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PubMed1993

Regulation of prefrontal cortical dopamine release by dopamine receptor agonists and antagonists.

The effect of dopamine D1 and D2 receptors agonists and antagonists on extracellular dopamine release was evaluated by microdialysis in the prefrontal cortex. Nomifensine (5 microM) was included in the Ringer solution during the experiments. Cortical dopamine release was tetrodotoxin- and calcium-dependent and was stimulated by high potassium (60 mM) Ringer solution. 1-Methyl-4-phenylpyridinium ion (MPP+) (10 mM) increased the extracellular output of dopamine. SKF-38393 decreased the release of dopamine in a dose-related manner to about 80, 40 and 0% of the control values at 0.1, 1 and 10 microM, respectively. The decrease produced by SKF-38393 (10 microM) was partially antagonized by SCH-23390 at a concentration of 1 microM. Perfusion of CY-208243 (10 microM) produced a decrease in the release of dopamine to about 70% of controls. Quinpirole, at a concentration of 10 microM, produced a decrease in the release of dopamine to about 65% of controls. SCH-23390 and sulpiride, at 10 microM, increased the extracellular output of dopamine to about 150% of controls. These results indicate that dopamine D1 and D2 receptors are implicated in the autoregulation of dopamine release in the prefrontal cortex.

1-Methyl-4-phenylpyridinium↗
PubMed2000

Dopamine control of striatal gene expression during development: relevance to knockout mice for the dopamine transporter.

The aim of this study was to determine at which developmental stage and how dopamine regulates the expression of striatal dopamine receptor and neuropeptide mRNAs. For this, we studied the expression of these mRNAs, in relation to dopamine innervation, in normal mice from gestational day 13 (G13) to adult. Particularly, we investigated the adaptive changes in the expression of these markers in mice lacking the dopamine transporter during development. We detected tyrosine hydroxylase, by immunohistochemistry, in the ventral mesencephalon and the striatal anlage in both genotypes at G13, whereas the dopamine transporter appeared in the striatum of normal mice at G14. By in situ hybridization, we detected striatal dopamine D1, D2, D3 receptor, and substance P mRNAs at G13, preproenkephalin A mRNA at G14 and dynorphin mRNA at G17 in normal mice. Although the time of initial detection and the distribution were not affected in mutant mice, quantitative changes were observed. Indeed, D1 and D2 receptor as well as preproenkephalin A mRNA levels were decreased from G14 on, and dynorphin mRNA level was increased from G17 on. In contrast, substance P mRNA level was unaffected. Our data demonstrate that the influence of dopamine on striatal neurons occurs early during the development of the mesostriatal system as quantitative changes appeared in mutant mice as soon as G14. These findings bring new insights to the critical influence of dopamine on the expression of striatal dopamine receptor and neuropeptide mRNAs during development, and suggest that mesostriatal dopamine transmission functions from G14 on.

Animals↗
PubMed1992

Dopamine denervation leads to an increase in the intramembrane interaction between adenosine A2 and dopamine D2 receptors in the neostriatum.

We have previously found, in striatal membrane preparations from young (2 months old) rats, that stimulation of adenosine A2 receptors (with the selective adenosine A2 agonist CGS 21680) increases the dissociation constants of high- (Kh) and low-affinity (Kl) dopamine D2 binding sites (labelled with the selective dopamine D2 antagonist [3H]raclopride) without changing the proportion of high affinity binding sites (Rh). In the present study in striatal preparations from adult (6 months old) rats, it was found that in addition to the increase in both Kh and Kl values, stimulation of adenosine A2 receptors is associated with an increase in Rh. These results suggest that, in the adult rat, adenosine A2 stimulation may inhibit the behavioural effects induced by dopamine D2 stimulation both by decreasing the affinity and the transduction of dopamine D2 receptors. We have also studied the intramembrane A2-D2 receptor interaction in an experimental model of Parkinson's disease, namely in rats with a unilateral 6-OH-dopamine-induced lesion of the nigro-striatal dopamine pathway. It was found that a unilateral dopamine denervation is associated with a higher density of striatal dopamine D2 receptors in the order of 20%, without any change in their affinity compared with the unlesioned neostriatum. Furthermore, the density (Bmax values) of dopamine D2 receptors in the contralateral neostriatum was significantly higher (about 20%) than in the striatum from naive animals. This finding suggests that an unilateral dopamine denervation also induces compensatory long-lasting changes of dopamine D2 receptors in the contralateral neostriatum.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

Stimulation of acetylcholine or dopamine receptors in the nucleus accumbens differentially alters dopamine release in the striatum of freely moving rats.

