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PubMed2000

Time-course and dose-response study on the effects of chronic L-DOPA administration on striatal dopamine levels and dopamine transporter following MPTP toxicity.

Despite a long-lasting therapeutic use of L-DOPA in Parkinson's disease, doubts still remain concerning the possibility that chronic L-DOPA might accelerate the progression of this movement disorder. To address this point, in the present study we examined the effects of chronic L-DOPA administration either in intact or MPTP-treated parkinsonian mice. We produced an intermediate striatal dopamine loss by administering a low dose of MPTP (30 mg/kg); then, we treated mice chronically, for different time intervals, with a daily dose of L-DOPA (50 mg/kg). In particular, to study the time-course of the effects of L-DOPA on the recovery of nigrostriatal dopamine axons, mice were sacrificed at 5, 30, 60, and 90 days after a daily L-DOPA administration. To evaluate presynaptic integrity of the nigrostriatal pathway we measured dopamine, metabolite levels, and dopamine uptake sites. In the same animals, we measured striatal serotonin levels and we analysed monoamine content in the olfactory bulb. Administration of MPTP produced a neurotoxic effect, which fully recovered in 2-3 months. Daily L-DOPA administration did not modify this recovery process. Additionally, there was no significant effect of L-DOPA in intact mice, despite a slight decrease in striatal dopamine levels at 5 and 30 days. However, this effect was neither worsened nor reproduced by administering higher doses of L-DOPA (up to 400 mg/kg) for the same amount of time. These data rule out neurotoxic effects induced by prolonged L-DOPA administration, both in intact and MPTP-treated mice. Moreover, administration of L-DOPA does not change the recovery process which takes place after a nigrostriatal lesion.

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

PubMed1994

Ascorbic acid inhibits 125I-SCH 23982 binding but increases the affinity of dopamine for D1 dopamine receptors.

Effects of ascorbic acid (AA) on 125I-SCH 23982 binding to D1 dopaminergic receptors in membrane preparations from rat striatum were investigated. AA in the range of 0.03 microM-0.33 mM inhibited 75% of specific binding of 125I-SCH 23982 in a dose-dependent manner. At higher concentrations, this inhibition of binding activity by AA was less potent, and 3.3 mM AA inhibited only 30% of specific binding. Reduced glutathione did not alter the inhibition of binding by 0.33 mM AA, but reduced the inhibition by 3.3 mM AA to 8% of specific binding. The loss of specific binding by AA was rescued by 1 mM EDTA, an inhibitor of lipid peroxidation. In the absence of AA, competition experiments with the agonist, dopamine, revealed the presence of high-affinity (Kh = 224.9 +/- 48.9 nm) and low-affinity (Kl = 21,100 +/- 2,400 nM) binding sites. Although the maximum binding of 125I-SCH 23982 decreased to 40% without affecting the KD value in the presence of 1.67 mM AA, the value of the high-affinity site for dopamine was increased (Kh = 23.3 +/- 9.4 nM) and that of the low-affinity site was decreased (Kl = 136,800 +/- 40,900 nM). These results suggest that AA may affect D1 dopamine receptor function by lipid peroxidation, competition with dopamine for low-affinity sites, and reduced oxidation of dopamine.

Animals↗

PubMed1998

Carrier-mediated release, transport rates, and charge transfer induced by amphetamine, tyramine, and dopamine in mammalian cells transfected with the human dopamine transporter.

Amphetamine and related substances induce dopamine release. According to a traditional explanation, this dopamine release occurs in exchange for amphetamine by means of the dopamine transporter (DAT). We tested this hypothesis in human embryonic kidney 293 cells stably transfected with the human DAT by measuring the uptake of dopamine, tyramine, and D- and L-amphetamine as well as substrate-induced release of preloaded N-methyl-4-[3H]phenylpyridinium ([3H]MPP+). The uptake of substrates was sodium-dependent and was inhibited by ouabain and cocaine, which also prevented substrate-induced release of MPP+. Patch-clamp recordings revealed that all four substrates elicited voltage-dependent inward currents (on top of constitutive leak currents) that were prevented by cocaine. Whereas individual substrates had similar affinities in release, uptake, and patch-clamp experiments, maximal effects displayed remarkable differences. Hence, maximal effects in release and current induction were approximately 25% higher for D-amphetamine as compared with the other substrates. By contrast, dopamine was the most efficacious substrate in uptake experiments, with its maximal initial uptake rate exceeding those of amphetamine and tyramine by factors of 20 and 4, respectively. Our experiments indicate a poor correlation between substrate-induced release and the transport of substrates, whereas the ability of substrates to induce currents correlates well with their releasing action.

