estrous cycle, whereas it was similar in gonadectomized male rats, intact male rats and ovariectomized rats. Binding affinity was in general similar for all the groups of rats examined. The affinity of dopamine for striatal [3H]GBR-12935 binding sites was similar in males and ovariectomized females, and did not change during the female estrous cycle. In summary, striatal dopamine uptake site density was lower in male compared to intact female rats and was shown to fluctuate during the female estrous cycle. These results suggest that gonadal hormones could influence the activity of psychoactive drugs acting on neuronal dopamine uptake sites.

Using high-performance liquid chromatography and gas chromatography, we reevaluated the 24-h influence of a serotonin- and dopamine-rich diet on platelet serotonin and serotonin, 5-hydroxyindoleacetic acid (5-HIAA), and major catecholamine metabolites in the urine of 15 healthy adults. Although there were significant responses in urinary free serotonin and catecholamine metabolites, their concentrations did not exceed the upper limits of the reference ranges for any of the participants. For urinary 5-HIAA, pronounced effects were observed within 2-4 h. After 6-8 h, results for 11 participants exceeded the upper limit of the reference range. The median recovery of dietary serotonin as urinary 5-HIAA was 20% and subject to a large range (1-50%). There was no significant change in platelet serotonin. We conclude that, using specific analytical methods, no dietary restrictions need be imposed to diagnose catecholamine (metabolite)-producing tumors. For diagnosis of carcinoids on the basis of urinary 5-HIAA it is appropriate to completely abstain from serotonin-containing foods for greater than or equal to 12 h before testing. Platelet serotonin is a more sensitive marker for carcinoids that produce only small amounts of serotonin, and is unaffected by dietary serotonin.

Biogenic amine metabolism may be altered in hypertension and thus contribute to its pathophysiology. This report describes an abnormality in dopamine excretion in hypertensive subjects in the postabsorptive state that persists despite an increase in dietary precursors for dopamine supplied by a protein meal. We studied seven normotensive and six nonmedicated hypertensive men after two different meals: 60 g protein and a noncaloric electrolyte-equivalent broth. Overall mean sodium excretion was 56% higher in the hypertensive group throughout both meal studies (p less than 0.01), implying higher chronic dietary sodium intake. Despite this, overall urinary excretion of dopamine tended to be lower in hypertensive than in normotensive subjects (p = 0.06). Hypertensive also differed from normotensive subjects in their response to protein feeding. In the normotensive subjects there was a 23% increase in urinary dopamine excretion (p less than 0.05), which was not seen after the noncaloric meal. In the hypertensive subjects, there was no change in urinary dopamine after the protein meal. In the normotensive subjects there was a 74% increase in sodium excretion (p less than 0.01) after the protein meal, but no significant change was seen in the hypertensive subjects. There were no differences in baseline renal plasma flow or glomerular filtration rate between the groups and no statistically significant differences between the groups in their renal hemodynamic responses to the meals. In summary, hypertensive subjects have less renal dopamine production for the amount of sodium ingested and a decreased renal dopamine production in response to a protein load as compared with normotensive subjects, consistent with a renal defect in conversion of DOPA to dopamine.

Clinical and experimental evidence suggests that degeneration of the locus coeruleus (LC) may be responsible for certain symptoms of Parkinson's disease (PD). We have, therefore, studied the effects of LC lesion on dopamine (DA) metabolism in the rat striatum. Unilateral depletion of norepinephrine (NE) was obtained by stereotaxic injection of 6-hydroxydopamine (6-OHDA) into the dorsal NE bundle (DNEB). Rats were sacrificed 1 or 3 weeks after lesioning. 6-OHDA induced approximately 50% depletion of NE in the ipsilateral hippocampus at 1 week postinjection, and over 75% depletion after 3 weeks. DNEB lesions had no effect on DA or DOPAC levels in the ipsi- or contralateral striatum at either time point. Lesions also failed to affect DA synthesis or utilization in either striatum. The metabolism of exogenous levodopa in the striatum was also unaffected. It is suggested that any possible effect of the LC on DA transmission in the striatum is not mediated by the DNEB.

