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PubMed1995

In vivo activity of tyrosine hydroxylase in rat adrenal glands following administration of quinpirole and dopamine.

Using adrenal dopamine as indicator we have previously obtained evidence that quinpirole and several other agonists on dopamine D2-like receptors acutely stimulate the synthesis of adrenal catecholamines. In the present study we measured the effect of quinpirole and dopamine on the hydroxylation of tyrosine in the adrenals, using the method of DOPA (3,4-dihydroxyphenylalanine) accumulation following the administration of the inhibitor of aromatic L-amino acid decarboxylase NSD 1015 (3-hydroxybenzylhydrazyne). In view of the large amounts of catecholamines in the adrenal tissue samples, this necessitated a modification of the method for analysing DOPA. Both quinpirole and dopamine significantly enhanced the rate of DOPA accumulation in the adrenals, indicating stimulation of adrenal tyrosine hydroxylase. The effect of dopamine was blocked by domperidone, a dopamine D2 receptor antagonist that penetrates poorly into the central nervous system. Thus the effect of dopamine, which itself penetrates poorly into the central nervous system, was presumably mediated peripherally. Similarly epinine, i.e. the N-methyl derivative of dopamine, appeared to enhance adrenal catecholamine synthesis, as indicated by an elevated adrenal dopamine level. The data support the view that stimulation of peripherally located dopamine D2-like receptors can enhance the rate of adrenal catecholamine synthesis by stimulating the activity of tyrosine hydroxylase.

Adrenal Glands↗
PubMed1980

Effect of 6-hydroxydopamine lesions of the medial prefrontal cortex on neurotransmitter systems in subcortical sites in the rat.

The effect of lesions of the catecholamine nerve terminals in the medial prefrontal cortex of the rat on neurotransmitter mechanisms within the basal ganglia has been investigated. Bilateral 6-hydroxydopamine lesions were stereotaxically placed in the dopamine-rich (DA) area of th frontal cortex. Animals were pretreated with desmethylimipramine to block the uptake of neurotoxin into noradrenergic (NA) terminals and to make it more selective for DA terminals. The lesion produced a selective reduction of both NA and DA from the medial prefrontal cortex, a result related to falls in tyrosine hydroxylase activity at this site. Lesioned animals showed enhanced DA turnover and utilisation in striatal and limbic regions. There was no change in subcortical tyrosine hydroxylase activity. In addition there were significant falls in other putative neurotransmitters within basal sites, including 5-hydroxytryptamine and GABA. Decreased activity of the neurotransmitter-synthesizing enzyme glutamate decarboxylase and choline acetyltransferase was also recorded in certain regions of the basal ganglia. The results suggest that frontal cortical catecholamine systems may serve to regulate various neurotransmitter mechanisms in the basal ganglia.

Animals↗
PubMed2003

Thrombin induces in vivo degeneration of nigral dopaminergic neurones along with the activation of microglia.

Seven days after the injection of different concentrations of thrombin into the nigrostriatal pathway, a strong macrophage/microglial reaction was observed in the substantia nigra (SN), indicated by immunostaining, using OX-42 and OX-6 antibodies, and by the induction of iNOS, IL-1alpha, Il-1beta and TNF-alpha. Moreover, selective damage to dopaminergic neurones was produced after thrombin injection, evidenced by loss of tyrosine hydroxylase immunostaining and tyrosine hydroxylase mRNA-expressing cell bodies, and the unaltered transcription of glutamic acid decarboxylase mRNA in the SN and striatum. These thrombin effects could be produced by its ability to induce the activation of microglia described in in vitro studies, and are in agreement with the effects described for other proinflammatory compounds. Thrombin effects are produced by its biological activity since they almost disappeared when thrombin was heat-inactivated or injected along with its inhibitor alpha-NAPAP. Thrombin is a multi-functional serine protease rapidly produced from prothrombin at the sites of tissue injury, and also upon breakdown of the blood-brain barrier, which strongly suggests it could easily enter into the CNS. These results could have special importance in some degenerative processes of the nigrostriatal dopaminergic system.

