Dopamine Release In Striatum Research Articles

Profound Decreases in Dopamine Release in Striatum in Detoxified Alcoholics: Possible Orbitofrontal Involvement

The value of rewards (natural rewards and drugs) is associated with dopamine increases in the nucleus accumbens and varies as a function of context. The prefrontal cortex has been implicated in the context dependency of rewards and in the fixated high value that drugs have in addiction, although the mechanisms are not properly understood. Here we test the hypothesis that the prefrontal cortex regulates the value of rewards by modulating dopamine increases in nucleus accumbens and that this regulation is disrupted in addicted subjects. We used positron emission tomography to evaluate the activity of the prefrontal cortex (measuring brain glucose metabolism with [18F]fluorodeoxyglucose) and dopamine increases (measured with [11C]raclopride, a D2/D3 receptor ligand with binding that is sensitive to endogenous dopamine) induced by the stimulant drug methylphenidate in 20 controls and 20 detoxified alcoholics, most of whom smoked. In all subjects, methylphenidate significantly increased dopamine in striatum. In ventral striatum (where the nucleus accumbens is located) and in putamen, dopamine increases were associated with the rewarding effects of methylphenidate (drug liking and high) and were profoundly attenuated in alcoholics (70 and 50% lower than controls, respectively). In controls, but not in alcoholics, metabolism in orbitofrontal cortex (region involved with salience attribution) was negatively associated with methylphenidate-induced dopamine increases in ventral striatum. These results are consistent with the hypothesis that the orbitofrontal cortex modulates the value of rewards by regulating the magnitude of dopamine increases in the ventral striatum and that disruption of this regulation may underlie the decreased sensitivity to rewards in addicted subjects.

Limited regulation of somatodendritic dopamine release by voltage‐sensitive Ca2+channels contrasted with strong regulation of axonal dopamine release

The mechanism underlying somatodendritic release of dopamine (DA) appears to differ from that of axon-terminal release. Specifically, somatodendritic DA release in the substantia nigra pars compacta (SNc) persists in low extracellular Ca2+ concentrations that are insufficient to support axonal release in striatum, suggesting that limited Ca2+ entry is necessary to trigger somatodendritic release. Here, we compared the role of voltage-dependent Ca2+ channels in mediating DA release in striatum versus SNc using specific blockers of N-, P/Q-, T-, R- and L-type Ca2+ channels individually and in combination. Release of DA evoked by a single stimulus pulse in the dorsal striatum and SNc of guinea-pig brain slices was monitored in real time using carbon-fiber microelectrodes with fast-scan cyclic voltammetry. Single-pulse evoked DA release was shown to be independent of regulation by concurrently released glutamate or GABA acting at ionotropic receptors in both regions. Under these conditions, striatal DA release was completely prevented by an N-type channel blocker, omega-conotoxin GVIA (100 nm), and was decreased by 75% by the P/Q-type channel blocker omega-agatoxin IVA (200 nm). Blockade of T-type channels with Ni2+ (100 microm) or R-type channels with SNX-482 (100 nm) decreased axonal release in striatum by 25%, whereas inhibition of L-type channels with nifedipine (20 microm) had no effect. By contrast, none of these Ca2+-channel blockers altered the amplitude of somatodendritic DA release in the SNc. Even a cocktail of all blockers tested did not alter release-signal amplitude in the SNc, although the duration of the release response was curtailed. The limited involvement of voltage-dependent Ca2+ channels in somatodendritic DA release provides further evidence that minimal Ca2+ entry is required to trigger the release process, compared with that required for axon-terminal release.