Amphetamine↗

PubMed2001

Direct binding and functional coupling of alpha-synuclein to the dopamine transporters accelerate dopamine-induced apoptosis.

Mutations in alpha-synuclein, a protein highly enriched in presynaptic terminals, have been implicated in the expression of familial forms of Parkinson's disease (PD) whereas native alpha-synuclein is a major component of intraneuronal inclusion bodies characteristic of PD and other neurodegenerative disorders. Although overexpression of human alpha-synuclein induces dopaminergic nerve terminal degeneration, the molecular mechanism by which alpha-synuclein contributes to the degeneration of these pathways remains enigmatic. We report here that alpha-synuclein complexes with the presynaptic human dopamine transporter (hDAT) in both neurons and cotransfected cells through the direct binding of the non-A beta amyloid component of alpha-synuclein to the carboxyl-terminal tail of the hDAT. alpha-Synuclein--hDAT complex formation facilitates the membrane clustering of the DAT, thereby accelerating cellular dopamine uptake and dopamine-induced cellular apoptosis. Since the selective vulnerability of dopaminergic neurons in PD has been ascribed in part to oxidative stress as a result of the cellular overaccumulation of dopamine or dopamine-like molecules by the presynaptic DAT, these data provide mechanistic insight into the mode by which the activity of these two proteins may give rise to this process.

Apoptosis↗

PubMed1995

Dopamine D3 receptor antisense influences dopamine synthesis in rat brain.

Intracerebroventricular infusion of an all-phosphorothioate antisense oligodeoxynucleotide targeted at the rat dopamine D3 receptor mRNA (10 micrograms h-1, 5 days) resulted in a significant reduction (19%) of the binding of the [D2 + D3] ligand [3H]spiperone in the limbic forebrain, where D3 receptors are relatively abundant, but not in caudate-putamen, where D3 receptors are sparse. In nucleus accumbens antisense treatment also caused an increase in dopamine synthesis; in contrast, antisense administration did not counteract the effect of apomorphine on dopamine formation. No effect of antisense administration on dopamine synthesis was observed in caudate-putamen. The results support the usefulness of the antisense strategy for the study of D3 receptors and suggest that D3 receptors may influence dopamine synthesis.

Animals↗

PubMedDate not supplied

Effects of dopamine receptor agonists and antagonists at peripheral neuronal and vascular dopamine receptors in the anaesthetised dog.

The interactions between several putative dopamine receptor agonists and antagonists have been examined at neuronal and vascular dopamine receptors in the femoral and mesenteric vascular beds, respectively, of anaesthetised dogs. N,N-di-n- propyldopamine (DPDA) and apomorphine caused vasodilatation in both vascular beds. Cis alpha-flupenthixol, fluphenazine, and sulpiride were much more potent at antagonising DPDA at neuronal than at vascular dopamine receptors. Fluphenazine and sulpiride were as potent against apomorphine as against DPDA at neuronal receptors, but cis alpha-flupenthixol was much less effective. Fluphenazine antagonised the vasodilator effect of apomorphine in the mesenteric vascular bed, but cis alpha-flupenthixol and sulpiride did not, even when used in doses much larger than were effective against DPDA. Further experiments, in dogs pretreated with phenoxybenzamine and propranolol, revealed that cis alpha-flupenthixol, fluphenazine, and sulpiride also antagonised the mesenteric vasodilator effects of dopamine, 2-amino-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene, 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene, and 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine, suggesting a common site of action of these drugs and DPDA. Only fluphenazine antagonised responses to apomorphine. The results support the view that neuronal and vascular dopamine receptors in the dog are different. They also show that apomorphine stimulates different receptors from DPDA in the mesenteric vascular bed and, perhaps, in the femoral vascular bed as well.

