Release Of Endogenous Dopamine Research Articles

Cocaine and Amphetamine Depress Striatal GABAergic Synaptic Transmission through D2 Dopamine Receptors

The striatum is a brain area implicated in the pharmacological action of drugs of abuse. To test the possible involvement of both cocaine and amphetamine in the modulation of synaptic transmission in this nucleus, we coupled whole-cell patch clamp recordings from striatal spiny neurons to the focal stimulation of glutamatergic or GABAergic nerve terminals. We found that neither cocaine (1–600 μM) nor amphetamine (0.3–300 μM) significantly affected the glutamate-mediated EPSCs recorded from these cells. Conversely, both pharmacological agents depressed GABA-mediated IPSCs in a dose-dependent manner. This effect was mediated by the stimulation of dopamine (DA) D2 receptors since it was prevented by 3 μM L-sulpiride (a DA D2-like receptor antagonist), mimicked by the DA D2-like receptor agonist quinpirole (0.3–30 μM), and absent in mice lacking DA D2 receptors. A presynaptic mechanism was likely involved in this action since both cocaine and amphetamine depress GABAergic transmission by increasing paired-pulse facilitation. Cocaine and amphetamine failed to affect GABAergic IPSCs after 6-OHDA-induced nigral lesion, indicating that both drugs cause their effects through the release of endogenous DA. The modulation of GABAergic synaptic transmission in the striatum might underlie some motor and cognitive effects of psychostimulants in mammalians.

The power of belief

l-Dopa and apomorphine are active drugs used in the treatment of patients suffering from Parkinson's disease (PD), a neurodegenerative disease in which the dopaminergic pathway involved in the regulation of behavioral and sensorimotor functions is severely impaired. The mechanisms involved are still poorly understood; however, a recent study has demonstrated that the level of expectation of benefit from treatment might influence and enhance the endogenous release of dopamine from the nigralstriatal pathway independently of the efficacy of the drug. In order to evaluate the power of the placebo effect in PD, researchers have studied the binding of the competitive dopamine receptor ligand [11C] raclopride by PET scanning. Patients receiving placebo or active drug showed comparably less binding of RAC in the striatum, indicating endogenous release of dopamine. The results published in Science (293, 1164–1166) highlight the importance of placebo controls in evaluating therapeutical intervention. SS

Histamine H1 receptor-mediated inhibition of potassium-evoked release of 5-hydroxytryptamine from mouse forebrains

The release of endogenous serotonin and dopamine from slices of mouse forebrains induced by high extracellular K + was examined in histamine H1 receptor knockout mice. The release of 5-hydroxytryptamine (5-HT) evoked by 30 mM K + significantly decreased in the presence of 10–50 μM histamine in wild-type mice, but was not inhibited in the mutant mice. Histamine H1 receptor-mediated inhibition of serotonin release in wild-type mice was also observed in the presence of thioperamide, an H3 antagonist. From these data, we postulate that endogenous histamine indirectly inhibits the release of 5-HT through H1 receptors in addition to H3 receptors. The treatment of 2 μM tetrodotoxin could partly abolish the effects of histamine on K +-evoked 5-HT release. Bicuculline, a GABA A antagonist, could reverse the histamine-induced inhibition of 5-HT release in wild-type mice, suggesting that H1 receptors facilitate the release of GABA, which in turn inhibits 5-HT release through GABA A receptors. The difference in the effects of d- and l-chlorpheniramine on K +-evoked 5-HT release in wild-type mice further supports the evidence of the function of H1 receptor modulating 5-HT release.

Apomorphine-induced changes in synaptic dopamine levels: positron emission tomography evidence for presynaptic inhibition.

