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PubMed2001

Effects of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) on alpha2-adrenoceptors which regulate the synthesis and release of noradrenaline in the rat brain.

N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) induces a degeneration of noradrenergic axons originating in the locus coeruleus. The sensitivity of alpha2-adrenoceptors which regulate the synthesis and release of noradrenaline was investigated in three brain regions which receive an unequal innervation from locus coeruleus, 21 days after DSP4 (50 mg/kg) administration. After giving treated rats a dopa decarboxylase inhibitor, the in vivo tyrosine hydroxylase activity and the tissue concentrations of noradrenaline were also evaluated. Relevant reductions of noradrenaline levels were found in hippocampus and parietal cortex (91% and 77.5%, respectively; P<0.001) together with a less pronounced reduction in hypothalamus (32%, P<0.01). The administration of the neurotoxin led to decreases of the basal tyrosine hydroxylase activity, determined as the accumulation of 3,4-dihydroxyphenylalanine, in hippocampus and parietal cortex (75% and 50.5%, respectively; P<0.001), but not in hypothalamus. The inhibitory effect of clonidine on tyrosine hydroxylase activity was markedly reduced in hippocampus of rats treated with DSP4 (10+/-5% vs 57+/-3% in the control group, P<0.001) but was not changed in parietal cortex and hypothalamus. Moreover, in hippocampus, a lack of functionality of the alpha2-adrenoceptors which regulate K(+)-evoked [3H]noradrenaline release was determined. However, in cortical synaptosomes the concentration-effect curve for the oxymetazoline shifted to the right. The administration of the neurotoxin did not modify the inhibitory effects of the agonist in hypothalamus. These results support the previously described selectivity of DSP4 for noradrenergic terminals arising from locus coeruleus and suggest a more severe lesioning of the hippocampus than the parietal cortex.

Animals↗
PubMed1997

The insulin gene is transcribed in the human thymus and transcription levels correlated with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes.

Type 1, or insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease associated with loss of tolerance to several pancreatic islet cell molecules, including insulin, glutamic acid decarboxylase (GAD), ICA69 and the tyrosine phosphatase IA-2 (refs 1-3). Among several predisposing loci, IDDM2 maps to the insulin gene (INS) VNTR (variable number of tandem repeats) minisatellite on chromosome 11p15 (refs 4-9). Allelic variation at this VNTR locus correlates with steady-state levels of INS mRNA in pancreas and transfected rodent cell lines, but it is difficult to reconcile the association of lower INS mRNA levels in the pancreas with class III VNTRs that are dominantly protective from IDDM. We show that during fetal development and childhood, mRNAs for insulin and other islet cell autoantigens (GAD, ICA69, IA-2) are expressed at low levels in the human thymus. Critically, we also detect proinsulin and insulin protein. VNTR alleles correlate with differential INS mRNA expression in the thymus where, in contrast to the pancreas, protective class III VNTRs are associated with higher steady-state levels of INS mRNA expression. This finding provides a plausible explanation for the dominant protective effect of class III VNTRs, and suggests that diabetes susceptibility and resistance associated with IDDM2 may derive from the VNTR influence on INS transcription in the thymus. Higher levels of (pro)insulin in the thymus may promote negative selection (deletion) of insulin-specific T-lymphocytes which play a critical role in the pathogenesis of type-1 diabetes.

Aging↗
PubMed2002

Desensitization of alpha(2)-adrenoceptors which regulate noradrenaline synthesis and release after chronic treatment with clorgyline in the rat brain.

The sensitivity of alpha(2)-adrenoceptors which regulate synthesis and release of noradrenaline was investigated in hippocampus, parietal cortex, and hypothalamus of rats treated with clorgyline. After administering a DOPA decarboxylase inhibitor, the in vivo tyrosine hydroxylase activity and the noradrenaline content were evaluated. Acute and chronic treatment with clorgyline led to both increases of noradrenaline levels and decreases of tyrosine hydroxylase activity, determined as the accumulation of DOPA. Whereas the alpha(2)-adrenoceptor agonist clonidine induced a similar reduction in tyrosine hydroxylase activity in the group subjected to the acute treatment and in the control group, it failed to do so after chronic clorgyline treatment. In hippocampal and cortical synaptosomes, a reduction in the sensitivity of alpha(2)-adrenoceptors which regulate [(3)H]noradrenaline release, reflected by the shift to the right of the concentration-effect curves for oxymetazoline, was also found after the repeated treatment. These results indicate a desensitization of alpha(2)-adrenoceptors after chronic treatment with clorgyline.