Anesthesia↗

PubMed2004

Dopamine under alpha1-blockade, but not dopamine alone or fenoldopam, increases depressed gastric mucosal oxygenation.

OBJECTIVE: To compare the effects of dopamine, both in the presence and absence of alpha1-blockade, and fenoldopam on microvascular gastric mucosal oxygenation and systemic oxygen transport under compromised circulatory conditions, both without and with fluid resuscitation. DESIGN: Randomized controlled animal study. SETTING: University department of anesthesiology. SUBJECTS: Eight anesthetized dogs with chronically implanted ultrasound flow probes around the pulmonary artery for continuous measurement of cardiac output. INTERVENTIONS: On different days, the dogs received in random order either dopamine (2.5 and 5.0 microg.kg(-1).min(-1), with or without alpha1-blocker pretreatment), the selective DA1-agonist fenoldopam (0.1 and 1.0 microg.kg(-1).min(-1), with and without DA1-blocker pretreatment), or saline (control). These interventions were performed under compromised cardiocirculatory conditions (induced by ventilation with positive end-expiratory pressure [PEEP] of 10 cm H2O), both without and with fluid resuscitation. MEASUREMENTS AND MAIN RESULTS: We continuously measured regional microvascular hemoglobin saturation (microHbO2) in gastric mucosa by reflectance spectrophotometry and systemic oxygen transport ([U1E0A]O2). Ventilation with PEEP significantly decreased [U1E0A]O2 (from 19 +/- 2 to 9 +/- 1 mL.kg(-1).min(-1), mean +/- sem) and gastric mucosal microHbO2 (from 57 +/- 2% to 37 +/- 3%). Fluid resuscitation restored [U1E0A]O2 back to baseline (from 9 +/- 1 to 19 +/- 2 mL.kg(-1).min(-1)) but only partially restored microHbO2 (from 37 +/- 3% to 50 +/- 4%). Under both conditions, dopamine with and without alpha1-blockade significantly increased [U1E0A]O2 (by about 5 mL.kg-1.min-1 in the nonresuscitated state and 10 mL.kg-1.min-1 in the fluid resuscitated state, respectively), but only dopamine in the presence of alpha1-blockade also significantly increased gastric mucosal microHbO2 (by 5 +/- 1% and 7 +/- 2% in the nonresuscitated and fluid resuscitated states, respectively). Fenoldopam under all study conditions did not significantly affect [U1E0A]O2 or microHbO2, either in the presence or absence of DA1-blockade. CONCLUSIONS: During compromised cardiocirculatory conditions, alpha1-receptor activation during dopamine infusion prevented an increase in gastric mucosal oxygenation. Furthermore, selective DA1-stimulation (by fenoldopam) was insufficient to overcome the PEEP-induced depression of microHbO2. The responses of gastric mucosal oxygenation did not parallel changes in systemic oxygen transport. These findings were independent of fluid resuscitation.

Animals↗

PubMed1979

Dopamine auto- and postsynaptic receptors: electrophysiological evidence for differential sensitivity to dopamine agonists.

The responses of dopamine cells in the substantia nigra to iontophoretically administered dopamine and intravenous apomorphine were compared to the responses of spontaneously active neurons in the caudate nucleus. Dopaminergic cells were six to ten times more sensitive to dopamine and intravenous apomorphine than 86 percent of the caudate cells tested. This differential sensitivity of dopamine auto- and postsynaptic receptors may explain the apparently paradoxical behavioral effects induced by small compared to large doses of some dopamine agonists and may provide a means of developing new types of drugs to antagonize dopaminergic influence in the central nervous system.

Action Potentials↗

PubMed1982

Effects of estradiol on intact and denervated striatal dopamine receptors and on dopamine levels: a biochemical and behavioral study.

