GABAergic modulation in the substantia nigra of the striatal dopamine release and of the locomotor activity in rats exposed to helium pressure

Helium-oxygen pressure induces in rodents an increase of both locomotor and motor activity (LMA) and of the striatal dopamine release, which could result from a decrease of GABA transmission in the substantia nigra. The effects of the GABA(A) receptor agonist muscimol and of the GABA(B) receptor agonist baclofen on the striatal dopamine release were measured using differential pulse voltammetry. Behavioural studies were performed in freely moving rats using actimetry. Whatever the drug used under helium pressure, bilateral administration in the substantia nigra pars reticulata (SNr) or in the substantia nigra pars compacta (SNc) counteracted the evoked dopamine release. However, only the baclofen reduced the LMA, while the muscimol administration in the SNr, but not in the SNc, increased it. These results indicate that different subtypes of GABA receptors would be involved in the control of the DA release and in the occurrence of LMA under helium pressure.     

Long-term depression in striatal dopamine release monitored by in vivo voltammetry in free moving rats

It was proposed to monitor in free moving rats, by in vivo voltammetry, the effects of intracerebroventricular (i.c.v.) administration of drugs known to act on the synthesis of dopamine (DA), using an original multifiber carbon electrode which enables without-discontinuity long-term recordings in extracellular DA release. Results show that i.c.v. administration of alpha-methyl-p-tyrosine, gamma-butyrolactone, and apomorphine induced long-term depression in striatal DA release, over periods of time of more than 24 h. These results are in agreement with the dopaminergic hypothesis; and we conclude that i.c.v. administration of drugs and the use of the multifiber carbon electrode constitutes a valuable tool to monitor DA metabolism in chronically implanted animals.     

Reproductive experience increases striatal and hypothalamic dopamine levels in pregnant rats

The effects of parity on the dopaminergic function of rats were studied. Striatal and hypothalamic levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), norepinephrine (NE), serotonin (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) as well as serum prolactin (PRL) levels of 7-days primigravid and multigravid rats were compared. Brains and trunk blood were collected from 1200–1400 h on day 7 of pregnancy and assayed for monoamines and their metabolites, and prolactin, respectively. Multigravid rats showed a significant increase in striatal and hypothalamic dopamine levels. A tendency to increase in striatal DOPAC levels was also observed in multigravid rats. Levels of other neurotransmitters and metabolites were not statistically different. Haloperidol (1 mg/kg) treatment induced a significant increase in multigravid 5-HT striatal levels. There was no statistical difference among primigravid and multigravid serum PRL levels after either saline or haloperidol treatment. These data suggest that prior parity produces a shift in dopaminergic activity in multigravid rats.     

Differential effects of dopamine agonists on evoked dopamine release from slices of striatum and nucleus accumbens in rats

The effects of dopamine receptor agonists on electrically evoked dopamine release from slices of nucleus accumbens were compared with the effects on release from striatal slices in rats. Apomorphine, which has equal potency at the dopamine D₂ and D₃ receptors, reduced the evoked dopamine release from both regions to the same extent (ED₅₀, 0.42 μM for nucleus accumbens; ED₅₀, 0.46 μM for striatum). Quinpirole of 7-[³H]hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OHDPAT), which are much more potent at the D₃ receptor than at the D₂ receptor, reduced the evoked dopamine release from the nucleus accumbens (ED₅₀, 0.12 μM for quinpirole; 0.02 μM for 7-OHDPAT) much more than the release from the striatum (ED₅₀, 1.6 μM for quinpirole; 0.55 μM for 7-OHDPAT). These results suggest that the contribution of D₃ receptors in nucleus accumbens to regulate dopamine release from dopamine nerve terminals is much greater than that in striatum.     

Altered striatal dopamine release following a sub-acute exposure to manganese

Certain metals that are necessary for regulating biological function at trace levels hold the potential to become neurotoxic when in excess. Specifically, chronic exposure to high levels of manganese leads to manganism, a neurological disorder that exhibits both motor and learning deficits similar to Parkinson's disease. Since Parkinson's disease symptomatology is primarily attributed to dopamine neurodegeneration in the striatum, dopamine system dysfunction has been implicated in the onset of manganism. In this study, dopamine system function in the dorsal striatum was evaluated in C57Bl/6 mice, 1, 7, and 21 days following repeated injections of manganese(II) chloride (50 mg/kg, subcutaneous) intermittently for 7 days. Tissue content analysis confirmed the presence of persistent accumulation of manganese in the striatum up to 21 days after cessation of treatment. In vitro fast scan cyclic voltammetry examined the effect of sub-acute manganese on electrically stimulated dopamine release and uptake in the striatum. While no difference was observed in uptake rates following manganese treatment, dopamine release was attenuated on days 7 and 21, compared to control levels. Basal levels of extracellular dopamine determined by the zero net flux microdialysis method were significantly lower in manganese-treated mice at 7 days post-treatment. On the other hand, potassium stimulated increases in extracellular dopamine were attenuated at all three time points. Together, these findings indicate that repeated manganese exposure has long-term effects on the regulation of exocytotic dopamine release in the striatum, which may be involved in the mechanism underlying manganese toxicity.     