Animals↗
PubMed1985

Evaluation of neurotropic drug actions on tyrosine hydroxylase activity and dopamine metabolism in clonal cell lines.

Two clonal cell lines (the pheochromocytoma clone PC-12 and the neuroblastoma clone N1E-115) were used to compare direct and indirect drug effects on tyrosine hydroxylase and dopamine turnover. Both clones contain the cofactor of tyrosine hydroxylase, tetrahydrobiopterin, in sufficient concentrations. 2,4-Diamino-6-hydroxy-pyrimidine (DAO-Pyr), an inhibitor of GTP cyclohydrolase, which is the rate-limiting enzyme in tetrahydrobiopterin biosynthesis, lowers DOPA production indicating that cofactor supply is a limiting factor for catecholamine synthesis. DOPA synthesis in the PC-12 cells can be stimulated by incubation with the natural cofactor tetrahydrobiopterin, but also by its possible precursors sepiapterin and dihydrobiopterin or the analogs methyl-tetrahydropterin and dihydropterin. The regulating enzyme for DOPA synthesis, tyrosine hydroxylase, can be inhibited by certain drugs either directly or indirectly by increasing dopamine concentrations in the cytoplasm after release from its vesicular stores. Using the neuroblastoma clone N1E-115 which lacks DOPA decarboxylase and thus contains only low levels of dopamine the site of action of certain drugs could be determined. Drugs affecting the tyrosine hydroxylase directly (alpha-methyl-para-tyrosine, apomorphine) decreased DOPA production in both clones, while drugs acting via interference with the vesicular stores (reserpine, amphetamine, nigericin) were effective only in the PC-12 cells. After total depletion of dopamine by nigericin at high concentrations or long-term incubation with 3-hydroxybenzyl-hydrazine (NSD 1015), DOPA production increased in the PC-12 cells indicating a usually occurring regulation of tyrosine hydroxylase by cytoplasmic dopamine. Dopamine concentration in the cytoplasm was calculated to be in the range of 1 X 10(-6) mol/l.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1998

Effect of melatonin on 24-hour rhythms of ornithine decarboxylase activity and norepinephrine and acetylcholine synthesis in submaxillary lymph nodes and spleen of young and aged rats.

Young (50 days old) and old (18 months old) Sprague-Dawley rats were injected with mycobacterial Freund's adjuvant to produce an inflammatory disease of the joints and were studied the day before, and on days 6, 12 and 18 after injection. At every postinjection interval examined, old rats had significantly lower circadian amplitudes of pineal melatonin content. On day 18 of arthritis development, decreased levels of pineal melatonin were also seen in young rats. A second study, carried out 18 days after the injection of Freund's complete adjuvant and after 17 daily injections of 10 or 100 microg of melatonin in the evening, indicated that melatonin treatment restored the inflammatory response in old rats (assessed plethysmographically in hind paws) to the level found in young animals. In young rats, an inflammation-promoting effect of 100 microg melatonin could be demonstrated. As a consequence of the immune reaction, submaxillary lymph node and splenic ornithine decarboxylase activity (an index of lymph cell proliferation) augmented significantly, with acrophases of 24-hour rhythms in the afternoon for lymph nodes or in the morning for spleen. Mesor and amplitude of ornithine decarboxylase rhythm were lowest in old rats, while melatonin injection generally augmented its amplitude. Lymph node and splenic tyrosine hydroxylase activity (a presynaptic adrenergic marker) reached maximal values during early night hours while maximal values of [3H]acetylcholine synthesis (a presynaptic cholinergic marker) occurred during the afternoon in lymph nodes. Amplitude and mesor of these rhythms were lowest in old rats, an effect generally counteracted by melatonin treatment. The results suggest that inflammation is accompanied by an age-dependent, significant depression of pineal melatonin synthesis during adjuvant-induced arthritis and a decreased amplitude of the circadian rhythm of immune cell proliferation and autonomic activity in lymph nodes and spleen. These effects are counteracted by injection of melatonin, mainly in old rats.