The present study describes the effect of chronic estrogen treatment on striatal dopamine levels and dopamine receptors, as well as on apomorphine-induced circling, a behavioral model reflecting dopaminergic activity in the rat striatum. Although estradiol itself does not show any affinity for the striatal dopamine receptor, its administration for 2 weeks in adult ovariectomized rats leads to a small increase in [3H]spiroperidol, [3H]haloperidol, and [3H]apomorphine binding in the striatum; this increase is associated with a greater number of binding sites. In order to dissociate possible pre- and post-synaptic effects of estrogens, these studies were next performed in animals bearing an unilateral 6-hydroxydopamine lesion of the substantia nigra. The apomorphine-induced circling behavior of rats bearing such a lesion was not affected by estrogen treatment. Estradiol treatment induced an increase of [3H]spiroperidol binding in both the intact and lesioned striatum, thus suggesting an estrogenic effect on a population of postsynaptic receptors. Chronic estradiol treatment reduced the concentration of dopamine in the striatum while the turnover of this amine measured using alpha-methyl-p-tyrosine remained unchanged. The present results show that estradiol exerts effects at the striatal level on both dopamine metabolism and receptor levels.

Animals↗

PubMed2003

D1 dopamine receptor supersensitivity in the dopamine-depleted striatum animal model of Parkinson's disease.

Dopamine acts in the striatum principally through the D1 and D2 dopamine receptor subtypes, which are segregated to the direct and indirect striatal projection neurons, respectively. As a consequence, degeneration of the dopamine input to the striatum results in opposing affects in these pathways. The resulting functional imbalance is thought to be responsible for the bradykinesia of Parkinson's disease, which may be temporarily normalized by dopamine replacement therapy. However, direct striatal projection neurons become irreversibly supersensitive to D1 dopamine receptor activation, despite the fact that there is an actual decrease in receptor number. Recent studies show that this D1 -supersensitive response results from a switch from the normal D1-mediated activation of protein-kinase A to an aberrant activation of ERK1/2/MAPkinase. This switch in D1-receptor-mediated regulation of protein kinase systems responsible for neuronal plasticity is suggested to underlie dyskinesia produced by L-DOPA treatment of Parkinson's disease.

Animals↗

PubMed2005

Frontal and temporal dopamine release during working memory and attention tasks in healthy humans: a positron emission tomography study using the high-affinity dopamine D2 receptor ligand [11C]FLB 457.

Experimental studies on animals have shown that dopamine is a key neurotransmitter in the regulation of working memory (WM) functions in the prefrontal cortex. In humans, blood flow studies show prefrontal involvement in WM functions, but direct evidence for the involvement of the dopaminergic system in WM is lacking. Using positron emission tomography with a recently developed high-affinity dopamine D2 receptor tracer, [11C]FLB 457, we explored frontal, temporal, and parietal D2 receptor availability in 12 healthy volunteers while they were performing verbal WM and sustained attention tasks. During the performance of both tasks, reduced D2 receptor availability was observed in the left ventral anterior cingulate, suggesting an attention or arousal-related increase in dopamine release during these tasks. Compared with the sustained attention task, the verbal WM task reduced D2 receptor availability in the ventrolateral frontal cortex bilaterally and in the left medial temporal structures (amygdala, hippocampus), suggesting that dopamine release in these regions might have a specific role in WM. In addition, correlation analyses indicated that increased dopamine release in the right ventrolateral frontal cortex and the left ventral anterior cingulate during the WM task was associated with faster and more stable WM performance, respectively. Our results indicate that regionally specific components of the frontotemporal dopaminergic network are functionally involved in WM performance in humans.

Adult↗

PubMed2002

Peroxynitrite inactivates the human dopamine transporter by modification of cysteine 342: potential mechanism of neurotoxicity in dopamine neurons.