The present study examined whether unilateral stimulation of acetylcholine or dopamine receptors in the nucleus accumbens induces an asymmetry in dopamine transmission in the ventrolateral striatum. For this purpose, a microdialysis technique was used to measure dopamine release in both sides of the ventrolateral striatum following unilateral injections of carbachol (5 micrograms/0.5 microliter) or a mixture of dopamine D1 and dopamine D2 receptor agonists (1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine-7,8-diol 5 micrograms + quinpirole 10 micrograms/0.5 microliter) into the nucleus accumbens. The results show that carbachol injection increased dopamine release in the ipsilateral striatum without changing dopamine release in the contralateral striatum, whereas the dopamine D1/D2 receptor agonist mixture injected unilaterally into the nucleus accumbens produced an increase followed by a decrease in dopamine release in the ipsilateral striatum, but only a decrease in dopamine release in the contralateral striatum. The biochemical effects of the cholinergic treatment greatly outlasted the drug-induced contralateral turning, whereas the biochemical effects of the dopaminergic treatment showed a good correlation with the drug-induced contralateral turning. The present study provides biochemical evidence that unilateral stimulation of acetylcholine or dopamine receptors in the nucleus accumbens elicits an asymmetry in dopaminergic activity in the ventrolateral striatum. The present study also provides biochemical evidence that two distinct neural substrates are involved in the effects of cholinergic and dopaminergic manipulation of the nucleus accumbens.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1981

Interactions between dopamine and prostaglandins on vascular reactivity to noradrenaline: dopamine inhibits the action of PGE1.

Interactions between dopamine and responses to noradrenaline as modulated by prostaglandins (PGs) were studied in the perfused rat mesenteric vascular bed. When perfused alone dopamine up to a concentration of 10(-7)M neither changed baseline pressure nor modified the pressor response to noradrenaline. Dopamine at 10(-9) to 10(-7)M significantly inhibited responses to noradrenaline which had been enhanced by the presence of 10(-10) to 10(-8) M PGE1. In preparations in which vascular responses to noradrenaline had been abolished by indomethacin and restored by adding PGE1, 10(-9) to 10(-7)M dopamine significantly inhibited the restored responses. Dopamine also attenuated the inhibitory effects of prostacyclin on pressor responses to noradrenaline but it did not change the actions of either PGE2 or PGF2 alpha. Pimozide, a mainly centrally acting dopamine antagonist, did not interfere with these peripheral actions of dopamine. The dopamine effects were blocked by another dopamine antagonist, metoclopramide. Dopamine can inhibit the effects of PGE1 and prostacyclin in the rat mesenteric vascular bed, possibly by interacting with specific dopamine receptors.

Alprostadil↗
PubMed1995

Dopamine causes stimulation of protein kinase C in rat renal proximal tubules by activating dopamine D1 receptors.

Although it is suggested that in the renal proximal tubules, dopamine D1 receptor activation causes inhibition of Na+/K+ATPase via a phospholipase C and protein kinase C coupled pathway, the direct stimulation of protein kinase C by dopamine has not been reported. The present study was designed to examine the effects of dopamine and selective dopamine D1 receptor and dopamine D2 receptor agonists on protein kinase C activity. The renal proximal tubule suspensions were obtained from male Sprague-Dawley rats. The tubules were incubated separately with dopamine and fenoldopam in the presence or absence of dopamine D1 receptor antagonist, SCH 23390 ([(R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepine]). The protein kinase C activity was measured by using a kinase target peptide, conjugated to a fluorescent molecule in water. The amino acid sequence of this peptide is, Proline-Leucine-Serine-Arginine-Threonine-Leucine-Serine-Valine-Alanine- Alanine-Lysine(PKSRTLSVAAK). We found that dopamine and fenoldopam [6-chloro-2,3,4,5-tetrahydro-1-(4-hydroxyphenyl)-1H-3-benzazepine-7,8-di ol] produced concentration-dependent increases in protein kinase C activity, which was blocked by SCH 23390. However, the dopamine D2 receptor agonist, bromocriptine [(5' alpha)-2-bromo-12'-hydroxy-2'-(1-methyl-ethyl)-5'-(2-methylpropyl)erg o- taman-3',6',18-trione] failed to stimulate protein kinase C activity at all the concentrations tested. These results provide direct evidence that dopamine stimulates protein kinase C activity via activation of dopamine D1 receptors.