Acetylcholine↗
PubMed1985

Effect of neonatal optic nerve transection on some classes of amacrine cells in the rat retina.

An optic nerve section of the right eye of rat pups was carried out and the retina of the left and right eyes analyzed eight weeks later. Immunocytochemical studies for the localization of tyrosine-hydroxylase, choline acetyltransferase and substance P in amacrine cells revealed no qualitative differences in the distribution of the cell bodies or dendrites for the right and left retinas. Biochemical analysis showed a higher level of choline acetyltransferase, dopamine and glutamate decarboxylase in the right than in the left retina, though the glutamate decarboxylase difference was statistically insignificant. The biochemical difference is thought to reflect the differences in the protein or wet weight content of the retinas due to degeneration of the ganglion cells. It is concluded that destruction of the ganglion cells has no obvious effect upon the development or survival of some classes of amacrine cells.

Animals↗
PubMed1993

Serotonin 5-HT1A receptors mediate inhibition of tyrosine hydroxylation in rat striatum.

The role of serotonin (5-HT)1A heteroreceptors as modulators of dopamine synthesis was investigated by using in vitro and in vivo methods. In vitro studies were conducted utilizing either synaptosome-rich preparations of rat striatal tyrosine hydroxylase or soluble preparations of rat striatal tyrosine hydroxylase enzyme. 5-HT1A receptor modulation of tyrosine hydroxylation in vitro was estimated by using a radiometric, coupled enzyme assay. For in vivo investigations of the modulation of tyrosine hydroxylation, striatal dopa accumulation was measured (high-performance liquid chromatography-electrochemical detection) after administration of the aromatic amino acid decarboxylase inhibitor NSD-1015 (3-hydroxybenzylhydrazine). Both serotonin and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a selective 5-HT1A receptor agonist, were moderately potent, receptor-mediated inhibitors of tyrosine hydroxylation in synaptosomes, with EC50 values of 8.4 and 7.0 microM, respectively. The inhibitory activity of 8-OH-DPAT was attenuated by 5-HT1A-selective antagonists [10 microM propranolol, 10 microM (-)-alprenolol, 10 microM NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-pthalimido)butyl] piperazine hydrobromide) and 10 microM pindolol] but not by a beta adrenoceptor antagonist devoid of activity at the 5-HT1A receptor (10 microM atenolol) or by a D2-dopamine-selective receptor antagonist [10 microM (-)-sulpiride]. In vivo 8-OH-DPAT exhibited a biphasic dose-response curve for inhibition of tyrosine hydroxylation, significant inhibition (30%, P < .05) occurred at a dose of 0.3 mg/kg s.c. In vivo, the 5-HT1A-selective antagonist NAN-190 (1 or 3 mg/kg s.c.) caused dramatic 2- to 2.5-fold elevations of dopa accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Butyrolactone↗
PubMed1995

Effects of BDNF on dopaminergic, serotonergic, and GABAergic neurons in cultures of human fetal ventral mesencephalon.