Administration of non-competitive N-methyl-D-aspartate (NMDA) antagonists in rodents leads to a characteristic motor syndrome which has been related to changes in monoamine metabolism in a variety of brain regions. We examined the question whether chronic MK-801 treatment in neonatal rats from postnatal day 8 through 19, which has been shown previously to alter NMDA receptor function, would also affect monoamine metabolism in striatum and frontal cortex of adult rats. Monoamines and their metabolites were determined 5 months after the treatment using high-performance liquid chromatography with electrochemical detection. Dihydroxyphenylacetic acid (DOPAC) concentration was elevated (greater than 40%) in both regions tested, while 5-hydroxyindoleacetic acid (5-HIAA) concentration was significantly elevated only in the cortex (19%), and 3-methoxy-4-hydroxyphenylglycol (MHPG) only in the striatum (47%). These results demonstrate that the long-lasting effects of chronic neonatal MK-801 treatment are not restricted to glutamate transmission, but include monoamine transmission as well.

Destruction of nigrostriatal dopamine (DA) neurons with 6-hydroxydopamine (6-OHDA) early in development results in hyperinnervation of striatum by the serotonergic afferents deriving from the dorsal raphe nucleus. We have used in vivo microdialysis to investigate the degree to which serotonergic neurotransmission in striatum is altered by this increase in the density of serotonin (5-HT) terminals. The effects of several manipulations known to influence 5-HT function on extracellular 5-HT and 5-hydroxyindoleacetic acid in striatum were compared in adult rats treated neonatally with 6-OHDA and in intact adult rats. Basal levels of 5-HT in extracellular fluid (ECF) of striatum were similar in neonatally DA-depleted rats and in intact rats. Perfusion with the 5-HT reuptake blocker, fluoxetine (100 microM), increased 5-HT in striatal ECF of neonatally DA-depleted rats to levels that were threefold greater than those achieved in intact rats. Likewise, K(+)-depolarization of the 5-HT terminals (100 mM in perfusate) or systemic administration of the 5-HT releaser, (+/-)-fenfluramine (10 mg/kg i.p.), increased the concentration of 5-HT in striatal ECF of neonatally DA-depleted rats to levels approximately threefold greater than those observed in striatum of intact rats. These findings indicate that the 5-HT hyperinnervation of striatum that takes place in rats depleted of DA at infancy is associated with an increased capacity for neurotransmitter release in this system. Concomitant increased in high-affinity 5-HT uptake may prevent the occurrence of any measurable changes in the resting concentration of 5-HT in striatal ECF.

Levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), noradrenaline (NA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA) in the CSF of patients with Huntington's disease (HD) were measured by HPLC. CSF DA, DOPAC, and MHPG levels were found to be increased in HD patients. Levels of HVA, 5-HIAA, and NA in the CSF of HD patients did not differ from those of controls. Changes in CSF DA and DOPAC levels were consistent with previous findings of increased DA tissue content in some brain areas of patients with HD. These results suggest that CSF DOPAC levels could be a more reliable index of overactive dopaminergic brain systems in HD than CSF HVA levels.

The sodium-ion coupled transporters for 5-hydroxytryptamine (5HT), noradrenaline and dopamine function to reduce extracellular levels of biogenic amines. Over the past fifteen years selective inhibitors of these transport systems have been developed including fluoxetine, citalopram, paroxetine, litoxetine (for 5HT), nisoxetine, desipramine, maprotiline (for noradrenaline) and GBR-12935 (for dopamine). Some of these inhibitors, including drugs selective for noradrenaline transport and particularly those selective for the 5HT transport system are currently widely used in the clinical management of affective disorders. Selective biogenic amine uptake inhibitors have, in addition, provided tools to undertake molecular pharmacological and biochemical studies of their respective transporters. By this means, the rat brain 5HT and dopamine transporters have been identified as polypeptides with relative molecular masses of 73,000 and 80,000, respectively, using affinity-chromatographic purification and photoaffinity-labelling techniques. Recently, the biogenic amine transporters have been cloned and a comparison of their predicted amino acid sequences reveals that these proteins share a considerable degree of similarity with notably 12-13 transmembrane spanning domains. Perspectives for future fundamental and clinical research on biogenic amine transport systems using molecular biological techniques are discussed.