Animals↗
PubMed2000

Dopamine transporter proline mutations influence dopamine uptake, cocaine analog recognition, and expression.

Analyses of mutation effects can aid in understanding how large proteins act. The dopamine transporter (DAT) mediates complex actions in recognizing cocaine and in recognizing and translocating dopamine, sodium, and chloride. DAT proline residues, especially those in transmembrane (TM) domains, are good candidates for involvement in these DAT actions. We now report production of mutants substituting alanine and/or glycine residues for 16 prolines located in or near putative DAT TM domains. We examine effects of these modifications on DAT expression, dopamine uptake, and cocaine analog binding. Mutants in prolines located in five DAT TM domains and four connecting loops alter apparent DAT membrane targeting. Five mutations decrease dopamine affinities more than threefold without significantly decreasing cocaine analog affinities. One decreases cocaine analog affinity without decreasing dopamine affinity. Two mutations decrease affinities for both dopamine and cocaine analog. P101 is especially implicated in dopamine uptake. Alanine substitution for this proline yields dopamine V(max) values of less than 3% of wild-type values despite dopamine affinities more than fourfold higher than wild-type and normal Na(+) and Cl(-) dependence. These DAT proline mutants identify DAT regions likely for dopamine translocation and for recognition of dopamine and cocaine.

Amino Acid Sequence↗
PubMed2002

Specific binding of [(11)C]raclopride and N-[(3)H]propyl-norapomorphine to dopamine receptors in living mouse striatum: occupancy by endogenous dopamine and guanosine triphosphate-free G protein.

According to the ternary complex model of G-protein linkage to receptors, agonists increase the affinity of the receptors for the G protein. The model predicts that an endogenous agonist's constant of inhibition toward an agonist radioligand is lower than that toward an antagonistic radioligand. The authors hypothesized that competition from endogenous dopamine in striatum of living mice should have a greater effect on the binding of the D2,3 partial agonist N-[3H]propylnorapomorphine than on the binding of the D2,3 antagonist [(11)C]raclopride. The baseline binding potential (pB(0)), defined as the ratio of bound-to-unbound ligand in the absence of competition from endogenous dopamine, was simultaneously measured in mouse striatum for [(11)C]raclopride (pB(0) = 8.5) and N-[(3)H]propylnorapomorphine (p'B(0) = 5.3). The baseline was established by treatment with alpha-methyl-p-tyrosine and reserpine. Relative to these baseline values in saline-treated mice, the pB of N-[(3)H]propylnorapomorphine decreased 52% whereas the pB of [(11)C]raclopride decreased only 30%, indicating greater sensitivity of the former compound to inhibition by synaptic dopamine. Furthermore, amphetamine decreased the pB of N-[(3)H]propylnorapomorphine to a greater extent (73%) than that of [(11)C]raclopride (43%) relative to the reserpine condition. For both radioligands, the occupancy of the dopamine receptors by endogenous agonist obeyed Michaelis-Menten kinetics over a wide range of agonist concentrations established by the pharmacologic treatments. The apparent inhibition constant of endogenous dopamine depended on the dopamine occupancy and decreased to a value 1.66 times greater for N-[(3)H]propylnorapomorphine than for [(11)C]raclopride at its highest occupancies. The results are consistent with the hypothesis that agonist binding is more sensitive than antagonist binding to competition from endogenous dopamine. Therefore, dopamine agonist ligands may be superior to benzamide antagonist ligands for the estimation of dopamine receptor occupancy by endogenous synaptic dopamine. The analysis of the effect of dopamine occupancy on the inhibition of N-[(3)H]propylnorapomorphine binding indicated a limited supply of G protein with a maximum ternary complex fraction of 40% of maximum agonist binding capacity.