Locomotor activity and evoked dopamine release are reduced in mice overexpressing A30P-mutated human α-synuclein

We have generated a transgenic mouse line overexpressing mutated human A30P alpha-synuclein under the control of the prion-related protein promoter. Immunohistology revealed mutated human A30P alpha-synuclein protein in numerous brain areas, but no gross morphological changes, Lewy bodies, or loss of dopaminergic cell bodies. The transgenic mice displayed decreased locomotion, impaired motor coordination, and balance. In vivo voltammetry showed that A30P mice responded to longer stimulation of the ascending dopaminergic pathways with less dopamine release in striatum and had a slower rate of dopamine decline after repeated stimulations or after alpha-methyl-p-tyrosine-HCl treatment. However, dopamine re-uptake or transporter levels were similar in transgenic and control mice. Our data provide evidence that overexpression of mutated human A30P alpha-synuclein in mice leads to a reduced size of the dopamine storage pool. This is in agreement with the previously postulated involvement of alpha-synuclein in the turnover of transmitter vesicles and may explain the observed motor deficits in A30P mice.

Elevation of Ambient Room Temperature has Differential Effects on MDMA-Induced 5-HT and Dopamine Release in Striatum and Nucleus Accumbens of Rats

3,4-Methylenedioxymethamphetamine (MDMA) produces acute dopamine and 5-HT release in rat brain and a hyperthermic response, which is dependent on the ambient room temperature in which the animal is housed. We examined the effect of ambient room temperature (20 and 30 degrees C) on MDMA-induced dopamine and 5-HT efflux in the striatum and shell of nucleus accumbens (NAc) of freely moving rats by using microdialysis. Locomotor activity and rectal temperature were also evaluated. In the NAc, MDMA (2.5 or 5 mg/kg, i.p.) produced a substantial increase in extracellular dopamine, which was more marked at 30 degrees C. 5-HT release was also increased by MDMA given at 30 degrees C. In contrast, MDMA-induced extracellular dopamine and 5-HT increases in the striatum were unaffected by ambient temperature. At 20 degrees C room temperature, MDMA did not modify the rectal temperature but at 30 degrees C it produced a rapid and sustained hyperthermia. MDMA at 20 degrees C room temperature produced a two-fold increase in activity compared with saline-treated controls. The MDMA-induced increase in locomotor activity was more marked at 30 degrees C due to a decrease in the activity of the saline-treated controls at this high ambient temperature. These results show that high ambient temperature enhances MDMA-induced locomotor activity and monoamine release in the shell of NAc, a region involved in the incentive motivational properties of drugs of abuse, and suggest that the rewarding effects of MDMA may be more pronounced at high ambient temperature.

3H]Dopamine release in striatum in response to cortical stimulation in a corticostriatal slice preparation

A new method has been developed to investigate corticostriatal glutamatergic influence on [ 3H]dopamine release in striatum in complex corticostriatal slice preparation in vitro. Horizontal slices containing the striatum and the adjacent prefrontal cortex of rat brain were cut in a plane that maintains corticostriatal connections. After incubation with [ 3H]dopamine, slices were submerged in a two-compartment bath so that the cortical region was contained entirely in one compartment, corpus callosum passed through a silicone greased slot, and the striatal region was contained in the other compartment. A cannula was placed just above the striatal part of the slice and effluent was collected with a peristaltic pump, released tritiated materials were counted with a liquid scintillation counter. Electric field stimulation of cortex increased the release of [ 3H]dopamine in the striatum. Bicuculline (1 mM) increased the basal and stimulated release of [ 3H]dopamine in the striatum in response to cortical stimulation of cortex indicating the GABAergic control on dopamine release. This method allows investigation of the effect of cortical stimulation on glutamate–dopamine–GABA interactions in the striatum in vitro that might help to understand better the neurochemical background of schizophrenia or Parkinson's disease.