This report describes experiments designed to determine whether (-)-deprenyl potentiates dopaminergic transmission and whether its mechanism involves the inhibition of dopamine catabolism. Intraperitoneal administration of (-)-deprenyl (0.5-8 mg kg-1) produced a dose-dependent inhibition of striatal monoamine oxidase type B activity whereas monamine oxidase type A activity in the striatum was inhibited only by 8 mg kg-1 of (-)-deprenyl. Intraperitoneal administration of (-)-deprenyl (0.5-4 mg kg-1) did not alter the striatal concentrations of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) or homovanillic acid. DOPAC concentrations were decreased by 8 mg kg-1 of (-)-deprenyl. In contrast, administration of clorgyline (2 mg kg-1), a monoamine oxidase type A inhibitor, increased the striatal concentrations of DA and decreased the striatal concentrations of DOPAC and homovanillic acid. The striatal concentrations of 2-phenylethylamine (PE), a putative modulator of striatal DA transmission, were increased by (-)-deprenyl (1-8 mg kg-1) but were unaffected by clorgyline (2 mg kg-1). In electrophysiological studies, single caudate neuron responses to iontophoretically applied (-)-apomorphine and (+/-)-2-(N-phenethyl-N-propyl) amino-5-hydroxytetralin were potentiated by intracarotid injections of PE (30 micrograms kg-1) and i.p. injections of (-)-deprenyl (2 mg kg-1). Both PE and (-)-deprenyl reduced the IT50 of responses to apomorphine and (+/-)-2-(N-phenethyl-N-propyl)amino-5-hydroxytetralin.(ABSTRACT TRUNCATED AT 250 WORDS)

Microinjection of the indirect GABAA antagonist, picrotoxin, or the mu opioid agonist, Tyr-D-Ala-Gly-NMe-Phe-Gly-ol (DAGO), into the ventral pallidum and substantia innominata (VP/SI) increases locomotor activity in rats. The VP/SI has direct and indirect projections to the region of the ventral mesencephalon containing dopamine perikarya, and to certain dopamine terminal fields, including the nucleus accumbens. Thus, it is possible that modulation of the mesocorticolimbic dopamine system by pharmacological stimulation in the VP/SI may play a role in the locomotor stimulant response. It was shown that pretreatment with dopamine receptor antagonists, either peripherally or microinjected into the nucleus accumbens significantly attenuated the motor stimulant effect of DAGO or picrotoxin injection into the VP/SI. Injection of either picrotoxin or DAGO into the VP/SI increased the levels of dopamine metabolites in the nucleus accumbens and prefrontal cortex. Thus, the motor stimulant response following pharmacological stimulation of the VP/SI appears to be mediated by increased dopamine neurotransmission via feedback mechanisms to the mesocorticolimbic dopamine system.

The effect of a low single dose of lindane (gamma-hexachlorocyclohexane) on monoaminergic neurotransmission during brain postnatal development was studied in 8-, 15-, 22- and 29-day-old suckling rats. Concentrations of noradrenaline, serotonin, dopamine and their metabolites were determined in eight cerebral regions 1 h after dosing (20 mg/kg lindane per os). All these aminergic systems were altered in a regional- and age-related pattern. Decreases of noradrenaline in regions rich with noradrenergic terminals together with increases of the ratio 5-HIAA/serotonin and DOPAC/dopamine suggest, as a whole, an enhanced release of the monoamines. This increased neuronal activity does not exclude an initial action of lindane on the inhibitory GABAergic system that would activate the neurotransmitter release in other systems shortly after a single administration of the neurotoxic agent.