The neurotrophin brain-derived neurotrophic factor (BDNF) was tested for its ability to promote the survival and regulation of expression of phenotypic markers of dopaminergic, serotonergic, and GABAergic neurons in free-floating roller tube cultures of human fetal ventral mesencephalon. This culture system contains neurons of the anlage of the substantia nigra as well as that of the rostral raphe nucleus. Dopaminergic neuron number and tyrosine hydroxylase (TH) fiber density was monitored by TH immunocytochemistry. Measurement of dopamine (DA) content, TH enzymatic activity, serotonin (5-HT) content, and glutamic acid decarboxylase (GAD) activity were used as indices of their respective neurotransmitter function. The presence of GABAergic and serotonergic neurons in this culture system was confirmed by GABA and 5-HT immunocytochemistry. In cultures maintained in the presence of BDNF (10 ng/ml), the density of TH-positive cells was increased by 2.5-fold (P F 0.05), and the TH-positive fiber density was increased by 3.5-fold (P F 0.01), relative to control cultures. Similarly, the relative increases in DA content and TH activity were 2.6- and 2.3-fold, respectively, in the BDNF-treated cultures (P F 0.01 and P F 0.01). On a per neuron basis, DA content and TH activity were not markedly changed by BDNF treatment, suggesting that the increases in DA content and TH activity are due to more DA neurons surviving. Relative elevations were also observed in serotonin content (2.0-fold, P F 0.01) and GAD enzymatic activity (1.4-fold, P F 0.01). Future studies will need to determine whether these changes result from the direct action of BDNF on these neurons or through some indirect mechanism. The results demonstrate that BDNF has beneficial effects on cultured human fetal tissue, which may be relevant in optimizing neuronal transplantation techniques, and that multiple systems are simultaneously influenced by BDNF.

Abortion, Induced↗
PubMed1991

Regulation of c-myc and ornithine decarboxylase expression by distinct protein kinase systems in IL-3-dependent myeloid cells.

We have investigated whether PK-C-regulated events are independent of those biochemical events related to IL-3-induced tyrosine kinase activation by 32Dcl cells. The depletion of functional PK-C isoform activity by prolonged PMA treatment reduced the proliferative response to IL-3 by half that of untreated control cells. PK-C-deficient 32Dcl cells were unable to respond to PMA for the induction of c-myc and ODC mRNA accumulation. PK-C down-regulation did not affect IL-3-induced tyrosine phosphorylation and inhibited IL-3-regulated c-myc and ODC mRNA expression by only 30%. However, PK-C down-regulation had a pronounced inhibitory effect on IL-3 regulation of ODC enzymatic activity. While a PK-C-dependent and -independent pathway for the regulation of c-myc and ODC mRNA expression could be demonstrated, the regulation of ODC enzymatic activity appeared to require an intact PK-C system. The data suggest that the optimum biological and biochemical responses to IL-3 requires both pathways intact, however, tyrosine kinase activation and significant increases in gene products associated with proliferation can be achieved in the absence of a functional PK-C system.

Animals↗
PubMed1995

Localization of serotonin-4 receptors in the striatonigral pathway in rat brain.

Rats were injected unilaterally with 6-hydroxydopamine either in the medial forebrain bundle or in the dorsolateral substantia nigra. Another group was injected unilaterally with kainate in the striatum. The loss of neurons was assessed by a reduction in tyrosine hydroxylase-like immunoreactivity for dopaminergic neurons, and choline acetyltransferase-like and glutamate decarboxylase-like immunoreactivities for cholinergic and GABAergic neurons, respectively. Brain sections also were analysed by autoradiography on 20 micron sections with the radio-iodinated serotonin-4 receptor antagonist [125I]SB 207710 [Brown A. M. et al. (1993) Br. J. Pharmac. 110, 10P]. Kainate injections in the striatum resulted in loss of choline acetyltransferase- and glutamate decarboxylase-like immunoreactive cell bodies in this area. There was also a decrease in glutamate decarboxylase-like immunoreactivity on the ipsilateral side in the substantia nigra and entopeduncular nucleus. These changes were accompanied by substantial (> 50%) decreases in [125I]SB 207710 binding in both the ipsilateral striatum (confined to the lesioned area) and substantia nigra, with no change in either the nucleus accumbens or the globus pallidus. There was also significant loss of [125I]SB 207710 binding in the ipsilateral entopeduncular nucleus. 6-Hydroxydopamine lesions placed either in the medial forebrain bundle or in the substantia nigra failed to decrease [125I]SB 207710 binding in any of these areas, although there was total loss of tyrosine hydroxylase-like immunoreactive terminals in the striatum and cell bodies in the nigra. We conclude that serotonin-4 receptors are present on projection neurons, both on their perikarya in the striatum and terminals in the nigra and entopeduncular nucleus. It is likely that these receptors are located on the GABAergic projection neurons and possibly on cholinergic and GABAergic interneurons. However, serotonin-4 receptors are not located on dopaminergic neurons, either on their cell bodies in the substantia nigra or terminals in the striatum.