Evidence for different exocytosis pathways in dendritic and terminal dopamine release in vivo

Although dendritic release was first proposed in the 1970s, the mechanism of release is still subject to debate. We have used in vivo microdialysis to study the acute effects of botulinum toxin A, B and tetanus toxin injected in the substantia nigra or striatum of freely moving rats. Spontaneous and evoked dopamine release decreased in both regions after treatment with the SNAP-25 (synaptosome-associated protein of 25 kDa) cleaving protease botulinum toxin A (1000 mouse lethal doses, MLD). Tetanus toxin (4000 MLD) did not significantly change spontaneous or evoked dopamine release in striatum or in the substantia nigra. Another synaptobrevin cleaving protease, botulinum toxin B, inhibited release in the striatum by 55% but did not affect dopamine release when injected in the substantia nigra. The results indicate that both terminal and somatodendritic dopamine release need intact SNAP-25 to occur, but somatodendritic dopamine release in contrast to terminal release depends on a botulinum toxin B resistant pathway.

Effect of simple motor performance on regional dopamine release in the striatum in Parkinson disease patients and healthy subjects: a positron emission tomography study.

To investigate changes in dopamine release in the striatum during motor exercise in human subjects with and without striatal dopamine denervation, eight healthy subjects and eight patients with Parkinson disease (PD) were measured during unilateral foot extension/flexion movement using positron emission tomography with [11C]raclopride. Five subjects in each group were later scanned in the resting condition. Estimation of binding potential (k3/k4) of [11C]raclopride was based on Logan plot method. Significant reductions in [11C]raclopride k3/k4 were found in the dorsal putamen contralateral to the exercise side in the healthy group and ipsilaterally in the PD group. Spearman rank correlation analysis showed that [11C]raclopride k3/k4 correlated inversely with the decrease in performance (velocity and motion range) in the dorsal putamen contralaterally in the healthy group and ipsilaterally in the PD group. These results suggest that simple but laborious motor exercise (motor stimulation) generates significant dopamine release in the dorsal striatum contralateral to the motor execution in humans. Lack of the crossed pattern and ipsilateral increase in dopamine release in the dorsal striatum during the unilateral limb movement may reflect the pathophysiology for hypokinetic and insufficient coordinating movement in PD.

Dopaminergic dysfunction in alcoholism and schizophrenia – psychopathological and behavioral correlates

Dysfunction of central dopaminergic neurotransmission has been implicated in the pathogenesis of schizophrenia as well as drug and alcohol dependence. Different drugs of abuse stimulate dopamine release in the ventral striatum and thus reinforce drug consumption. Increased subcortical dopamine release has also been associated with the pathogenesis of positive symptoms in schizophrenia and may be driven by a prefrontal dopaminergic dysfunction. These seemingly heterogeneous findings may be explained by recent research in non-human primates. According to these studies, reward anticipation but not anticipated reward consumption is accompanied by a phasic dopamine release in the striatum and prefrontal cortex. In the striatum, phasic dopamine release primarily affects motivation, psychomotor activation and reward craving, while in the prefrontal cortex, dopaminergic stimulation is involved in the activation of working memory and reward anticipation. In alcoholism, previously neutral stimuli that have been associated with alcohol intake can become conditioned cues which activate phasic dopamine release and reward craving. In schizophrenia, stress-induced or chaotic activation of dopamine release may attribute incentive salience to otherwise irrelevant stimuli and thus be involved in the pathogenesis of delusional mood and other positive symptoms. Studies in humans and non-human primates emphasize the role of dopaminergic neurotransmission in reward anticipation and its dysfunction in different neuropsychiatric diseases.

MK801 influences l-DOPA-induced dopamine release in intact and hemi-parkinson rats

In vivo microdialysis was used to investigate the influence of dizocilpine (MK801) on basal and levodopa ( l-DOPA)-induced extracellular dopamine levels in striatum and substantia nigra of intact and 6-hydroxydopamine-lesioned rats. In lesioned rats, extracellular dopamine was decreased in striatum but not in substantia nigra. l-DOPA (25 mg/kg i.p. after benserazide 10 mg/kg i.p.) increased the dopamine levels in striatum and substantia nigra of intact and dopamine-depleted rats. This increase was significantly higher in dopamine-depleted compared to intact striatum. Pretreatment with MK801 (0.1 and 1.0 mg/kg i.p.) dose-dependently attenuated the l-DOPA-induced dopamine release in substantia nigra of intact rats. In dopamine-depleted striatum, MK801 enhanced l-DOPA-induced dopamine release. The present results indicate that the influence of MK801 on l-DOPA-induced dopamine release in striatum and substantia nigra depends on the integrity of the nigrostriatal pathway. In Parkinson's disease, NMDA receptor antagonists could be beneficial by enhancing the therapeutic efficacy of l-DOPA at the level of the striatum.