Peroxynitrite (ONOO(-)) has been implicated as a causative factor in dopamine neuronal damage resulting from exposure to methamphetamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and it may be involved in the etiology of Parkinson's Disease. ONOO(-) causes a concentration-dependent and irreversible reduction in dopamine uptake by EM4 cells stably expressing the human dopamine transporter (hDAT). The effect of ONOO(-) is manifested as a reduction in V(max). Cysteine, dithiothreitol, glutathione, and N-acetyl-cysteine, reagents that interact directly with ONOO(-), prevent this inhibition, whereas a scavenger of hydroxyl radical (dimethylsulfoxide), hydrogen peroxide (catalase), and superoxide (superoxide dismutase) did not. Dopamine in the extracellular medium protects the hDAT from ONOO(-), whereas intracellular dopamine does not. Parachloromercuribenzoic acid and 2-aminoethyl methanethiosulfonate (MTSEA), which share with ONOO(-) the ability to modify cysteine sulfhydryls, also inhibit hDAT function. ONOO(-) treatment lowers cysteine-specific labeling of the hDAT by MTSEA-biotin, suggesting that ONOO(-) reacts with one or more cysteines in hDAT. A mutant of hDAT (X7C) in which all intracellular and extracellular loop cysteines were mutated was resistant to inhibition by ONOO(-). Sensitivity to ONOO(-) was restored in mutants of hDAT in which reduced cysteines were present only in the first (C135) and third (C342) intracellular loops (CD-DAT), or in which C342 alone had been reintroduced into X7C (X7C-M342C). These results indicate that the hDAT is inhibited by ONOO(-) through oxidation of cysteine 342. Our studies also substantiate the possibility that drugs known to decrease DAT function in vivo (e.g., methamphetamine and MPTP) may exert their effects through ONOO(-)-mediated oxidative stress.

Antioxidants↗

PubMed1990

[The effect of the simultaneous dopamine- and glutamatergic stimulation of the nucleus accumbens on synaptic dopamine release in the striatum of freely moving rats].

The influence of n. accumbens on the striatal synaptic dopamine release was investigated in freely moving male Sprague-Dawley rats using in vivo intracranial dialysis followed by radioenzymatic analysis. It was shown that amphetamine or glutamic acid dialysis infusion in the n. accumbens resulted in a decrease in striatal extracellular dopamine level while simultaneous infusion of these drugs led to increase in striatal level of extracellular dopamine. It is suggested that there exist an influence of the n. accumbens on dopamine release in the striatum, the sign of this influence being mediated by dopamine-glutamic acid interaction in the n. accumbens.

Amphetamine↗

PubMed1990

Clinical, autonomic and therapeutic observations in two siblings with postural hypotension and sympathetic failure due to an inability to synthesize noradrenaline from dopamine because of a deficiency of dopamine beta hydroxylase.

A brother and sister with long-standing symptoms of postural hypotension are described. They were considerably worse in the morning, after exercise and in warm weather. In the male, erection was unaffected but ejaculation was prolonged or absent. Both had nocturia, but there were no urinary bladder, bowel or sweating abnormalities. Autonomic function tests confirmed sympathetic adrenergic failure with spared sympathetic cholinergic and intact parasympathetic function. There were no other neurological abnormalities. Noradrenaline and adrenaline were undetectable in the plasma, but plasma dopamine was elevated. Urinary levels of noradrenaline and adrenaline metabolites were below detection limits, but dopamine metabolites were normal or elevated. Dopamine beta-hydroxylase activity was undetectable in the plasma. Immunohistochemical studies of perivascular cutaneous tissue confirmed normal peptidergic and tyrosine hydroxylase immunoreactivity, with absent dopamine beta-hydroxylase immunoreactivity. The findings were consistent with an enzymatic deficit in the conversion of dopamine to noradrenaline. The parents were clinically and biochemically normal. Treatment of both patients with the synthetic amino acid, d-l-threo-dihydroxyphenylserine, which contains a hydroxyl group and is converted to noradrenaline by dopa-decarboxylase, reduced symptoms and signs of postural hypotension and increased levels of plasma noradrenaline and its urinary metabolites. In the male, ejaculation became possible. Behavioural changes included a feeling of confidence and optimism, with a tendency to be argumentative. The laevo isomer also raised blood pressure and plasma noradrenaline levels. The drug had no direct pressor effects, as its actions were prevented by the dopa-decarboxylase inhibitor, carbidopa.