Animals↗
PubMed1987

Dopamine released from nerve terminals activates prejunctional dopamine receptors in dog mesenteric arterial vessels.

The fractional release of dopamine and noradrenaline (NA) from the main trunk of the dog mesenteric artery and its proximal branches, when elicited by K+ (52 mM), was measured by high pressure liquid chromatography with electrochemical detection. K+-induced depolarization released both dopamine and NA. For the main trunk of the mesenteric artery, the fractional release of dopamine and NA were of the same order of magnitude, whereas for the proximal branches dopamine fractional release was significantly lower than that of NA. Phentolamine (0.2 microM) significantly increased dopamine and NA release in both segments of the mesenteric artery. However, for the proximal branches the effect of phentolamine on dopamine and NA release was greater than that observed in the main trunk. Sulpiride (1 microM) significantly increased dopamine and NA release in the proximal branches of the mesenteric artery, whereas in the main trunk sulpiride did not increase amine release. In the proximal branches of the mesenteric artery, sulpiride significantly enhanced dopamine and NA fractional release even after it had been augmented by phentolamine. Apomorphine (0.3 microM) significantly reduced dopamine and NA release in both segments of the mesenteric artery under study; this effect was abolished by sulpiride but not by phentolamine. These results suggest that dopamine and NA released during depolarization by K+ activate prejunctional dopamine and alpha-adrenoceptors, respectively, thereby playing a role in the control of transmitter release.

Animals↗
PubMed1984

Evidence for alteration in the processing of dopamine in the anterior pituitary gland of aged rats: receptors and intracellular compartmentalization of dopamine.

Receptors for dopamine and the subcellular localization of dopamine in the anterior pituitary gland were studied in young cycling female rats and in aged, constant estrous female rats. Dopamine receptors were quantified in membrane preparations of anterior pituitary tissue using [3H] spiperone as the ligand. On the basis of saturation isotherms, it was calculated that the equilibrium dissociation constant (Kd) and binding capacity for [3H]spiperone binding to pituitary membranes from young rats were 34.2 pM and 82 fmol/mg protein, respectively. The relative binding capacity of membranes from aged rats was 35% greater than that of membranes from young rats. There was no difference in the Kd values in aged and young rats. When the relative binding of [3H]spiperone by anterior pituitary membranes from individual animals was quantified by incubation with a saturating concentration of the ligand, it was found that [3H]spiperone binding in aged rats was significantly greater than that in young rats. When the subcellular localization of dopamine in anterior pituitary tissue was examined by means of density gradient centrifugation, it was found that the subcellular distribution of dopamine in tissue of aged rats was quantitatively different from that in young rats. In young rats, a small amount of dopamine was associated with light particles, whereas a large amount of dopamine was associated with heavy particles, which cosedimented with PRL-containing granules. In aged rats, the amount of dopamine associated with light particles was 5 times that found in young rats, whereas the amount of dopamine associated with heavy particles was the same as that in young rats. We speculate that altered intracellular compartmentalization of dopamine, leading to a marked accumulation of dopamine in the light particles, is related to increased secretion of PRL in aged rats.

Aging↗
PubMed2006

Dopamine selectively induces migration and homing of naive CD8+ T cells via dopamine receptor D3.

The nervous systems affect immune functions by releasing neurohormones and neurotransmitters. A neurotransmitter dopamine signals via five different seven-transmembrane G protein-coupled receptors termed D1 to D5. The secondary lymphoid tissues are highly innervated by sympathetic nerve fibers that store dopamine at high contents. Lymphocytes also produce dopamine. In this study, we examined expression and function of dopamine receptors in lymphocytes. We found that D3 was the predominant subtype of dopamine receptors in the secondary lymphoid tissues and selectively expressed by naive CD8+ T cells of both humans and mice. Dopamine induced calcium flux and chemotaxis in mouse L1.2 cells stably expressing human D3. These responses were almost completely inhibited by pertussis toxin, indicating that D3 was coupled with the Galphai class of G proteins. Consistently, dopamine selectively induced chemotactic responses in naive CD8+ T cells of both humans and mice in a manner sensitive to pertussis toxin and D3 antagonists. Dopamine was highly synergistic with CCL19, CCL21, and CXCL12 in induction of chemotaxis in naive CD8+ T cells. Dopamine selectively induced adhesion of naive CD8+ T cells to fibronectin and ICAM-1 through activation of integrins. Intraperitoneal injection of mice with dopamine selectively attracted naive CD8+ T cells into the peritoneal cavity. Treatment of mice with a D3 antagonist U-99194A selectively reduced homing of naive CD8+ T cells into lymph nodes. Collectively, naive CD8+ T cells selectively express D3 in both humans and mice, and dopamine plays a significant role in migration and homing of naive CD8+ T cells via D3.