Adrenergic alpha-Agonists↗
PubMed2004

The degeneration of dopamine neurons in Parkinson's disease: insights from embryology and evolution of the mesostriatocortical system.

Parkinson's disease (PD) is, to a large extent, specific to the human species. Most symptoms are the consequence of the preferential degeneration of the dopamine-synthesizing cells of the mesostriatal-mesocortical neuronal pathway. Reasons for that can be traced back to the evolutionary mechanisms that shaped the dopamine neurons in humans. In vertebrates, dopamine-containing neurons and nuclei do not exhibit homogenous phenotypes. In this respect, mesencephalic dopamine neurons of the substantia nigra and ventral tegmental area are characterized by a molecular combination (tyrosine hydroxylase, aromatic amino acid decarboxylase, monoamine oxidase, vesicular monoamine transporter, dopamine transporter--to name a few), which is not found in other dopamine-containing neurons of the vertebrate brain. In addition, the size of these mesencephalic DA nuclei is tremendously expanded in humans as compared to other vertebrates. Differentiation of the mesencephalic neurons during development depends on genetic mechanisms, which also differ from those of other dopamine nuclei. In contrast, pathophysiological approaches to PD have highlighted the role of ubiquitously expressed molecules such as a-synuclein, parkin, and microtubule-associated proteins. We propose that the peculiar phenotype of the dopamine mesencephalic neurons, which has been selected during vertebrate evolution and reshaped in the human lineage, has also rendered these neurons particularly prone to oxidative stress, and thus, to the fairly specific neurodegeneration of PD. Numerous evidence has been accumulated to demonstrate that perturbed regulation of DAT-dependent dopamine uptake, DAT-dependent accumulation of toxins, dysregulation of TH activity as well as high sensitivity of DA mesencephalic neurons to oxidants are key components of the neurodegeneration process of PD. This view points to the contribution of nonspecific mechanisms (alpha-synuclein aggregation) in a highly specific cellular environment (the dopamine mesencephalic neurons) and provides a robust framework to develop novel and rational therapeutic schemes in PD.

Animals↗
PubMed1999

Predictive value of human leukocyte antigen class II typing for the development of islet autoantibodies and insulin-dependent diabetes postpartum in women with gestational diabetes.

Gestational diabetes mellitus (GDM) is a risk factor for the development of insulin-dependent diabetes mellitus (IDDM) and noninsulin-dependent diabetes mellitus postpartum. To evaluate whether there is any association of human leukocyte antigen (HLA) class II alleles (DR and DQ) with GDM and the postpartum development of IDDM, we analyzed 184 women with GDM from Germany for HLA class II alleles, islet autoantibodies [islet cell autoantibodies (ICA), glutamic acid decarboxylase autoantibodies (GADA), and protein tyrosine phosphatase IA-2 autoantibodies (IA-2A), and the postpartum development of diabetes. No elevation in the frequency of any HLA class II alleles was observed in GDM patients compared to 254 nondiabetic unrelated subjects. DR3 allele frequency was significantly increased in 43 women with islet autoantibodies [corrected P value (Pc) = 0.02], in particular in those with GADA (Pc = 0.002), or in the 24 women who developed IDDM postpartum (Pc = 0.005). In women with GADA, DR4 and DQB1*0302 were significantly elevated (Pc = 0.009). Twenty-five (59.5%) islet antibody-positive women and 17 (74%) women who developed IDDM postpartum had a DR3- or DR4-containing genotype. The cumulative risk to develop IDDM within 2 yr postpartum in GDM women with either DR3 or DR4 was 22% compared to 7% in women without those alleles (P = 0.02) and rose to 50% in the DR3- or DR4-positive women who had required insulin during pregnancy (P = 0.006). Combining the determination of susceptible HLA alleles (DR3, DR4) with islet autoantibody measurement increased the sensitivity of identifying GDM women developing postpartum IDDM to 92%, but did not improve risk assessment above that achieved using GADA measurement alone, which was the strongest predictor of IDDM. These results indicate that women with GDM who have islet autoantibodies at delivery or develop IDDM postpartum have HLA alleles typical of late-onset type 1 diabetes, and that both HLA typing and islet antibodies can predict the development of postpartum IDDM.

Alleles↗
PubMed2000

Organ-specific and non-organ-specific autoantibodies in children and young adults with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED).