Adult↗

PubMed1987

Comparison of the effects of the novel inotropic agent, ibopamine, with epinine, dopamine and fenoldopam on renal vascular dopamine receptors in the anesthetized dog.

The effect of i.v. administration of the novel, p.o. active inotropic prodrug, ibopamine, on canine renal vascular dopamine DA-1 receptors was determined in the anesthetized dog. These effects were compared with those produced by the active form of ibopamine, epinine, and with the standard DA-1 receptor agonists, dopamine and fenoldopam. After pretreatment of pentobarbital-anesthetized dogs with phenoxybenzamine (10 mg/kg i.v.) and propranolol (2 mg/kg i.v.) to block alpha and beta adrenoceptor-mediated effects, respectively, the renal blood flow responses to i.v. administration of ibopamine, epinine, dopamine and fenoldopam were determined before and after selective blockade of DA-1 receptors by i.v. infusion of SK&F R-83566 (0.5 microgram/kg/min). Under control conditions, ibopamine produced a dose-dependent increase in renal blood flow as a result of renal vasodilation (i.e., decrease in renal vascular resistance), and was approximately 10-fold less potent than epinine in this respect. Epinine elicited qualitatively similar renal hemodynamic changes to ibopamine with the exception of potency. Dopamine was approximately equipotent with epinine as a renal vasodilator, and both compounds were 10-fold less potent than fenoldopam. Concurrent with the renal vasodilation produced by all four compounds, there was a reduction in mean arterial blood pressure and total peripheral vascular resistance. After the administration of SK&F R-83566, the renal vasodilator responses to fenoldopam were antagonized markedly with an approximate 30-fold rightward shift in the log dose-response curve, whereas the renal vasodilator responses to dopamine were abolished completely and converted into small vasoconstrictor responses.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗

PubMed1986

Blockade of D-2 dopamine receptors strongly enhances the potency of enkephalins to inhibit dopamine-sensitive adenylate cyclase in rat neostriatum: involvement of delta- and mu-opioid receptors.

The interactions between dopamine receptors and opioid receptors coupled to adenylate cyclase in rat neostriatum were investigated. cAMP efflux from neostriatal slices induced by simultaneous activation of (stimulatory) D-1 and (inhibitory) D-2 dopamine receptors with 30 microM dopamine was inhibited by the preferential delta-opioid receptor agonist [D-Ala2-D-Leu5] enkephalin (DADLE) and the mu-opioid receptor agonist morphine with an EC50 of 100 and 800 nM, respectively. On selective D-1 receptor activation (i.e., with D-2 receptors blocked by 10 microM (-)sulpiride), the EC50 of DADLE was strongly reduced to 3 nM, whereas that of morphine was unaffected. When D-1 and D-2 receptors were activated simultaneously, the inhibitory effects of DADLE (0.3 microM) and morphine (3 microM) on cAMP efflux were antagonized equally well by naloxone, a mu-opioid receptor antagonist. In contrast, on selective D-1 receptor activation, naloxone was about 20 times more potent in antagonizing the inhibitory effect of morphine than DADLE. Moreover, the delta-opioid receptor antagonist ICI 174864 (0.75 microM) did not affect the inhibitory effect of morphine but antagonized that of DADLE, provided that D-2 receptors were blocked. The highly selective delta-opioid receptor agonist [D-Pen2-D-Pen5] enkephalin (DPDPE) inhibited dopamine-stimulated cAMP efflux only when D-2 receptors were blocked. Similar results were obtained when the agonists SKF 38393 and LY 141865 were used to activate D-1 and D-2 receptors, respectively. These data indicate that blockade of D-2 receptors in the neostriatum elicits the coupling of delta-opioid receptors to dopamine-sensitive adenylate cyclase, thereby making it considerably more sensitive to inhibition by the enkephalins.

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

PubMed1986

Dopamine enhances terminal excitability of hippocampal-accumbens neurons via D2 receptor: role of dopamine in presynaptic inhibition.