Animals↗
PubMed1987

Stimulation of both D1 and D2 dopamine receptors appears necessary for full expression of postsynaptic effects of dopamine agonists: a neurophysiological study.

The abilities of 4 dopamine agonists to inhibit the tonic single unit activity of substantia nigra dopamine neurons and stimulate tonic activity of globus pallidus neurons were compared to study the agonists' effects on pre- and postsynaptic dopamine receptors, respectively. The agonists studied were apomorphine and pergolide, which interact with both D1 and D2 receptors, and the selective D2 agonists quinpirole and RU 24926. Drugs were administered systemically. The 4 dopamine agonists were equipotent and equiefficacious at inhibiting the firing rates of dopamine neurons. In contrast, their effects on pallidal cells were not identical; apomorphine and pergolide induced significantly greater increases in pallidal cell activity than did quinpirole and RU 24926. In addition, pretreatment with a small dose of quinpirole did not attenuate the excitatory effect of apomorphine on globus pallidus cell activity, as low doses of apomorphine have previously been shown to do. Possible mechanisms underlying the differences in efficacy between the non-selective and D2 selective dopamine agonists in the globus pallidus were investigated. Coadministering quinpirole with apomorphine did not significantly attenuate the effect of apomorphine, suggesting that quinpirole is not a partial agonist at postsynaptic dopamine receptors. In addition, prazosin pretreatment did not attenuate the stimulatory effect of pergolide on firing rates of pallidal cells, indicating that the greater efficacy of the non-selective agonists was not due to concurrent stimulation of alpha 1 adrenergic receptors and dopamine receptors. However, the effect of quinpirole on pallidal cell activity was significantly potentiated by pretreatment with the D1 agonist RS-SKF 38393 but not its inactive enantiomer S-SKF 38393. These results suggest that concurrent D1 and D2 receptor stimulation may be necessary for the full expression of postsynaptic receptor-mediated effects of dopamine and dopamine agonists in the basal ganglia.

Adrenergic beta-Antagonists↗
PubMed2001

Effect of dopamine D2/D3 receptor antagonist sulpiride on amphetamine-induced changes in striatal extracellular dopamine.

Amphetamine increases extracellular dopamine and induces locomotor and stereotypical behaviors in rats. This study examined the effect of the dopamine D2/D3 receptor antagonist sulpiride (50 mg/kg s.c.) on the dopaminergic response to amphetamine (0.5, 2.0, or 8.0 mg/kg i.p.) in male Sprague-Dawley rats. Extracellular dopamine in the striatum was monitored using in vivo microdialysis and high performance liquid chromatography with electrochemical detection. Dopamine concentration curves were analyzed using non-linear regression and residual F-testing. Amphetamine enhanced extracellular dopamine in a dose-dependent manner. Sulpiride augmented the increase in dopamine induced by 0.5 and 2 mg/kg amphetamine by decreasing the rate of dopamine concentration fall off in the extracellular space (P<0.05). Sulpiride also potentiated the amount of dopamine increased by 8 mg/kg amphetamine, but did so by affecting the maximum concentration achieved (P<0.05), not the onset or offset rates. We conclude that the primary effect of a dopamine D2/D3 receptor antagonist is a potentiation of the effect of amphetamine on extracellular striatal dopamine levels, which may contribute to the enhanced stereotypic effects observed when paired with amphetamine.

Amphetamine↗
PubMed1991

Effects of neurotensin on midbrain dopamine neurons: are they mediated by formation of a neurotensin-dopamine complex?