OBJECTIVE: The aim of the study was to assess the complex of autoantibodies which can be detected in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a rare autosomal recessive disease in which the extent of autoimmunity is still unknown. DESIGN: Antibodies (A) to parathyroid glands, adrenal cortex (AC-A), ovary and testis (steroid cell antibodies, SC-A), pancreatic islet cells (IC-A), gastric parietal cells, and non-organ-specific antigens were investigated in 11 APECED patients living in the Salento region of southern Italy. Further measurements included antibodies to cytochrome P450 (CYP) enzymes: cholesterol side-chain cleavage enzyme (CYP11A), 21-hydroxylase (CYP21) and 17alpha-hydroxylase (CYP17); and to glutamic acid decarboxylase 65-kDa isoform (GAD65), tyrosine phosphatase-like protein IA2, thyroglobulin (TG), thyroperoxidase (TPO), thyrotropin receptor, liver CYP enzymes and intrinsic factor. METHODS: Antibodies to organs and subcellular fractions were detected by immunofluorescence. Radiobinding, immunoradiometric, and immunoblotting assays were used for the other measurements. RESULTS: AC-A and SC-A were positive in all sera; among antibodies to adrenal CYP enzymes, only CYP21-A were present in all the patients with Addison's disease of short-medium duration (<15 years). Of three patients with Addison's disease of long duration (>15 years), two tested positive for antibodies to all three CYP enzymes, and the other for only CYP11A-A. In all sera CYP11A-A and/or CYP17-A were found. Two patients tested positive for both IC-A and GAD65-A, one for both IC-A and IA2-A, and one for GAD65-A; the fasting C-peptide assay showed no statistical difference between these four subjects and the others. All four hypothyroid patients were positive for TPO-A, while two of them were positive and two were negative for TG-A; two euthyroid subjects had positivity for TG-A. Liver-kidney microsomal antibodies reacting against the CYP2A6 were detected in two patients with autoimmune hepatitis. All but one sera contained anti-nuclear antibodies at a titre ranging between 1:20 and 1:80; however, only two patients had a connective tissue disease (Sjögren's syndrome). CONCLUSIONS: Several autoantibodies may be detected in any APECED patient. Our data confirm that CYP21-A and TPO-A are major autoantibodies involved in APECED-associated Addison's disease and hypothyroidism respectively, while CYP11A-A and CYP17-A correlate with positivity for SC-A. Markers of islet cell autoimmunity are frequent, but prevalence and modalities of progression to overt beta-cell failure have to be clarified. Low-titre non-organ-specific autoantibodies are a feature of autoimmunity in APECED, but their role has yet to be fully explained.

Adolescent↗
PubMed2004

[Subclassification of seronegative type 1 diabetic subjects with HLA-DQ genotypes].

OBJECTIVE: To reveal the relationship between disease phenotype and HLA-DQ genotype in autoantibody-negative type 1 diabetics and to explore whether HLA-DQ genotypes can reclassify seronegative type 1 diabetic patients. METHODS: Sixty-one diabetics with unprovoked ketosis or ketoacidosis at presentation were tested for glutamic acid decarboxylase antibody (GAD-Ab), tyrosine phosphatase antibody (IA2-Ab), thyroglobulin antibody (TGA), thyroid peroxidase antibody (TPO-Ab) and HLA-DQ genotype. GAD-Ab and IA2-Ab were measured with radioligand assay. TGA and TPO-Ab were evaluated using RIA. Sequence-based genotyping (SBT) was used to determine the alleles of HLA-DQA1 and DQB1. Autoantibody negative patients were subdivided into group A (with type 1 diabetes susceptible alleles) and group B (without type 1 diabetes susceptible alleles). Clinical characteristics, including age, sex, mode of presentation, body mass index (BMI), islet beta-cell function and current treatment were compared between the autoantibody-positive and autoantibody-negative patients and between group A and B. RESULTS: Among the 61 patients, 29 (47.5%) were negative for all the antibodies tested, while 31 (50.8%) were positive for one or more antibodies tested. 5 (8.2%) were positive for all those 4 antibodies. As for genetic analysis, 18 of the 29 seronegative patients carried 1-4 HLA-DQ risk alleles, while the other 11 did not carry any type 1 diabetes susceptible alleles tested. As compared with the autoantibody-negative patients, younger age at onset, less obesity, severer degree of diabetic ketoacidosis (DKA) and lower C peptide were found in the autoantibody-positive ones. As compared with group B, less obesity [BMI: (22.4 +/- 4.4) kg/m(2) vs (25.8 +/- 3.7) kg/m(2), P = 0.03], severer degree of DKA [CO(2)CP: (16.3 +/- 7.1) mmol/L vs (19.2 +/- 2.0) mmol/L, P = 0.01; pH: 7.26 +/- 0.20 vs 7.34 +/- 0.06, P = 0.03], and lower C peptide [fasting C peptide: (254.6 +/- 189.4) pmol/L vs (458.7 +/- 274.1) pmol/L, P = 0.06] were observed in group A. During follow-up, 73% (8/11) patients in group B discontinued insulin therapy and maintained acceptable glycemic control by either diet or oral hypoglycemic agents (OHA), while only 28% (5/18) of the patients in group A discontinued and maintained control with OHA (28% vs 73%, P < 0.01). Among those who kept on using insulin, group A patients required higher insulin dosage than those of group B [(0.43 +/- 0.16) U x kg(-1) x d(-1) vs (0.24 +/- 0.18) U x kg(-1) x d(-1), P = 0.07]. CONCLUSIONS: Autoantibody-negative diabetics, if with susceptible HLA-DQ genotypes, presented more type 1A-like features, implying possible existence of as yet unidentified immunologic abnormalities in these patients. HLA-DQ risk genotypes may reclassify seronegative type 1 diabetics. Those who are autoantibody negative but carry susceptible HLA-DQ genotypes, should not be diagnosed as type 1B diabetes.