The authors developed a novel positron emission tomography method to estimate changes in the synaptic level of dopamine ([DA]) induced by direct dopamine agonists (for example, apomorphine) in patients with Parkinson disease. The method is based on the typical asymmetry of the nigrostriatal lesion that often occurs in Parkinson disease. Using the between-side difference (ipsilateral (I) and contralateral (C) putamen to the more affected body side) of the inverse of the putamen [11C]raclopride binding potential (BP), the authors obtained [equation: see text] at baseline (that is, before apomorphine administration) and [equation: see text] after apomorphine administration (assuming the concentration of apomorphine is equal in both putamina). The between-side difference in the estimated synaptic concentration of dopamine (diff[DA]) should remain constant unless apomorphine affects dopamine release differently between the two sides. The authors found that apomorphine given subcutaneously at doses of 0.03 and 0.06 mg/kg induced significant changes in their estimate of diff[DA] (P < 0.05). Such changes were more pronounced when only patients with a stable response to levodopa were considered (P < 0.01). These findings provide in vivo evidence that direct dopamine agonists can inhibit the release of endogenous dopamine. The authors propose that this effect is mainly mediated by the activation of presynaptic D2/D3 dopamine receptors.

11C]Raclopride binding was reduced in vivo by sigma1 receptor ligand SA4503 in the mouse brain, while [11C]SA4503 binding was not by raclopride

[11C]Raclopride is widely used as a representative dopamine D2-like receptor ligand in positron emission tomography (PET) studies, and [11C]1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride ([11C]SA4503) is a recently developed selective ligand for mapping sigma1 receptors in the brain. The striatal uptake of [11C]raclopride in mice was reduced by co-injection of an excess amount of SA4503, in spite of the fact that raclopride had no effect on the brain uptake of [11C]SA4503 as shown in a previous study. The blocking effect of SA4503 on the striatal uptake of [11C]raclopride was dose-dependent, but disappeared by 1 h or 6 h after intraperitoneal injection of SA4503. The brain uptake of [11C]SA4503 was not affected by a dopamine transporter inhibitor GBR 12909, nor was [11C]β-CIT-FP inhibited by SA4503. The IC50 values of raclopride for sigma1 and sigma2 receptor subtypes measured in vitro were 11800 nM and 4950 nM, respectively, suggesting that the affinity was too low for [11C]raclopride to bind in vivo to sigma receptors. On the other hand, the IC50 value of SA4503 for dopamine D2 receptors was 470 nM, that is approximate 1/25 of the affinity of raclopride for the dopamine D2 receptors. Therefore, possible explanations for the partial blocking effects of SA4503 on the striatal uptake of [11C]raclopride are: (1) an excess amount of SA4503 may reduce the [11C]raclopride uptake due to its low affinity for dopamine D2 receptors, or (2) SA4503 may enhance endogenous dopamine release, which results in the competitive inhibition of the [11C]raclopride uptake. These findings support that both [11C]raclopride and [11C]SA4503 are selective in vivo ligands for dopamine D2-like receptors and sigma1 receptors, respectively, in spite of the partial blocking effect of SA4503 on the striatal uptake of [11C]raclopride.

Expectation and Dopamine Release: Mechanism of the Placebo Effect in Parkinson's Disease

The power of placebos has long been recognized for improving numerous medical conditions such as Parkinson's disease (PD). Little is known, however, about the mechanism underlying the placebo effect. Using the ability of endogenous dopamine to compete for [11C]raclopride binding as measured by positron emission tomography, we provide in vivo evidence for substantial release of endogenous dopamine in the striatum of PD patients in response to placebo. Our findings indicate that the placebo effect in PD is powerful and is mediated through activation of the damaged nigrostriatal dopamine system.

Repetitive Transcranial Magnetic Stimulation of the Human Prefrontal Cortex Induces Dopamine Release in the Caudate Nucleus

Dopamine is implicated in movement, learning, and motivation, and in illnesses such as Parkinson's disease, schizophrenia, and drug addiction. Little is known about the control of dopamine release in humans, but research in experimental animals suggests that the prefrontal cortex plays an important role in regulating the release of dopamine in subcortical structures. Here we used [(11)C]raclopride and positron emission tomography to measure changes in extracellular dopamine concentration in vivo after repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex in healthy human subjects. Repetitive TMS of the left dorsolateral prefrontal cortex caused a reduction in [(11)C]raclopride binding in the left dorsal caudate nucleus compared with rTMS of the left occipital cortex. There were no changes in binding in the putamen, nucleus accumbens, or right caudate. This shows that rTMS of the prefrontal cortex induces the release of endogenous dopamine in the ipsilateral caudate nucleus. This finding has implications for the therapeutic and research use of rTMS in neurological and psychiatric disorders.