Inasmuch as sustained treatment with the 5-hydroxytryptamine1A (5-HT1A) agonist, ipsapirone, is necessary for inducing anxiolytic and antidepressant effects in the clinic, investigations were performed for assessing the possible changes in serotoninergic and dopaminergic neurotransmission in the brain of rats 24 hr after a 2-week treatment with this drug. Receptor binding assays with membranes and quantiative autoradiography indicated that the twice-daily administration of ipsapirone (5 mg/kg i.p.) for 14 days did not alter the characteristics of 5-HT1A sites in the hippocampus, septum and dorsal raphe nucleus. In contrast, significant decreases in the Bmax values for 5-HT2 sites (-24%) and 5-HT3 sites (-19%) were found in the frontal and posterior cortex, respectively. As expected from unchanged postsynaptic 5-HT1A receptors, inhibition of forskolin-stimulated adenylate cyclase by 5-HT1A agonists (8-hydroxy-2-(di-n-propylamino)tetralin, ipsapirone) exhibited the same characteristics in hippocampal homogenates from both control and ipsapirone-treated animals. An acute administration of 8-hydroxy-2-(di-n-propylamino)tetralin (0.5 mg/kg i.p.) or ipsapirone (1 or 5 mg/kg i.p.) 24 hr after the last injection for the chronic treatment produced a similar decrease in the rate of 5-HT turnover in various brain areas in rats treated for 2 weeks with saline or ipsapirone. At the highest dose (5 mg/kg i.p.), acute ipsapirone also increased the rate of dopamine turnover in the striatum and cerebral cortex approximately to the same extent in both treatment groups. In vitro recording of the firing of serotoninergic neurons in brain stem slices revealed a desensitization of the somatodendritic 5-HT1A receptors, which might be responsible for the increased 5-HT turnover in the brain stem and striatum of rats chronically treated with ipsapirone as compared with controls. These data demonstrated that chronically administered ipsapirone produces adaptive changes in central serotoninergic neurotransmission which might account for the anxiolytic and antidepressant properties of this drug after sustained treatment.

Microinjection of the gamma-aminobutyric acidA agonist, muscimol, into the A10 region of the rat produced a dose-dependent increase in motor activity. This effect was antagonized by intra-A10 administration of the gamma-aminobutyric acidA antagonist, bicuculline, and by peripheral administration of haloperidol, and was associated with an increase in extracellular levels of dopamine metabolites in the nucleus accumbens. Although microinjection of the gamma-aminobutyric acidB agonist, baclofen, into the A10 region did not alter motor activity, it abolished the capacity of intra-A10 injection of mu opioid agonist, Tyr-D-Ala-Gly-MePhe-Gly(ol), or muscimol to increase motor activity. Baclofen also prevented the motor stimulant response to peripheral injection of cocaine or amphetamine, but was ineffective in blocking caffeine-induced behavioral activity. Pretreatment with baclofen prevented the capacity of a mu opioid agonist to elevate dopamine metabolite levels in the nucleus accumbens and prefrontal cortex in postmortem tissue. Baclofen also prevented the elevation of extracellular dopamine content in the nucleus accumbens produced by injection of a mu opioid agonist into the A10 region, as measured in the conscious rat with in vivo dialysis. Finally, when dopamine metabolite levels were elevated in the prefrontal cortex by mild footshock, it was shown that pretreatment with baclofen in the A10 region abolished this response. These data support electrophysiological studies suggesting that activation of gamma-aminobutyric acidB receptors on dopamine perikarya inhibits dopaminergic activity, while activation of gamma-aminobutyric acidA receptors results in an indirect disinhibition of dopaminergic function.

Uptake of the catecholamines (CA), dopamine (DA) and norepinephrine (NE) into synaptosomes prepared from rat and bovine brains was potentiated by ATP (from 0.1 to 5.0 mM) in a dose-dependent manner. Other nucleotides, particularly the nonhydrolyzable ATP analogs beta,gamma-imidoadenosine-5'-triphosphate (AMP-PNP) and beta,gamma-methyladenosine-5'-triphosphate (AMP-PCP) also potentiated [3H]DA and [3H]NE uptake. Several endogenous 5'-nucleotide triphosphates (e.g. GTP, UTP and CTP) potentiated [3H]CA uptake, but were less effective than ATP. Among the ATP metabolites, only ADP potentiated uptake whereas AMP and adenosine did not. [3H]Dopamine uptake measured in Krebs bicarbonate buffer had a Km of 2.1 microM and a Vmax of 163.9 pmol/mg prot./min. In presence of ATP, [3H]DA uptake had much higher affinity (Km = 0.56 microM) and larger capacity (Vmax = 333 pmol/mg prot./min) than uptake in absence of added ATP. Furthermore, [3H]DA uptake in presence of ATP had faster rate of uptake, and was independent of temperature while in absence of added ATP it was temperature-dependent. This ATP-dependent [3H]DA uptake was retained by synaptosomal ghosts that were obtained after lysing the striatal synaptosomes and removing their contents of synaptic vesicles and mitochondria. It is proposed that, in addition to the carrier-mediated (neuronal) uptake of CA, there is neuronal uptake that is regulated by ATP and inhibited by cocaine, which may be more relevant for terminating the synaptic action of CA because of its faster rate of uptake and larger capacity.