The effects of neurotensin on midbrain dopamine neuron activity were studied in brain slices using single-unit recording techniques. At low concentrations (0.2-10 nM), neurotensin attenuated dopamine-induced inhibition without a significant effect on the basal firing rate. At higher concentrations (greater than 10 nM), however, it consistently caused an increase in cell activity. At even higher concentrations (greater than 100 nM), a sudden cessation of cell activity preceded by an increase in firing rate was observed. Whether this effect of neurotensin was due to depolarization inactivation or to a toxic effect of the peptide at high concentrations remains to be determined. To determine whether the effects of neurotensin were mediated by formation of a neurotensin-dopamine complex, several neurotensin analogues were studied. Neurotensin (8-13), which binds to both neurotensin receptors and dopamine, mimicked the effects of native neurotensin. Neuromedin N, which competes with neurotensin for the same receptor but does not bind to dopamine, also mimicked the effects. However, neurotensin (1-11), which forms a complex with dopamine but is inactive in competing for neurotensin receptors, was ineffective. In addition, the excitatory effect of neurotensin was not attenuated in the presence of dopamine receptor blockade by sulpiride. These results suggest that formation of a neurotensin-dopamine complex may not account for the action of neurotensin on dopamine cells. When combined with the fact that there is a high density of neurotensin receptors on dopamine cells, our results support the suggestion that the observed effects of neurotensin on dopamine neurons are most likely mediated by an activation of neurotensin receptors.

Animals↗
PubMed1982

Peripheral dopamine receptors, potential targets for a new class of antihypertensive agents. Part II: Sites and mechanisms of action of dopamine receptor agonists.

Relatively selective dopamine receptor agonists, like bromocriptine, lergotrile, pergolide and N,N-di-n-propyl-dopamine, lower arterial pressure in conscious spontaneously hypertensive rats and in several anesthetized animal preparations. This effect has been attributed to stimulation of dopamine receptors since it can be specifically antagonized by several dopamine receptor blocking agents (domperidone, haloperidol, pimozide, sulpiride). The two main mechanisms which can theoretically intervene in the antihypertensive effects of dopamine agonists are direct smooth muscle relaxation mediated by stimulation of post junctional DA1-dopamine receptors and the reduction of the neural release of norepinephrine resulting from activation of of DA2-dopamine receptors on ganglionic bodies or sympathetic nerve terminals. Other accessory mechanisms of undoubted interest might be a natriuretic effect or a decrease of aldosterone release. On the basis of the presently available pharmacological results in experimental animals, it is not unreasonable to advance the hypothesis that agonists of DA1- and DA2-dopamine receptors produce cardiovascular changes most compatible with an antihypertensive activity being due to a fall in peripheral resistance. However, before any of these compounds can become of therapeutic interest further research in this field is necessary to explore whether it is possible to minimize or even entirely avoid certain unwanted effects (vomiting, nausea, endocrinological alterations) that appear to be intimately associated particularly with those agents stimulating the DA2-dopamine receptors subtype. A more thorough pharmacological characterization of human dopamine receptors would be useful to provide an insight into whether novel chemical approaches can solve some of these problems. Finally, the ideal profits of future dopamine receptor agonists aimed at the treatment of elevated arterial pressure is discussed.

Animals↗
PubMed1995

Role of vesicular dopamine in the in vivo stimulation of striatal dopamine transmission by amphetamine: evidence from microdialysis and Fos immunohistochemistry.