Endogenous dopamine release during sequential movement in healthy volunteers and patients with Parkinson's disease: a PET study

Endogenous dopamine release during sequential movement in healthy volunteers and patients with Parkinson's disease: a PET study

Day/night variations of dopamine ocular content during Xenopuslaevis ontogeny

Concentration of dopamine (DA) and its metabolite, 3,4-dihydroxyphenylacetic acid is quantified by high-pressure liquid chromatography with a coulometric detection system in the eye of Xenopus laevis through ontogeny and in adults at two times during photocycle (midday and midnight). Ocular dopaminergic activity remains low during pre- and prometamorphosis and significantly rises in postmetamorphic froglets. This increase is more pronounced at midnight than at midday. The dualism of DA content versus DA release in Xenopus ocular tissue is studied in an eyecup culture system. On a 24-h cycle of DA release from adult Xenopus eyecups the highest DA release by eyecups is produced during daytime, and significantly decreases in darkness. From these results it can be concluded that in spite of the early development of the retinal dopaminergic system in the ontogeny of Xenopus, the final maturation must occur during the metamorphic climax. Endogenous DA release is significantly inhibited by light offset, which explains the higher ocular DA content found at midnight as compared to midday in postmetamorphic froglets and adults.

Sleep deprivation as a model experimental antidepressant treatment: findings from functional brain imaging.

This paper reviews the functional brain imaging studies in depressed patients treated with sleep deprivation. Sleep deprivation is an excellent experimental model of antidepressant treatments which offer new opportunities to understand the basic neural mechanisms. Its antidepressant effects are efficacious and rapid; sleep deprivation is easy to administer, inexpensive, and relatively safe; it can be studied in patients, normal controls, and animals; and it may lead to new treatments and new paradigms for antidepressant therapies. Seven published papers, coming from five different research centers, using either positron emission tomography (PET) with 18fluorodeoxyglucose (FDG) or single photon emission computerized tomography (SPECT) with Technetium-99-bexamethyl propyleneamine oxime (HMPAO) have relatively consistent findings. First, before sleep deprivation, responders have significantly elevated metabolism compared with non-responders, and usually the normal controls, in the orbital medial prefrontal cortex, and especially in the ventral portions of the anterior cingulate cortex. Secondly, after sleep deprivation, these hyperactive areas normalize in the responders. The magnitude of the clinical improvement was significantly correlated with decreased local glucose metabolic rate or cerebral blood flow in three studies. The results are consistent with some but not all functional brain imaging studies of antidepressant medications in depressed patients. Finally, a SPECT study using a radioactively labeled D2 receptor antagonist suggests that the antidepressant benefits of sleep deprivation are correlated with endogenous release of dopamine.

Dopamine transporter density in young patients with schizophrenia assessed with [ 123]FP-CIT SPECT

Disturbances in the dopamine (DA) system are thought to play a major role in schizophrenia. Amphetamine-induced release of endogenous DA is shown to be enhanced in schizophrenia, as is striatal [ 18F]FDOPA uptake in the striatum. It is not clear if the density of DA neurons is altered in schizophrenia. By studying the DA transporter with [ 123I]FP-CIT single photon emission computed tomography (SPECT), the density of nigrostriatal dopaminergic cells can be studied. Using [ 123I]FP-CIT SPECT, DA transporter density in the striatum was studied in 36 young patients with schizophrenia. Ten patients were antipsychotic (AP)-naive, 15 were treated with olanzapine, eight with risperidone and three were AP-free. A control group of 10 age-matched volunteers was included. Striatal [ 123I]FP-CIT binding was not significantly different between AP-naive patients (2.87), patients treated with olanzapine (2.76), patients treated with risperidone (2.76), AP-free patients (2.68) and controls (2.82) (F=0.07, p=0.98). Unexpectedly, striatal [ 123I]FP-CIT binding in females was significantly higher than in males (3.29 and 2.70, respectively; t=−2.56, p=0.014). Concluding, functional changes in the dopaminergic system in schizophrenia are not likely to be reflected in a change in DA transporter density. Moreover, DA transporter density does not seem to be altered by AP medication.