545. A double-blind, placebo-controlled study of naltrexone in the treatment of pathological gambling disorder

release of dopamine (DA) following the application of this alkaloid through a microdialysis probe placed in the striatum. We also measured the expression of mRNAs encoding for a3, a4, a7 and b2 nicotinic acetylcholine receptor (nAChR) subunits and, the density of high-affinity nAChRs in the striatum. The DA content in the dialysate was measured before and after 1-min local perfusion of nicotine (6, 10 and 20 nmoles/min) and the resulting DA increase was taken as a measure of the alkaloid’s intrinsic activity. The nicotine-induced increase of striatal DA release in FSL rats at all doses was greater than in the FRL rats. Mecamylamine, a non-competitive antagonist for nAChRs, attenuated nicotine-induced striatal dialysate DA increase to the same extent in both lines, suggesting that the intrinsic activity of nicotine was greater in the FSL rats than in the FRL rats. This suggestion was supported by the density of high-affinity nAChRs (measured by H-epibatidine binding) in FSL rats that was 44% greater than in the FRL rats while the KD was virtually identical in the two groups of rats. Also, the expression of mRNA encoding for a4, a7, and b2 subunits was greater in FSL than in FRL rats (attomol/mg total RNA, a4: 98.0 6 10.3 vs 77.3 6 7.4; a7: 278.8 6 16.3 vs 184 6 15.7; b2: 310.3 6 19.3 vs 200.8 6 11.6). We hypothesize that the differences in nicotine-induced DA release in striatum of FSL and FRL rats are probably associated with differences in nAChR subunit expression in the two lines. The Flinders rats could be used as animal model for nicotine self-administration studies to evaluate the sensitivity of FSL and FRL rats to nicotine dependence.

Inhibitory glutamatergic regulation of evoked dopamine release in striatum

Certain aspects of schizophrenia and Parkinson's disease suggest that glutamate might have an inhibitory effect on dopamine release. Several studies have reported that the excitatory actions of ionotropic glutamate agonists on extracellular dopamine levels in striatum are resistant to tetrodotoxin, which suggests that glutamate excites an impulse-independent mechanism of dopamine release. We tested the hypothesis that an inhibitory action of glutamate on dopamine terminals in the striatum specifically involves an impulse-dependent mechanism of dopamine release. We used voltammetry to monitor electrically-evoked dopamine release in striatal slices, which is completely tetrodotoxin- and Ca 2+-sensitive and so provides a model of impulse-dependent dopamine release. Agonists of the ionotropic glutamate receptors significantly decreased the amplitude of the response, while antagonists significantly increased the amplitude of the response, by as much as ≈60% in the case of kynurenic acid. These results support the hypothesis that ionotropic glutamate receptors can inhibit impulse-dependent dopamine release by a mechanism that acts locally within the striatum. This finding contrasts with previous reports that glutamate can excite impulse-independent dopamine release. This extends earlier findings that glutamate may both excite and inhibit subcortical dopamine systems by suggesting that the excitatory and inhibitory actions of striatal ionotropic glutamate receptors are specifically associated with impulse-independent and impulse-dependent dopamine release, respectively.