Adolescent↗
PubMed1979

[Psychological problems of incurable patients in old age (author's transl)].

Biological functions are regulated by feedback mechanisms. In old age disorders occur in this regulation by insufficiency of biochemical transmitters. The synthesizing enzymes of Tyrosine Hydroxylase, Tryptophan Hydroxylase, Dopa Decarboxylase and 5-Hydroxytryptophan Decarboxylase are diminished in old age. Minus symptoms as depression, or exhaustion and disorders of circulation occur. A substitution by biogenic transmitters is not possible, because these don't pass the blood-brain-barriere. Therefore a medication of psychopharmacological drugs is necessary. For instance Anxiety--tranquilizer, exhaustion--anti depressive drugs.

Aged↗
PubMedDate not supplied

[The development of a graft of embryonic mediobasal hypothalamus in the 3rd cerebral ventricle of the adult rat].

Development of the mediobasal hypothalamus from 15-day rat foetuses and 8-week human foetuses transplanted in the 3rd ventricle of the adult rat brain has been morphologically analyzed. The graft was shown to fill the ventral area of the 3rd ventricle and integrate with the host brain, as was especially distinct in the region of optic chiasma. The graft was abundantly vascularized and its vessels connected with the host brain vessels. The graft neurons were normally differentiating in situ. Some neurons migrated in the host brain. The graft neuropile ultrastructure was characterized by the abundance of synaptic contacts. Some graft neurons expressed dopaminergic phenotype by synthesizing tyrosine hydroxylase and DOPA-decarboxylase and displaying specific capture of 3H-dopamine. Dopaminergic axons of the neurons were spreading both within the graft and penetrating in the host tissue, especially in the region of optic chiasma and tracts. Unlike allotransplantation in rats, survival of xenotransplants of the human embryonic nervous tissue in the 3rd ventricle of the adult rat brain was possible only under the conditions of constant immunosuppression.

Animals↗
PubMed2001

Biochemical markers of type 1 diabetes: clinical use.

In type 1 diabetes, a number of specific and non-specific antigens have been identified. The major autoantigens involved in the destructive process of beta-cells leading to the development of type 1 diabetes are proinsulin/insulin, glutamic acid decarboxylase (GAD) and the transmembrane protein tyrosine phosphatase (IA-2). These are the only autoantigens that partially satisfy the criteria by which an autoantigen or cross-reactive nonself antigen could be evaluated for a pathogenic role in autoimmune diseases. Antigens by definition induce antibody production and in type 1 diabetes, such (auto) antibodies are accepted as biochemical markers for the disease. Here we describe the main features and usefulness of these markers for disease prediction.

Animals↗
PubMed1997

Antibodies to the tyrosine phosphatase-like protein IA-2 are highly associated with IDDM, but not with autoimmune endocrine diseases or stiff man syndrome.