Haloperidol catalepsy consolidation in the rat as a model of neuromodulatory integration

Haloperidol, a non-selective D 2 dopamine antagonist, both in vitro (1 μM) and in vivo (2.5 mg/kg i.p.), induced a long-term potentiation of K +-induced Ca 2+-dependent release of endogenous noradrenaline and dopamine in rat brain cortical slices, by increasing the content of noradrenaline and dopamine known to be controlled by dopamine auto- and heteroreceptors. Haloperidol administration (2.5 mg/kg i.p.) evoked catalepsy and increased the content of noradrenaline and dopamine in the same structures of the brain. Haloperidol catalepsy consolidated without any additional learning and could be retrieved up to two weeks later by placing the animals in the test box. The catalepsy is disordered and retrieved only in the test box. The catalepsy was more intense on day 14 than on day 7. Injection of haloperidol immediately after conditioning evened the reflex retrieval on the following days. Moreover, learning increased the intensity of catalepsy in animals tested on the day of injection. Repeated testing of the reflex on the following days led to specific modifications of catalepsy retrieval. Pre-conditioned rats exhibited maximal catalepsy when tested immediately after being placed in the test box. These results suggest that both the processes of long-term potentiation and catalepsy consolidation are mediated by the same type of receptors, long-term modulation-inducing receptors. Endogenous neuromodulators, acting non-specifically or diffusely via their respective long-term modulation-inducing receptors, can initiate and consolidate generalized states which form the basis for emotional and motivational states.

Interaction between α-MSH and acetylcholinergic system upon striatal cAMP and IP 3 levels

The interaction between the neuropeptide α-MSH and the acetylcholinergic system as reflected by changes in cAMP and inositol 1–3-5 triphosphate(IP 3)production was investigated in an in vitro model of striatal slices. The possible involvement of D 1 receptors in cholinergic and α-MSH- stimulated cAMP and IP 3 production in slices of rat striatum was also examined, because it has been demonstrated that acetylcholinergic drugs induce endogenous dopamine release in the striatum. α-MSH, pilocarpine(PL) and the selective muscarinic M1 agonist McN-A-343 increased cAMP and IP 3 striatal levels, effects blocked by the D 1 antagonist SCH-23390, except for the effects of α-MSH on IP 3 .The muscarinic M 2 antagonist gallamine (GL) brought about an increase in cAMP levels, an effect blocked by SCH-23390. The M 1 antagonist pirenzepine (Pz) induced a decrease both in cAMP and IP 3 content, and the nicotinic antagonist di-hydro-β-eritroidine(DBE) only diminished cAMP production. When α-MSH and cholinergic agents were simultaneously added, cAMP and IP 3 levels were modified with respect to the values reached when these agents were added alone. An interaction between the acetylcholinergic system and α-MSH through M 1 and nicotinic receptors was also observed. These results suggest that the intracellular signaling pathways related to cAMP and IP 3 production gated by α-MSH and these cholinergic receptors are probably related. α-MSH striatum cAMP IP 3 muscarinic and nicotinic receptors an in vitro model.

P2 receptor-mediated inhibition of dopamine release in rat neostriatum

Axon terminal nucleotide P2 receptors mediating an inhibition of transmitter release have, so far, been detected in various sympathetically innervated tissues, 8,27 and on central noradrenergic, 14,26 glutamatergic 15 and serotonergic neurons. 28 We have now investigated the effect of ATP and related nucleotides on the release of endogenous dopamine from slices of rat neostriatum using fast cyclic voltammetry. Mutual interactions between the two neurotransmitters have been observed previously: ATP and related nucleotides induce a release of dopamine in PC12 pheochromocytoma cells, a frequently used model for sympathetic neurons; 10,22 they also increase the dopamine concentration in rat brain measured by in vivo microdialysis 16,32 and stimulate the uptake of dopamine by rat striatal synaptosomes. 3 Dopamine, in contrast, facilitates activation of ligand-gated cation channels (i.e. P2X 2 receptors) by ATP. 11,20 Here, we show that ATP and two of its analogues decrease the electrically evoked release of endogenous dopamine in rat neostriatum. The inhibitory effect of ATP is blocked by the P2 receptor antagonists suramin, reactive blue 2 and cibacron blue 3GA. Suramin, in addition, partly prevents the attenuation of dopamine release evoked by a single stimulus that follows a brief train of high-frequency pulses. These findings suggest the existence of release-inhibiting P2 receptors on dopaminergic nerve terminals and indicate that dopaminergic transmission in rat neostriatum might be modulated by an endogenous P2 receptor ligand, presumably ATP.