Animals↗
PubMed2004

[Dopamine synthesis by non-dopaminergic neurons of the rat fetus arquate nucleus].

Our hypothesis was tested in respect to dopamine synthesis by non-dopaminergic neurons expressing individual complementary enzymes of the DA synthetic pathway. According to the hypothesis, L-dihydroxyphenylalanine (L-DOPA) synthesised in tyrosine hydroxylase(TH)-expressing neurons for conversion to dopamine. The mediobasal hypothalamus of rats on the 21st embryonic day was used as an experimental model. The fetal substantia nigra containing dopaminergic neurons served as control. Dopamine and L-DOPA were measured by high performance liquid chromatography in cell extracts and incubation medium in presence or absence of L-tyrosine. L-tyrosine administration increased L-DOPA synthesis in the mediobasal hypothalamus and substantia nigra. Moreover, L-tyrosine provoked an increase of dopamine synthesis in substantia nigra and a decrease in the mediobasal hypothalamus. This is, probably, due to an L-tyrosine-induced competitive inhibition of the L-DOPA transport to monoenzymatic AADC neurons after its release from the monoenzymatic TH neurons. This study provides a convincing evidence of dopamine synthesis by non-dopaminergic neurons expressing TH or AADC, in cooperation.

Animals↗
PubMed1975

In vivo rates of tyrosine and tryptophan hydroxylation in regions of rat brain at four times during the light-dark cycle.

The in vivo rates of tyrosine and tryptophan hydroxylation were studied in three regions of young adult rat brains at 4 times the light-dard cycle. The procedure utilized was to analyze the accumulation of Dopa and 5-HTP after injection of a centrally effective L-amino acid decarboxylase inhibitor, NSD 1015. Monoamine levels were also determined in all control animals and some treated animals. The reate of tyrosine dydrosylation in the telencephalon was significantly higher 7 hrs after dard onset than at the other three times tested. Smaller variations in tyrosine and tryptophan hydroxylation rates as a function of time of day were also observed. 5-HT levels were significantly higher during the light phase than the dark in the telencephalon with the same trend occurring in the diencephalon and brainstem. NA was stable in the telencephalon but reached lower levels in the light and higher levels in the dark in the other two regions. In the telencephalon DA reached high levels early in the light and in the dark phases, showing a biphasic variation. Of particular interest was the apparent lack of carrelation between cyclic changes in the monoamine levels and the changes in hydroxylation rates. Rates of hydroxylation can be considered indicative of rates of monoamine synthesis. This observation is discussed in relation to feedback and other mechanisms regulating synthesis and release of monoamines.

Amino Acids↗
PubMed1977

Regulation of catecholamine biosynthesis in a transplantable rat pheochromocytoma.