Endogenous GABA potentiates the potassium-induced release of dopamine in striatum of the freely moving rat: a microdialysis study

Using microdialysis, a study was made of the effects of an increase of endogenous GABA on basal and potassium-stimulated release of dopamine in striatum of the awake rat. The dopamine metabolites DOPAC and HVA were also measured. Extracellular concentrations of GABA were increased by inhibiting its uptake with nipecotic acid. TTX (10 μM) reduced basal extracellular concentrations of dopamine, and dopamine metabolites, but not GABA. Nipecotic acid (200, 500, and 1000 μM) produced a dose-related increase in basal extracellular concentrations of GABA, but did not change basal extracellular concentrations of dopamine and dopamine metabolites. However, nipecotic acid significantly enhanced the dopamine release produced by perfusion of potassium (50 mM) and also enhanced the extracellular increase of GABA produced by high potassium. These results suggest that an increase of endogenous GABA is facilitating the stimulated release, but not the basal release, of dopamine in the striatum of the awake rat.

Group I mGlu receptor modulation of dopamine release in the rat striatum in vivo

The present study investigated the ability of mGlu (metabotropic glutamate) receptor to modulate dopamine release in the striatum of freely moving rats assessed using the microdialysis technique. The group I and II mGlu receptor agonist (1 S,3 R)-ACPD (1-amino-cyclopentane-1,3-dicarboxylate; 1–3 mM) increased dopamine release (367% of basal levels) which was prevented by the non-selective mGlu receptor antagonist, (+)-MCPG (alpha-methyl-4-carboxyphenylglycine; 10 mM). The group I mGlu receptor agonist, DHPG (3,5-dihydroxyphenylglycine; 0.3–1 mM), also increased dopamine release (maximum increase 229%) which was also antagonised by (+)-MCPG (10 mM). In contrast, the group II mGlu receptor agonist, DCG-IV (2-(2,3-dicarboxycyclopropyl)glycine; 3–50 μM), induced a more modest increase in dopamine release (156% of basal levels). Combined administration of DHPG (1 mM) and DCG-IV (50 μM) maximally increased dopamine release by 252% of basal levels which was antagonised completely by (+)-MCPG (10 mM). Such findings indicate that group I (and possibly group II) mGlu receptors facilitate rat striatal dopamine release in vivo.

Electrochemical Studies of the Effects of Substance P on Dopamine Terminals in the Rat Striatum

The purpose of this study was to investigate the regulation of dopamine (DA) release and clearance by Substance P (SP) in striatum.In vivohigh speed chronoamperometric recording techniques, with Nafion-coated carbon-fiber electrodes, were used to evaluate extracellular DA concentrations in urethane-anesthetized Sprague–Dawley rats. SP was locally applied to striatum. Our data indicate that SP can induce DA release in striatum. However, only about half of the striatal sites respond to SP. Readministration of SP to the same site elicited a smaller DA release. These data suggest that SP-evoked release shows tachyphyllaxis and is heterogeneous in the striatum. Lesioning of DA neurons with 6-OHDA into the medial forebrain bundle abolished DA release induced by SP. It has been shown that SP interacts with three different tachykinin receptors. We found that application of the Neurokinin-1 (NK1) agonist [Sar9, Met (O2)11]SP, but not the NK3agonist senktide, induced DA release, suggesting that SP-induced DA release may be mediated through NK1receptors. We further examined SP effects on DA clearance in striatum. We found that pretreatment with SP significantly attenuated extracellular levels of DA after exogeneous application of DA, suggesting that DA clearance is augmented by SP. Taken together, our data demonstrate that substance P facilitates dopamine release and clearance in the striatum.

Role of excitatory amino acids in the regulation of dopamine synthesis and release in the neostriatum.