1. Psychotropic drugs ameliorate psychotic symptoms only after repeated administration. 2. To assess the neurochemical effects of chronic haloperidol and lithium administration, microdialysis was performed simultaneously in the prefrontal cortex, the nucleus accumbens, and the striatum after haloperidol, and separately in the lateral hypothalamus and the hippocampus after lithium. 3. Chronic administration of haloperidol decreased dopamine turnover in the prefrontal cortex and the striatum. It did not affect the nucleus accumbens detectably. 4. No tolerance to haloperidol developed in any of the three regions. 5. Lithium enhanced the response of the serotonergic system to amphetamine in the lateral hypothalamus but not in the hippocampus. 6. The antipsychotic effect of haloperidol might be related to dopamine turnover decrease in the prefrontal cortex. 7. The antidepressant effect of lithium might be related to enhancement of serotonin responsiveness in the hypothalamus.

Post-decapitation seizures (PDR) are a spinal reflex which seems regulated by some monoaminergic neurons present in the spinal cord (S.C.). In order to better characterize the role of dopaminergic neurons in PDR, we studied the effect of treatment with opiates, which are known to increase dopamine (DA) and serotonin (5HT) metabolism in the brain, on the duration of PDR and on the metabolism of DA and 5HT in S.C. Morphine, given either IP or ICV, reduced the duration of PDR and increased DA metabolism. Both effects were more evident after systemic administration. [D-Ala2]Met5 enkephalin amide acted similarly to ICV administered morphine. Biochemical and behavioral effects were significantly correlated.

The dopamine theory of depression was studied by assessing the effect of antidepressant drugs on uptake of dopamine, noradrenaline, and serotonin in synaptosomes from rat brain. Five newer drugs--butriptyline, maprotiline, trimipramine, iprindole, and mianserine--exhibited rather potent inhibition of 3H-dopamine uptake in corpus striatum, as their IC50 values, which were in the order of 10(-6)-10(-5) M, were only about 50 times higher than for nomifensine (IC50 = 10(-7) M). The five drugs were weak, compared to chlorimipramine, on 14C-serotonin uptake in the whole forebrain, as their IC50 were about 10(-5) M. Butriptyline, trimipramine, and iprindole were very weak uptake inhibitors of 3H-noradrenaline in the occipital cortex. Their IC50 values were about 10(-6) M, which is almost 1000 times higher than for desmethylimipramine. These results are discussed in relation to comprehensive recent literature as further indicating a link between dopamine and depression.

DSP4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine) treatment (50 mg/kg i.p., 10 days previously) significantly decreased the noradrenaline (NA) content of the rostral part of the nucleus accumbens. The medial and caudal areas were not affected. The nucleus accumbens appears to receive noradrenergic innervation predominantly from subcoeruleus nuclei of the pons-medulla while the locus coeruleus neurons project to the rostral area. The isoproterenol-induced enhancement of the K+-evoked release of [3H]dopamine (DA) was not affected by DSP4 treatment. Noradrenergic denervation does not appear to have been sufficient to cause up-regulation of postsynaptic beta-adrenoceptors.