Simultaneous action of MK-801 (dizclopine) on dopamine, glutamate, aspartate and GABA release from striatum isolated nerve endings

The simultaneous effect of MK-801 on the baseline- and depolarization (20 μM veratridine or 30 mM high K +)-evoked release of endogenous dopamine, glutamate (Glu), aspartate (Asp), and GABA is investigated in the same preparation of rat striatum isolated nerve endings. MK-801, in the μM range, selectively increases the baseline and high K + depolarization-evoked release of dopamine, without causing any effect on the baseline or on the high K +-evoked release of Glu, Asp and GABA. In addition to this selective action on dopamine release, MK-801 inhibits the veratridine depolarization-evoked release of all the neurotransmitters tested, including dopamine. In SBFI and fura-2 preloaded striatal synaptosomes, MK-801 inhibits the elevation of internal Na + (Na i) and the elevation of internal Ca 2+ (Ca i) induced by veratridine depolarization. The elevation of Ca i induced by high K + depolarization is unchanged by MK-801. This study reveals two separate MK-801 actions. (1) The voltage-independent action, which increases dopamine release selectively, and might contribute to the effects of MK-801 on motor coordination. (2) The voltage-dependent action, which inhibits all the veratridine-evoked responses including the evoked release of the excitatory amino acids (which are particularly concentrated in striatum nerve endings), and might contribute to the anticonvulsant and neuroprotective effects of MK-801.

Effects of Cannabinoids on Dopamine Release in the Corpus Striatum and the Nucleus Accumbens In Vitro

Cannabinoid receptors are widely distributed in the nuclei of the extrapyramidal motor and mesolimbic reward systems; their exact functions are, however, not known. The aim of the present study was to characterize the effects of cannabinoids on the electrically evoked release of endogenous dopamine in the corpus striatum and the nucleus accumbens. In rat brain slices dopamine release elicited by single electrical pulses was determined by fast cyclic voltammetry. Dopamine release was markedly inhibited by the OP2 opioid receptor agonist U-50488 and the D2/D3 dopamine receptor agonist quinpirole, indicating that our method is suitable for studying presynaptic modulation of dopamine release. In contrast, the CB1/CB2 cannabinoid receptor agonists WIN55212-2 (10(-6) M) and CP55940 (10(-6)-10(-5) M) and the CB1 cannabinoid receptor antagonist SR141716A (10(-6) M) had no effect on the electrically evoked dopamine release in the corpus striatum and the nucleus accumbens. The lack of a presynaptic effect on terminals of nigrostriatal and mesolimbic dopaminergic neurons is in accord with the anatomical distribution of cannabinoid receptors: The perikarya of these neurons in the substantia nigra and the ventral tegmental area do not synthesize mRNA, and hence protein, for CB1 and CB2 cannabinoid receptors. It is therefore unlikely that presynaptic modulation of dopamine release in the corpus striatum and the nucleus accumbens plays a role in the extrapyramidal motor and rewarding effects of cannabinoids.

Release of endogenous dopamine in cultured mesencephalic neurons: influence of dopaminergic agonists and glucocorticoid antagonists.

Several electrochemical techniques allow the measurement of dopamine release in freely moving animals and brain slices. In this report, we applied one of these techniques, coulometry, coupled to high-performance liquid chromatography (HPLC), to the study of dopamine release in primary cultures of embryonic mesencephalic dopaminergic neurons. Between day 9 and 33 of culture, concentrations of dopamine, above the detection threshold, were found in the incubation buffer (Krebs ringer buffer, KRB). Concentrations of dopamine in the incubation buffer reflected neuronal release as they were: (i) positively correlated with the number of tyrosine hydroxylase-positive dopamine neurons in the culture; (ii) tetrodotoxin (TTX) sensitive and Ca2+ dependent; (iii) increased by a depolarizing stimulus, e.g. K+ (20 mM), or by the indirect dopamine agonists amphetamine and cocaine; (iv) decreased by a hyperpolarizing stimulus, e.g. the dopamine D2-like receptor agonist quinpirole. Dopamine release in this model was also sensitive to the manipulation of glucocorticoids, potent modulators of dopamine release in vivo. Long-term treatment of the cell cultures with RU 39305, a selective antagonist of glucocorticoid receptors (GR), but not with spironolactone, a selective antagonist of mineralocorticoid receptors (MR), dose-dependently decreased K+-stimulated dopamine release. In conclusion, these results demonstrate an in vitro model that allows the studying of the release of endogenous dopamine in cell cultures and the effects of glucocorticoid hormones on the release dynamics.