We have explored the role of excitatory amino acids in the increased dopamine (DA) release that occurs in the neostriatum during stress-induced behavioral activation. Studies were performed in awake, freely moving rats, using in vivo microdialysis. Extracellular DA was used as a measure of DA release; extracellular 3,4-dihydroxyphenylalanine (DOPA) after inhibition of DOPA decarboxylase provided a measure of apparent DA synthesis. Mild stress increased the synthesis and release of DA in striatum. DA synthesis and release also were enhanced by the intra-striatal infusion of N-methyl-D-aspartate (NMDA), an agonist at NMDA receptors, and kainic acid, an agonist at the DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionate (AMPA)/kainate site. Stress-induced increase in DA synthesis was attenuated by co-infusion of 2-amino-5-phosphonovalerate (APV) or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), antagonists of NMDA and AMPA/kainate receptors, respectively. In contrast, intrastriatal APV, CNQX, or kynurenic acid (a non-selective ionotropic glutamate receptor antagonist) did not block the stress-induced increase in DA release. Stress-induced increase in DA release was, however, blocked by administration of tetrodotoxin along the nigrostriatal DA projection. It also was attenuated when APV was infused into substantia nigra. Thus, glutamate may act via ionotropic receptors within striatum to regulate DA synthesis, whereas glutamate may influence DA release via an action on receptors in substantia nigra. However, our method for monitoring DA synthesis lowers extracellular DA and this may permit the appearance of an intra-striatal glutamatergic influence by reducing a local inhibitory influence of DA. If so, under conditions of low extracellular DA glutamate may influence DA release, as well as DA synthesis, by an intrastriatal action. Such conditions might occur during prolonged severe stress and/or DA neuron degeneration. These results may have implications for the impact of glutamate antagonists on the ability of patients with Parkinson's disease to tolerate stress.

Effects of the dopamine D3 antagonist PD 58491 and its interaction with the dopamine D3 agonist PD 128907 on brain dopamine synthesis in rat.

The dopamine (DA) D3 receptor antagonist PD 58491 [3-[4-[1-[4-[2-[4-(3-diethylaminopropoxy)phenyl]benzoimidazol++ +-1-yl-butyl]-1H-benzoimidazol-2-yl]phenoxy]propyl]diethylamine] bound with high affinity and selectivity to recombinant human DA D3 versus D2L and D4.2 receptors transfected into Chinese hamster ovary cells: Ki values of 19.5 nM versus 2,362 and >3,000 nM, respectively. In contrast, the putative DA D3 receptor antagonist (+)-AJ76 displayed low affinity and selectivity for D3 versus D2L and D4.2 receptors (91 nM vs. 253 and 193 nM, respectively). In vitro, PD 58491 (1 nM-1 microM) exhibited D3 receptor antagonist activity, reversing the quinpirole (10 nM)-induced stimulation of [3H]thymidine uptake in D3 CHOpro-5 cells, but did not have any significant intrinsic activity by itself in this assay. PD 58491 did not decrease the gamma-butyrolactone-induced increase in DA synthesis (L-3,4-dihydroxyphenylalanine accumulation) in rat striatum, indicating that the compound possessed no in vivo DA D2/D3 receptor agonist action at DA autoreceptors. PD 58491 (3-30 mg/kg, i.p.) generally did not alter DA or serotonin synthesis in either the striatum or mesolimbic region of rat brain. The D3-preferring agonist PD 128907 decreased DA synthesis in striatum and mesolimbic regions, and this effect was attenuated by pretreatment with PD 58491. These findings support the hypothesis that DA D3 autoreceptors may in part modulate the synthesis and release of DA in striatum and mesolimbic regions.

Influence of cannabinoids on electrically evoked dopamine release and cyclic AMP generation in the rat striatum.