A high affinity (KD 35 nM) binding site for [3H]cocaine is detected in rat brain striatum present at 2-3 pmol/mg protein of synaptic membranes. This binding is displaced by cocaine analogues with the same rank order as their inhibition of [3H]dopamine ([3H]DA) uptake into striatal synaptosomes (r = 0.99), paralleling the order of their central stimulant activity. The potent DA uptake inhibitors nomifensine, mazindol, and benztropine are more potent inhibitors of this high affinity [3H]cocaine binding than desipramine and imipramine. Cathinone and amphetamine, which are more potent central stimulants than cocaine, displace the high affinity [3H]cocaine binding stereospecifically, but with lower potency (IC50 approximately equal to 1 microM) than does cocaine. It is suggested that the DA transporter in striatum is the putative "cocaine receptor." Binding of [3H]cocaine, measured in 10 mM Na2HPO4-0.32 M sucrose, pH 7.4 buffer, is inhibited by physiologic concentrations of Na+ and K+ and by biogenic amines. DA and Na+ reduce the affinity of the putative "cocaine receptor" for [3H]cocaine without changing the Bmax, suggesting that inhibition may be competitive. However, TRIS reduces [3H]cocaine binding noncompetitively while Na+ potentiates it in TRIS buffer. Binding of [3H]mazindol is inhibited competitively by cocaine. In phosphate-sucrose buffer, cocaine and mazindol are equally potent in inhibiting [3H]mazindol binding, but in TRIS-NaCl buffer cocaine has 10 times lower potency. It is suggested that the cocaine receptor in the striatum may be an allosteric protein with mazindol and cocaine binding to overlapping sites, while Na+ and DA are allosteric modulators, which stabilize a lower affinity state for cocaine.

The short- (during 12 h after last treatment) and long- (6 weeks after last treatment) term effects of repeated administration of cocaine on the total output of norepinephrine (NE) and its metabolites (sum NE), dopamine (DA) and its metabolites (sum DA) as well as the excretion of 5-hydroxyindoleacetic acid (5-HIAA) and phenylethylamine were evaluated in rats. The concentration of NE, DA and 3,4-dihydroxyphenylacetic acid (DOPAC) in the celiac ganglion after 1, 2 and 3 weeks of repeated cocaine administration were also measured. Sum NE remained unchanged during the cocaine treatment but NE and normetanephrine excretions were significantly decreased and increased respectively. 5-HIAA excretion was significantly reduced only after 3 weeks cocaine treatment. In the celiac ganglion NE and DOPAC contents showed tendencies towards being increased and decreased respectively. DA content was not changed. The excretions of DA, DOPAC, homovanillic acid (HVA) and phenylethylamine were significantly reduced during chronic exposure to cocaine. The above short-term changes in DA and phenylethylamine persisted for periods as long as 6 weeks after 1 week repeated exposure to cocaine. It is concluded that chronic exposure to cocaine can produce preferential long term deficiencies in the production of DA and phenylethylamine in the periphery. Peripheral noradrenergic and serotonergic neuronal systems are apparently minimally affected. The close association between DA or sum DA and phenylethylamine excretion suggest these 2 amines may coexist in the same neuron.

Previous studies have shown that fetal substantia nigra (SN) transplanted into a cavity overlying a dopamine (DA)-denervated caudate nucleus can reverse a number of the behavioral abnormalities induced by the denervation. While some histochemical and physiological evidence suggests that this reversal is the result of a functional DA input from the transplant to the host brain, there is little direct evidence for transmitter release from ingrowing graft-derived nerve fibers. In the present work in vivo electrochemistry was used to analyse the magnitude, time course and spatial distribution of neurotransmitter releases evoked by local application of potassium (K+) from DA-depleted, SN transplant-reinnervated striatum. Animals were injected unilaterally with 6-hydroxydopamine (6-OHDA) into the SN and screened by measuring apomorphine-induced rotation. Some were then given SN grafts, which were placed in a 'delayed cavity' just dorsal to the lesioned striatum. Nafion-coated graphite epoxy capillary (GEC) electrodes were employed for the electrochemistry to minimize signals derived from ascorbate or acidic DA metabolites. The GEC electrode was fixed to a K+-filled micropipette and this assembly was used to map the caudate nucleus of control, 6-OHDA-treated, and 6-OHDA-treated, grafted animals. The morphometric relationships between striatal recording sites and transplant location were subsequently verified histologically. Releases from striatal sites within 1.0 mm of the SN grafts were slightly, but not significantly, less than those obtained from control caudate.(ABSTRACT TRUNCATED AT 250 WORDS)