Cells prepared from a transplantable rat pheochromocytoma synthesize norepinephrine from 14C-tyrosine, at a rate of 9.4 +/- 0.5 pml/min/mg of protein, in vitro. Incubation of the cells in a medium containing 56 mM K+ results in a 2- to 6-fold increase in norepinephrine synthesis. This increase in norepinephrine synthesis is dependent upon the presence of Ca++ in the incubation medium. Stimulation of the cells by 56 mM K+ increases the conversion of tyrosine to dopa in the presence of brocresine (an inhibitor of aromatic L-amino acid decarboxylase), and has no effect on the conversion of 3H-dopa to norepinephrine. Cells can be depleted of up to 70% of their catecholamine stores by prior incubation in 56 mM K+. Norepinephrine synthesis in catecholamine-depleted cells incubated under control conditions in only slightly (20-40%) greater than it is in nondepleted cells. However, 56 mM K+ PRODUCES A SIMILAR INCREASE IN NOREPINEPHRINE SYNTHESIS IN DEPLETED CELLS AS IT DOES IN NONDEPLETED CELLS. Inhibition of amine oxidase (flavin containing) by preincubaiton with pargyline does not greatly affect catecholamine synthesis. Incubation of the cells in 56 mMK+ results in an increase in tyrosine 3-monooxygenase activity. These results indicate that the depletion of catecholamine stores plays only a minor role in the increase in norepinephrine synthesis caused by the stimulation of chromaffin cells and suggest that the activation of tyrosine 3-monooxygenase plays a more important role in this phenomenon.

Animals↗
PubMed1988

Differential afferent regulation of dopaminergic and GABAergic neurons in the mouse main olfactory bulb.

Peripheral deafferentation of the mouse main olfactory bulb following intranasal irrigation with ZnSO4 produced profound decreases in tyrosine hydroxylase activity and immunoreactivity in intrinsic dopamine neurons normally localized to the juxtaglomerular region of the bulb. In contrast, only modest alterations in GABA-immunoreactivity and glutamic acid decarboxylase (GAD) activity were observed in the same region. In fact, when GAD activity was expressed per mg tissue, a reflection of enzyme concentration, no changes in activity were observed 3 weeks postlesion and only relatively modest decreases in specific activity were found following long survival times (4 months). When the data were expressed per bulb, as an indication of the total amount of enzyme present, GAD activity and bulb weight exhibited similar reductions. Olfactory marker protein levels, determined as an indication of the completeness of the deafferentation, were at or below the limits of detection in all lesioned mice. These data indicate that afferent regulation of transmitter expression in the juxtaglomerular neurons of the olfactory system is phenotype specific.

Afferent Pathways↗
PubMed2004

The ability of grafted human sympathetic neurons to synthesize and store dopamine: a potential mechanism for the clinical effect of sympathetic neuron autografts in patients with Parkinson's disease.

We have investigated the potential of autologous sympathetic neurons as a donor for cell therapy of Parkinson's disease (PD). Our recent study demonstrated that sympathetic neuron autografts increase the duration of levodopa-induced "on" periods with consequent reduction in the percent time spent in "off" phase. We also found that human sympathetic neurons grown in culture have the ability to convert exogenous levodopa to dopamine and to store the synthesized dopamine. This may explain the clinically observed prolongation in the duration of levodopa effects. To further analyze the mechanism for the graft-mediated effect, the present study investigated the metabolic function of human sympathetic ganglionic neurons xenografted into the dopamine (DA)-denervated striatum of rats by monitoring striatal levels of DA and its primary metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), after systemic administration of levodopa. We also explored whether the graft-mediated effect above may last in four PD patients who had been given the grafts and followed for 12-36 months postgrafting. Clinical evaluations showed that an increase in the duration of levodopa-induced "on" phase is detected during a follow-up period of 12-36 months postgrafting in all the four patients tested. Accordingly, the percent time spent in "off" phase exhibited a 30-40% reduction as compared to the pregrafting values. The animal experiment showed that a significant increase in striatal DA levels is noted after systemic levodopa treatment, and that the DA levels remain high for longer periods of time in the grafted rats than in control animals. When given reserpine pretreatment, the levodopa-induced rise of striatal DA levels was significantly attenuated with concomitant increase in DOPAC levels. Histological examinations demonstrated that the grafts contain some tyrosine hydroxylase (TH)-positive cells. These cells were also found to express aromatic-l-amino acid decarboxylase (AADC) and vesicular monoamine transporter-2 (VMAT), both of which are important molecules for the synthesis and the storage of DA, respectively. These results indicate that grafted sympathetic neurons can provide a site for both the conversion of exogenous levodopa to DA and the storage of the synthesized DA in the DA-denervated striatum, explaining a mechanism by which sympathetic neuron autografts can increase the duration of levodopa-induced "on" phase in PD patients.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1979

Effects of cortical ablation on the neurotoxicity and receptor binding of kainic acid in striatum.