The role of vesicular and newly synthesized dopamine in the action of amphetamine was investigated by studying the effect of reserpine and alpha-methyl-p-tyrosine pretreatment on amphetamine-induced changes in extracellular dopamine and acetylcholine, estimated by brain microdialysis, and on c-fos expression, estimated by quantitative immunohistochemistry of the Fos antigene, in the dorsal caudate-putamen of rats. Blockade of dopamine synthesis by alpha-methyl-p-tyrosine pretreatment (1 or 2 h) only partially prevented the increase in extracellular dopamine concentrations elicited by 0.5 and 2 mg/kg s.c. of amphetamine. Inactivation of vesicular amine uptake by reserpine pretreatment (3 h) reduced the increase in extracellular dopamine by 2 mg/kg but not by 0.5 mg/kg of amphetamine. Combined pretreatment with reserpine (3 h) and alpha-methyl-p-tyrosine (1 h) drastically reduced the increase in extracellular dopamine by both doses of amphetamine (0.5 and 2 mg/kg s.c.). alpha-Methyl-p-tyrosine pretreatment reduced c-fos expression stimulated by amphetamine (2 mg/kg) in the dorsomedial and dorsolateral caudate-putamen while reserpine pretreatment reduced it only in the dorsolateral caudate-putamen. Amphetamine (2 mg/kg s.c.) stimulated acetylcholine release but this effect was not modified by reserpine or alpha-methyl-p-tyrosine pretreatment. The results indicate that blockade of dopamine synthesis, by itself, is insufficient to prevent the stimulation of dopamine transmission by amphetamine and, conversely, that inactivation of vesicular dopamine significantly reduces amphetamine effects at pre- and postsynaptic levels. Therefore, vesicular dopamine appears to contribute to the stimulation of dopamine transmission elicited by amphetamine in the dorsal caudate-putamen.

Acetylcholine↗
PubMed1994

Peripheral nerve-dopamine neuron co-grafts in MPTP-treated monkeys: augmentation of tyrosine hydroxylase-positive fiber staining and dopamine content in host systems.

Previous studies of rats in our laboratory indicate that a molecule or molecules released by Schwann cells exert survival and growth-promoting effects on mesencephalic dopamine neurons. In the present study, we have begun to investigate the potential for Schwann cell augmentation of host dopamine fiber systems and embryonic dopamine neuron grafts in non-human primates. Ten adult male St Kitts African Green monkeys treated with the dopaminergic neurotoxin 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine one year previously, but behaviorally asymptomatic, served as hosts for implant studies. A segment of young adult monkey saphenous nerve was collected to serve as an implanted tissue source of Schwann cell-derived growth factors. Nerve was enclosed in a hollow semi-permeable polymer fiber for implantation into the lateral ventricle, with embryonic ventral mesencephalic tissue co-grafts containing developing dopamine neurons aimed at nearby locations in the caudate nucleus. Control implants consisted of an empty polymer fiber co-grafted with embryonic ventral mesencephalon. Our morphological observations indicate that while no clear augmentation of the morphology of grafted dopamine neurons attributable to co-grafted nerve was observed, this lack of influence may be related to the spatial separation of the co-grafted tissues. In contrast, some monkeys with nerve segments in the lateral ventricle exhibited increased tyrosine hydroxylase-positive fiber staining in the immediately adjacent lateral septal area and the ventricular wall of the caudate nucleus. This enhancement was not associated with empty polymer implants. Levels of dopamine and its metabolite homovanillic acid derived from tissue punches in the caudate nucleus and septal area support the view that monkeys exhibiting morphological enhancement of host dopamine systems also show biochemical increases in dopamine levels and changes in the direction of normalization of the homovanillic acid/dopamine ratio. Biochemical values from a single septal area tissue punch in one animal were an exception to this rule. This study suggests that while the utility of peripheral nerve as a source of dopamine graft augmentation in non-human primates remains to be demonstrated, grafted nerve has a stimulatory effect on host brain dopamine systems in adult, dopamine-depleted monkeys, and that this morphological effect can be dissociated from previously hypothesized injury-induced regeneration.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2003

Afferent modulation of dopamine neuron firing differentially regulates tonic and phasic dopamine transmission.

The mesolimbic dopamine system is centrally involved in reward and goal-directed behavior, and it has been implicated in multiple psychiatric disorders. Understanding the mechanism by which dopamine participates in these activities requires comprehension of the dynamics of dopamine release. Here we report dissociable regulation of dopamine neuron discharge by two separate afferent systems in rats; inhibition of pallidal afferents selectively increased the population activity of dopamine neurons, whereas activation of pedunculopontine inputs increased burst firing. Only the increase in population activity increased ventral striatal dopamine efflux. After blockade of dopamine reuptake, however, enhanced bursting increased dopamine efflux three times more than did enhanced population activity. These results provide insight into multiple regulatory systems that modulate dopamine system function: burst firing induces massive synaptic dopamine release, which is rapidly removed by reuptake before escaping the synaptic cleft, whereas increased population activity modulates tonic extrasynaptic dopamine levels that are less influenced by reuptake.

Afferent Pathways↗