Antibodies to the 40 kD antigen (identified as tyrosine phosphatase IA-2) and glutamate decarboxylase (GAD65) are strongly associated with insulin dependent diabetes mellitus (IDDM). However, antibodies to GAD (GADA) can appear in the absence of IDDM, particularly in stiff man syndrome (SMS) and in some individuals with autoimmune polyendocrine syndrome type II (APS II) and organ specific autoimmune diseases. The aim of this study was to compare the specificity of IA-2 antibodies (IA-2A) and GADA for IDDM by determining their frequency in different patient groups. IA-2A were present in 64/114 (56%) IDDM patients and 9/19 (47%) APS II patients with IDDM but in only 4/28 (14%) SMS patients. 1/24 (4%) APS II patients without IDDM and 1/113 (0.9%) patients with organ specific autoimmune disease had low level IA-2A. In contrast GADA were present in 77/114 (68%) IDDM patients and 17/19 (89%) APS II patients with IDDM, but also in 25/28 (89%) SMS patients, 5/24 (21%) APS II patients without IDDM and 22/113 (19%) patients with organ specific autoimmune diseases. Furthermore, within the group of new onset IDDM, IA-2A seemed to be associated with ICA and age: 63% of ICA positive IDDM patients had IA-2A (74% had GADA) increasing to 77% in the group below 20 years of age (69% for GADA). Our results demonstrate that IA-2A may be more specific for IDDM than GADA, as the latter are also present in patients with SMS, APS II without IDDM and organ specific autoimmune diseases. IA-2A were less frequent in older patients with IDDM than GADA or ICA. A combination of IA-2A and GADA detected 84% of total and 93% of ICA positive IDDM patients.

Adolescent↗
PubMed1989

Cardiovascular effects of L-tyrosine: influence of blockade of tyrosine metabolism.

Tyrosine is the precursor of catecholamines. Small doses of tyrosine produce tachycardia and hypertension while higher doses produce bradycardia and hypotension in anaesthetised rats. The mechanism of these effects has not been established. An increased synthesis and release of catecholamines has been suggested to be the mechanism. Various pretreatments were given to anaesthetised Wistar rats to study the influence of a blockade of L-tyrosine metabolism and thus a blockade of catecholamine synthesis, on these cardiovascular effects: valine, which inhibits tyrosine uptake into brain, alpha-methyl-p-tyrosine, which blocks the rate-limiting enzyme, tyrosine hydroxylase, carbidopa and benserazide, which both inhibit dopa decarboxylase, and desipramine, which blocks catecholamine re-uptake. Benserazide and alpha-methyl-p-tyrosine partially blocked the stimulatory effects of tyrosine. None of the pretreatments were able to block effectively the inhibitory effects of L-tyrosine. Therefore, the metabolism of tyrosine to form catecholamines may be involved in the stimulatory but not in the inhibitory cardiovascular effects of L-tyrosine. Valine pretreatment did not antagonize the depressant effects of tyrosine. Since valine blocks the uptake of L-tyrosine into the brain, the depressant effects of L-tyrosine might be peripheral rather than central in origin.

Animals↗
PubMed1984

Genomic and phenotypic expression of autonomic neurons.

We found that catecholamine biosynthetic enzymes, tyrosine hydroxylase, dopamine B-hydroxylase and phenylethanolamine N-methyl-transferase share similar protein domains in their primary structures, and therefore are coded for by a single gene or a family of genes. In a recent report, we also demonstrated that antisera directed against tyrosine hydroxylase, choline acetyltransferase and glutamate decarboxylase cause specific complement-mediated lysis of dopaminergic, cholinergic and GABA-ergic subpopulation of synaptosomes, respectively. This implies that the neurotransmitter biosynthetic enzyme and the specific nerve ending protein(s) also share similar protein domain(s). Therefore, we postulate that the specific neurotransmitter biosynthetic enzyme and a certain membrane protein of the nerve endings probably share similar gene coding sequences and that coordinate expression of these proteins may determine the phenotype of the neuron.

Animals↗
PubMed1994

Adrenergic innervation of the urinary bladder body in the cat with special reference to structure of the detrusor muscle: an immunohistochemical study of noradrenaline and its synthesizing enzymes.