Using the endogenous cannabinoid receptor agonist anandamide, the synthetic agonist CP 55940 [[1alpha,2beta(R)5alpha]-(-)-5-(1,1-dimethylheptyl+ ++)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]phenol], and the specific antagonist SR 141716 [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1H-pyrazole-3-carboxamide hydrochloride], second messenger activation of the central cannabinoid receptor (CB1) was examined in rat striatal and cortical slices. The effects of these cannabinoid ligands on electrically evoked dopamine (DA) release from [3H] dopamine-prelabelled striatal slices were also investigated. CP 55940 (1 microM) and anandamide (10 microM) caused significant reductions in forskolin-stimulated cyclic AMP accumulation in rat striatal slices, which were reversed in the presence of SR 141716 (1 microM). CP 55940 (1 microM) had no effect on either KCl- or neurotransmitter-stimulated 3H-inositol phosphate accumulation in rat cortical slices. CP 55940 and anandamide caused significant reductions in the release of dopamine after electrical stimulation of [3H]dopamine-prelabelied striatal slices, which were antagonised by SR 141716. SR 141716 alone had no effect on electrically evoked dopamine release from rat striatal slices. These data indicate that the CB1 receptors in rat striatum are negatively linked to adenylyl cyclase and dopamine release. That the CB1 receptor may influence dopamine release in the striatum suggests that cannabinoids play a modulatory role in dopaminergic neuronal pathways.

5-HT3SEROTONIN HETERO-RECEPTORS INHIBIT [3H]ACETHYLCHOLINE RELEASE IN RAT CORTICAL SYNAPTOSOMES

The present study was designed to verify the presynaptic localization of 5-HT3serotonin receptors on cholinergic, serotonergic and dopaminergic nerve endings in rat brain regions where they have been shown to modulate the release of these neurotransmitters. We measured the effect of 5-HT3agonists on [3H] neurotransmitter release from superfused synaptosomes as a functional assay of the presence of 5-HT3serotonin receptors.m-Cl-phenylbyguanide (m-Cl-PBG, 1gmm) inhibited by 18% depolarization-evoked [3H]acethylcholine (ACh) release from cortical synaptosomes, and this effect was blocked by a potent and selective 5-HT3antagonist based on the arylpiperazine skeleton (VC 135, 0.03gmm). Ondansetron (0.1gmm)per sehad an inhibitory effect as well, thus making it difficult to evaluate its interaction with m-Cl-PBG.Up to 10gmm, m-Cl-PBG did not affect [3H]dopamine release in striatum, nucleus accumbens and frontal cortex. A similar, although not significant inhibition (16%) of [3H]ACh release, was obtained with 2-methylserotonin (10gmm), which, at this concentration, did not modify either basal or depolarization-induced release of [3H]serotonin in hippocampus or [3H]dopamine in striatum.In conclusion, our data suggest that 5-HT3hetero-receptors are located on cortical nerve endings where they directly inhibit acethylcholine release, but they do not seem to be located on serotonergic and dopaminergic nerve endings in the brain regions studied, probably having an indirect effect on these neurotransmitters release in rat brain.

Effects of (-)-sulpiride on dopamine release in striatum of developing rats: degree of depolarization influences responsiveness.

The purpose of this study was to determine the effects of localized delivery of the D2 antagonist (-)-sulpiride (via microdialysis) on spontaneous and evoked dopamine release in the neostriatum of urethane-anesthetized rats 5, 10, 15, 21, and 70 days of age. Sulpiride increased spontaneous dopamine release approximately threefold relative to baseline measures, and this effect decreased with maturation. The relationship between sulpiride- and potassium-evoked release was complex; sulpiride increased evoked dopamine outflow at 5, 10, and 15 days of age. At 21 and 70 days of age, however, the effects of sulpiride were inversely related to the degree of stimulation with potassium. Furthermore, the D2 agonist quinpirole (100 microM) reversed the effects of sulpiride (10 microM), suggesting receptor mediation. These experiments demonstrate that the maturational decline in the efficacy and potency of D2 antagonism appears to be related to the degree of stimulation at the nerve terminal.

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 μg/0.5 μl) or a mixture of dopamine D 1 and dopamine D 2 receptor agonists (1-phenyl-2,3,4,5,-tetrahydro-1 H-3-benzazepine-7,8-diol 5 μg + quinpirole 10 μg/0.5 μl) 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 D 1 D 2 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 contralteral 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.