The effects of dopamine on the axonal terminals of hippocampal-nucleus accumbens (HIPP-ACC) neurons were investigated in urethane-anesthetized rats using extracellular single-unit recording techniques. Antidromic responses recorded in the ventral subiculum of the hippocampus were evoked by stimulation of the medial accumbens. Baseline terminal excitability of these neurons, established by threshold stimulation of the accumbens, was markedly enhanced by conditioning stimulation (10 Hz) of the ventral tegmental area (VTA), the origin of the mesolimbic dopaminergic neurons. Iontophoretic application of sulpiride, a selective D2 antagonist, onto the HIPP-ACC terminals attenuated the increased terminal excitability of these neurons produced by conditioning VTA stimulation, while intraperitoneal injection of SCH23390, a selective D1 antagonist, failed to attenuate this effect. Iontophoretic application of dopamine or its selective D2 agonist, LY171555, onto the terminals of the HIPP-ACC neurons mimicked the prolonged enhancement of the terminal excitability produced by VTA stimulation, whereas SKF38393, a D1 agonist, had no effect. The effects of VTA stimulation, dopamine and LY171555 application were similar after the accumbens had been pretreated with ibotenic acid, suggesting a direct action of dopamine on the axonal terminals of HIPP-ACC neurons, and that changes in terminal excitability were not mediated via interneurons or feedback pathways from the accumbens to the hippocampus. Since iontophoretic application of potassium, a depolarizing agent, also enhanced the terminal excitability of the HIPP-ACC neurons, it appears that dopamine depolarized, via D2 receptors, the axonal terminals of HIPP-ACC neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1984

DARPP-32, a dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein enriched in dopamine-innervated brain regions. III. Immunocytochemical localization.

Immunocytochemical studies have been carried out to determine the regional and cellular distribution of DARPP-32, a protein the phosphorylation of which can be regulated by dopamine and cAMP in intact cells. These immunocytochemical studies indicate tha DARPP-32 is localized primarily in those brain regions enriched in dopaminergic nerve terminals. Moreover, the staining pattern supports the conclusion that the DARPP-32 is present in dopaminoceptive neurons, i.e., neurons that receive a dopamine input, and that it is absent from the dopaminergic neurons themselves. Within the caudatoputamen, nucleus accumbens, olfactory tubercle, bed nucleus of the stria terminalis, and portions of the amygdaloid complex, all of which receive a strong dopamine input, DARPP-32 immunoreactivity is present in neuronal cell bodies and dendrites. In brain regions that are known to receive projections from these nuclei, puncta (presumed nerve terminals) are strongly immunoreactive for DARPP-32 but indigenous cell bodies and dendrites are not immunoreactive. These target areas include the globus pallidus, ventral pallidum, entopeduncular nucleus, and the pars reticulata of the substantia nigra. No immunoreactivity is detected in neuronal cell bodies or dendrites in any of the dopaminergic nuclei. Furthermore, nerve terminals immunoreactive for DARPP-32 do not resemble dopaminergic varicosities in either their morphology or their pattern of distribution. Many neurons are weakly immunoreactive for DARPP-32 and some of these are found in areas that apparently lack a dopaminergic input: weakly labeled neuronal cell bodies and dendrites were found throughout the neocortex, primarily in layer VI, and in the Purkinje neurons of the cerebellum. DARPP-32 immunoreactivity is also present in certain glial cells, especially in the median eminence, arcuate nucleus, and medial habenula. The present immunocytochemical studies, taken together with biochemical studies (Hemmings, H.C., Jr., A.C. Nairn, D.W. Aswad, and P. Greengard (1984) J. Neurosci. 4: 99-110; Walaas, S.I., and P. Greengard (1984) J. Neurosci. 4: 84-98) on DARPP-32, indicate that DARPP-32, is present in the subclass of dopaminoceptive neurons containing D-1 receptors (dopamine receptors coupled to adenylate cyclase). DARPP-32 may be an effective marker for certain of the actions of dopamine that are mediated through cAMP and its associated protein kinase.

Animals↗