(-)Deprenyl, when administered continuously in small doses (0.25 mg/kg/day), facilitates the activity of the nigrostriatal dopaminergic neuron because of its highly characteristic complex spectrum of pharmacologic activity: it is a highly potent and selective inhibitor of B-type MAO; it inhibits the reuptake of dopamine; it inhibits dopamine autoreceptors; it enhances scavenger function. 1) (-)Deprenyl treatment decreased significantly the activity of the cholinergic interneurons. In a series of experiments the acetylcholine (ACh) content was found to be 0.69 nmole/mg protein in the striatum of untreated rats, whereas a significantly higher amount of ACh (0.86 nmol/mg protein) was found in the rat striatum after two week pretreatment with (-)deprenyl, and the fractional rate constant (kb) of ACh efflux from the cholinergic interneurons of the striatum decreased significantly in the (-)deprenyl-treated group from 9.1 +/- 0.8 to 6.2 +/- 0.55. 2) The (-)deprenyl-induced increase of the dopaminergic tone in the striatum was proved by measurements of the activity of the nigrostriatal dopaminergic neuron. Whereas the striatum of untreated rats contained 52.7 +/- 1.6 nmole/g dopamine (DA) and the turnover rate (TRDA) was found to be 13.7 +/- 1.3 nmole/g/hr, the striatum of rats pretreated with 0.25 mg/kg (-)deprenyl daily for 28 days contained significantly higher amount of DA (81.77 +/- 5.7 nmole) and the turnover rate increased significantly to 24.44 +/- 1.1. Using the Glowinski-Iversen preparation we found that from the striata of untreated rats 200.0 +/- 25.8 pmole/g/min DA was released to KCl stimulation, whereas the amount of DA released to stimulation from the striata of rats pretreated with (-)deprenyl for 3 weeks increased significantly to 1452.2 +/- 183.1 pmole/g/min. 3) (-)Deprenyl inhibits the uptake of dopamine into the nigrostriatal dopaminergic neuron. In a new series of experiments we found that 420 +/- 21 pmole/g protein 3H-DA was taken up within 5 minutes in the striatum slices of untreated rats. Pretreatment of the rats with 0.25 mg/kg (-)deprenyl daily for two weeks decreased significantly the uptake of DA to 284 +/- 28 pmole/mg. 4) In a new series of experiments we found that the striata of untreated rats emitted 404.2 +/- 36.2 pmole/g/min ACh to ouabain stimulation but the striata dissected from rats pretreated with 6-hydroxy-dopamine (6-OHDA) released 811.4 +/- 49.2 pmol/g/min (p less than or equal to 0.001).

Glutamic acid and excitatory amino acids specific for the glutamate receptor subtypes were microinjected into the A10 region of the rat. Glutamate produced an increase in motor behavior that was antagonized by pretreatment with the dopamine D2 receptor antagonist, haloperidol. This motor stimulant effect was produced by kainate, but not by N-methyl-D-aspartate (NMDA) or quisqualic acid. By using in vivo dialysis it was found that dopamine release in the nucleus accumbens and locomotor activity were enhanced by glutamate injection into the A10 region. Whereas glutamate was found to increase the postmortem concentration of dopamine metabolites in the medial prefrontal cortex, nucleus accumbens and A10 region, NMDA selectively increased dopamine metabolism in the prefrontal cortex, and kainate produced increases in the nucleus accumbens and A10 region. When glutamate and the NMDA receptor antagonist, 3-[(+/-)-2-carboxypiperazine-4-yl)propyl-1-phosphonic acid (CPP) were coadministered, CPP selectively abolished the effect of glutamate on medial prefrontal cortical dopamine metabolites. A physiological role for the NMDA receptor modulation of A10 dopamine neurons was shown by intra-A10 pretreatment with CPP antagonism of mild footshock-induced increase in dopamine metabolites in the prefrontal cortex. These data argue that glutamate is a regulatory transmitter of A10 dopamine neurons, and that the NMDA receptor subtype modulates neurons projecting to the prefrontal cortex whereas the kainate subtype modulates mesoaccumbens neurons.