The distribution of adrenergic nerves in the body detrusor muscle of the cat urinary bladder was studied by means of the immunohistochemical identification of noradrenaline (NA) and the NA synthesizing enzymes tyrosine hydroxylase, aromatic L-aminoacid decarboxylase and dopamine beta-hydroxylase. We identified the basic structural organization of the detrusor muscle, which had previously been described as lacking discernible layers. In the lateral wall, both outer longitudinal and inner circular muscle bundles were present, the latter extending in both anterior and posterior directions. The posteriorly running bundles came to lie on the outside of the posterior wall where they enabled recognition of inner longitudinal muscle bundles. Those running anteriorly were dispersed to enter the longitudinal bundles in the anterior wall. NA-immunoreactive nerve fibers in the detrusor muscle of the bladder were found to be similar to those immunoreactive for NA synthesizing enzymes in both distribution and density. In the upper and middle bladder body--including the dome (apex)--immunoreactive nerve fibers were always more abundant in the outer part of the detrusor muscle than in the inner part, regardless of the course of muscle bundles. Even in individual muscle bundles running from the inside to the outer surface, the outer part was more richly innervated by immunoreactive fibers than the inner part. In the bladder dome, a moderate number of immunoreactive nerve fibers preferentially innervated the outer part of the muscle layer. In the lower bladder body, these nerve fibers increased in density in the inner part of the detrusor muscle. There was no sexual difference in density or distribution of nerve fibers. NA- and NA synthesizing enzyme-immunoreactive nerve fibers were markedly decreased in number after 6-hydroxydopamine treatment. No dopamine- or phenylethanolamine-N-methyltransferase-immunoreactive nerve fibers were present in the bladder. The findings of this study indicate that the cat bladder musculature includes longitudinal and circular muscle bundles, both of which are extensively innervated by adrenergic nerves, particularly in the outer part of the bladder.

Adrenergic Fibers↗
PubMed1989

Evidence that dopaminergic sympathetic axons supply the medullary arterioles of human kidney.

The ability of the kidney to excrete sodium appears to depend on release of dopamine from intrarenal sources. In the present study, we have used immunohistochemistry to examine the possibility that renal dopaminergic nerves constitute one of these sources. We found that the sympathetic axons supplying cortical structures in human kidney contain tyrosine hydroxylase-like immunoreactivity but lack DOPA decarboxylase-like immunoreactivity. By contrast, the vasa recta arterioles of the renal medulla are supplied by varicose tyrosine hydroxylase-positive nerve fibres, some of which also contain DOPA decarboxylase. As DOPA decarboxylase has been demonstrated in other situations to be a selective marker for dopaminergic terminal axons, our results suggest the innervation of renal medullary blood vessels in man by both noradrenergic and dopaminergic sympathetic nerves.

Adult↗
PubMed1990

The GABA and substance P input to dopaminergic neurones in the substantia nigra of the rat.

In order to examine the synaptic input to dopaminergic neurones in the substantia nigra from GABAergic terminals and terminals that contain substance P, double and triple immunocytochemical studies were carried out at the light and electron microscopic levels in the rat. In a first series of experiments sections of the substantia nigra were incubated to reveal axon terminals containing either substance P or glutamate decarboxylase and then incubated to reveal dopaminergic neurones using tyrosine hydroxylase immunocytochemistry. Examination of this material in the light microscope revealed that many substance P- and glutamate decarboxylase-immunoreactive boutons were associated with the dopaminergic cells. In the electron microscope it was found that the perikarya and dendrites of the dopaminergic neurons received symmetrical synaptic input from terminals that displayed immunoreactivity for substance P or glutamate decarboxylase. A small proportion of the substance P-positive boutons formed asymmetrical synapses. In a second series of experiments sections of the substantia nigra were processed by the pre-embedding immunocytochemical technique for tyrosine hydroxylase and then the post-embedding immunogold technique for gamma-aminobutyric acid (GABA). Examination in the electron microscope revealed that the tyrosine hydroxylase-positive neurons received symmetrical synaptic input from many GABA-positive terminals. Quantitative analyses demonstrated that a minimum of 50-70% of all boutons afferent to the dopaminergic neurones display glutamate decarboxylase or GABA immunoreactivity. Triple immunocytochemical studies i.e. pre-embedding immunocytochemistry for tyrosine hydroxylase and substance P, combined with post-embedding immunogold staining for GABA, revealed that some of the substance P-immunoreactive boutons that were in contact with the dopaminergic neurones also displayed GABA immunoreactivity. In a third series of experiments the combination of anterograde transport of lectin-conjugated horseradish peroxidase or biocytin with post-embedding GABA immunocytochemistry demonstrated that at least one of the sources of GABA-containing terminals in the substantia nigra is the striatum. The results of the present study: (1) demonstrate that dopaminergic neurones in the substantia nigra receive symmetrical synaptic input from GABAergic and substance P-containing terminals, (2) show that a proportion of these terminals contain both substance P and GABA and (3) suggest that the major synaptic input to dopaminergic neurones is from GABAergic terminals and that a part of this innervation is derived from the striatum.

Animals↗