Lesions of the cerebral cortex alter striatal neuronal vulnerability to locally injected kainic acid. Whereas extensive lesions involving the frontal-parietal-occipital cortex are most effective, lesions limited to the frontal or to the dorsal-lateral parietal cortex offer partial protection. The extensive cortical lesions are associated with selective, marked reductions in the presynaptic markers for glutamatergic afferents in striatum. The protective effects of decortication appear between 6 and 24 hours after the lesion and are maintained up to 30 days after decortication. Whereas decortication results in only a transient reduction of specific receptor binding of [3H]kainic acid to striatal membranes, lesion of striatal intrinsic neurons with kainic acid causes a delayed but marked reduction in specific binding of the ligand. Coadministration of L-glutamic acid (1 mumole) with kainic acid (9 nmoles) partially restores the neurotoxic action of kainic acid in the decorticate striatum; GABA, alanine, and proline (1 mumole) are ineffective with regard to restoring kainate's toxicity for striatal GABAergic neurons. These results suggest that afferent input exerts a permissive effect on the neurotoxic action of kainic acid and that neurotoxicity may involve a cooperative interaction between kainic acid at specific receptors on vulnerable neurons and synaptically released endogenous neurotransmitters, in particular L-glutamic acid.

Animals↗
PubMed1988

Peptide- and transmitter-containing neurons in the mediobasal hypothalamus and their relation to GABAergic systems: possible roles in control of prolactin and growth hormone secretion.

Indirect immunofluorescence histochemistry was used to study the relation among GABAergic, catecholaminergic, cholinergic, and peptidergic neurons in the rat mediobasal hypothalamus. By employing a direct double-labelling procedure using sheep antiserum against glutamic acid decarboxylase (GAD), mouse monoclonal and rabbit antibodies to neurotensin (NT) and rabbit antisera to tyrosine hydroxylase (TH), choline acetyltransferase (ChAT), galanin (GAL), growth hormone-releasing factor (GRF), or somatostatin (SOM), it was demonstrated that GAD-positive fibers and terminals in the external part of the median eminence co-contained immunoreactivity for TH, NT, GAL or GRF, but not for SOM. In the internal part of the median eminence-infundibular stalk, GAD-positive/NT-, GAL-, and GRF-negative and GAD-positive/TH-positive fiber plexa were shown. When a recently developed direct triple-labelling procedure with biotin-conjugated mouse secondary antibodies in conjunction with diethylaminocoumarin (DAMC)-conjugated avidin was employed, presence of GAD/GAL/NT- as well as GAD/GRF/NT-containing varicosities could be demonstrated close to hypophysial portal vessels. In colchicine-pretreated animals, GAD was shown to coexist with TH, NT, or GAL in cell bodies in both the dorsomedial and ventrolateral domains of the arcuate nucleus, but with GRF only in the ventrolateral division. ChAT-positive neurons in the ventrolateral region were also TH-positive. In the ventrolateral arcuate nucleus, triple-labelling followed by elution-restaining showed GAD/NT/GAL/TH-immunoreactivities in the same cells. Similarly, double-labelling with two following elution-restaining steps showed several NT/GAL/GRF/TH-containing cell bodies in this part of the arcuate nucleus. GAD-positive cells in the anterior hypothalamic periventricular area and fibers in the pituitary neurointermediate lobe were also TH-positive. The results demonstrate complex patterns of storage of chemical messengers in neurons of the arcuate nucleus-median eminence complex. Possible neuroendocrine interactions of these systems in the control of prolactin and growth hormone secretion are discussed.

Animals↗