Loss of regulation by presynaptic dopamine D2 receptors of exogenous l-DOPA-derived dopamine release in the dopaminergic denervated striatum

To determine whether dopamine release derived from exogenous l-DOPA is under inhibitory control of presynaptic dopamine D2 receptors in the dopaminergic denervated striatum, extracellular dopamine levels were measured in the striatum of 6-hydroxydopamine-lesioned rats using in vivo brain microdialysis. Quinpirole, a D2 agonist, dose-dependently (0.01–3 mg/kg s.c.) inhibited endogenous dopamine release both in the intact and dopaminergic denervated striatum. The dose–response curve obtained from the denervated striatum showed a shift to the right. Administration of l-DOPA (30 mg/kg i.p.) with carbidopa (25 mg/kg i.p.) increased dopamine release to 130% of basal levels in the intact striatum and 770% of basal levels in the denervated striatum. In the intact striatum, dopamine release was continuously inhibited by quinpirole pretreatment (1 mg/kg s.c.) even after l-DOPA administration. In the denervated striatum, l-DOPA-derived dopamine release was not affected by quinpirole pretreatment. These results suggest that, in the striatum with dopaminergic denervation, regulation by presynaptic D2 receptors is still operative on endogenous dopamine release but it does not work on dopamine release derived from exogenously administered l-DOPA.

Effects of accumbens m-chlorophenylbiguanide microinjections on sleep and waking in intact and 6-hydroxydopamine-treated rats

Effects of the 5-HT 3 receptor agonist, m-chlorophenylbiguanide (10.0–40.0 μg), on sleep and waking were studied in control, vehicle-treated and 6-hydroxydopamine-injected rats. Bilateral injections of m-chlorophenylbiguanide into the nucleus accumbens of the control and the vehicle-infused animals significantly increased waking and reduced slow wave sleep. Rapid eye movement sleep (REM sleep) remained unchanged. Pretreatment with the selective 5-HT 3 receptor antagonist, MDL 72222 (1a H,3a,5a, H-tropan-3-yl-3,5-dichloro-benzoate) (0.5 mg/kg, s.c.), reversed the effects of m-chlorophenylbiguanide (10.0–20.0 μg) on sleep and waking in the control group. Administration of the 5-HT 3 receptor agonist to the 6-hydroxydopamine-treated animals modified only slightly the time spent in wakefulness and slow wave sleep, while REM sleep was significantly and dose dependently reduced. Our findings further support the proposal that increase of wakefulness and reduction of slow wave sleep after activation of 5-HT 3 receptors, is partly related to the release of endogenous dopamine.

Mazindol, nomifensine and desmethylimipramine inhibit potassium-induced release of dopamine: effect of stimulus strength.

Catecholamine uptake blockers exhibit a second action: They suppress the potassium (K+)-stimulated release of [3H]-dopamine (DA) from rat striatal tissue in vitro. In the present study, a K+ dose-response curve was obtained for the release of both [3H]-DA and endogenous DA from striatal tissue, in the absence and presence of catecholamine uptake blockers. Three drugs were used, namely, mazindol, nomifensine, and desmethylimipramine. The data showed that diminished release in the presence of mazindol or nomifensine was dependent upon the concentration of K+. Marked inhibition of stimulus-induced release of either 3H-DA or endogenous DA was observed at low concentrations of K+ (15 and 20 mM), but not at higher concentrations of K+ (40 and 60 mM). In contrast, the diminished release of DA in the presence of desmethylimipramine persisted over the K+ range of 20-60 mM. These data show that the drug action observed previously was not restricted to a specific neuronal pool of DA that was labelled with [3H]-DA. Further, the data emphasize the importance of the concentration of the depolarizing stimulus when evaluating the effects of drugs on release of catecholamines.