Systemic administration of thyrotropin-releasing hormone enhances striatal dopamine release in vivo

We examined the effects of systemically administered thyrotropin-releasing hormone (TRH) on the release of dopamine (DA), as assessed by brain microdialysis within the corpus striatum of anesthetized rats. A single dose (10 micrograms i.v.) elevated DA levels in brain extracellular fluid (ECF) by 240% above baseline levels after 150 min. Systemic tyrosine ([TME] 20 mg/kg i.v.) also increased DA release (by 190% after 150 min), while combined treatment with both agents was associated with significant potentiation of the DA response (to 640% after 150 min). None of the treatments significantly altered striatal tissue levels of DA or its metabolites. A large dose of TRH (50 micrograms i.v.) significantly increased DA release (by 1150%) whether or not animals had received an active or denatured prolactin (PRL) antiserum prior to the experiment, suggesting that the TRH effect is not mediated by PRL. Although TRH is rapidly metabolized in plasma and penetrates the blood-brain barrier only poorly, our results suggest that even relatively small doses of the hormone can affect striatal dopaminergic neurotransmission.     

Opposite presynaptic regulations by glutamate through NMDA receptors of dopamine synthesis and release in rat striatal synaptosomes

Purified striatal synaptosomes were superfused continuously with L-[3,5-³H]tyrosine to measure simultaneously the synthesis ([³H]water formed during the conversion of [³H]tyrosine into [³H]DOPA) and the release of [³H]dopamine ([³H]DA). Glutamate (10⁻³ M) and NMDA (10⁻³ M, in the absence of Mg²⁺) stimulated the release of [³H]DA, but they reduced the efflux of [³H]water. This reduction of [³H]DA synthesis was blocked by 2-amino-5-phosphonovalerate indicating the involvement of NMDA receptors. Although D,L--amino-3-hydroxy-5-methyl-4-isoxazole-4-propionate (AMPA) and kainate stimulated the release of [³H]DA, they did not affect its synthesis. The glutamate-evoked inhibition of [³H]DA synthesis was prevented when synaptosomes were superfused continuously with adenosine adenosine deaminase plus quinpirole, a treatment which markedly reduces the phosphorylation of tyrosine hydroxylase by cAMP dependent protein kinase. The opposite effects of glutamate on [³H]DA synthesis and release were mimicked by ionomycin (10⁻⁶ M). It is proposed that both an activation of a cyclic nucleotide phosphodiesterase and a dephosphorylation of tyrosine hydroxylase linked to the influx of calcium through NMDA receptors is responsible for the inhibition of dopamine synthesis by glutamate and that calcineurin could play a critical role in these processes.     

Effects of transient forebrain ischemia on long-term enhancement of dopamine release in rat striatal slices

We studied the effects of transient forebrain ischemia in vivo on long-term enhancement of dopamine (DA) release from rat striatal slices. One hour after the high-frequency tetanic stimulation (HFTS) or l-glutamate (10⁻⁶ M) application in Mg²⁺-free medium to striatal slices, the high concentration of KCl (high K⁺)-evoked DA release was measured. Tetanic stimulation or l-glutamate application significantly potentiated the high-K⁺-evoked DA release. When striatal slices were prepared from rats exposed to 3 min of ischemia followed by 24-h survival, the enhancement of DA release by HFTS was unaffected by ischemia. In contrast, the enhancement of DA release by HFTS was impaired in rats exposed to 5 min or 10 min of ischemia. In addition, high K⁺-evoked DA release per se was significantly impaired by 10 min of ischemia. The enhancement of DA release elicited by pretreatment with l-glutamate was also impaired in the rats exposed to 5 min of ischemia. When striatal slices were prepared from rats exposed to 5 min of ischemia with 7-day survival, the enhancement of DA release by HFTS was still impaired. The present results indicate that the neuronal mechanisms of the enhancement of DA release may be more sensitive to impairement from short periods of ischemia. Furthermore, the results suggest that an impairment of long-term enhancement of DA release by ischemia may be related the dysfunction of motor performance in rats exposed to ischemia.     

Sex differences in amphetamine-elicited rotational behavior and the lateralization of striatal dopamine in rats

Sex differences are described in both a lateralized behavior (amphetamine-elicited rotation) and in the lateralization of striatal dopamine (DA) content. Amphetamine (AMPH) elicited significantly more partial turns, total rotations and lateralized (net) rotations in female, than in male rats. The two sexes also differed in their pattern of net rotations over time. In females, but not males, the striatum containing higher DA levels after amphetamine was consistently found to be contralateral to the dominant direction of rotation observed in the first 5 min interval after AMPH. No relationship was found between rotational behavior and medial frontal cortex DA or norepinephrine. The results are discussed in reference to cerebral lateralization in humans, and to possible sex differences in the modulatory effects of gonadal steroid hormones on striatal function.     

Effect of naloxone on morphine-induced changes in striatal dopamine metabolism and glutamate, ascorbic acid and uric acid release in freely moving rats

Recent findings have shown that systemic morphine increases extracellular dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), ascorbic acid (AA) and uric acid concentrations in the striatum of freely moving rats. The morphine-induced increase in DA oxidative metabolism is highly correlated with that of xanthine. In the present study, we evaluated the effects of subcutaneous (s.c.) naloxone (1 mg/kg) on morphine-induced changes in DA, DOPAC, HVA, 5-hydroxyindoleacetic acid (5-HIAA), AA, uric acid and glutamate in the striatum of freely moving rats using microdialysis. Dialysates were assayed by high performance liquid chromatography with electrochemical detection or (glutamate) ultraviolet detection. Morphine (5–20 mg/kg) given s.c. increased DA, DOPAC+HVA, 5-HIAA, AA and uric acid and decreased glutamate dialysate concentrations over a 3 h period after morphine. Morphine (1 mM), given intrastriatally, did not affect all the above parameters, with the exception of an early short-lasting decrease in AA concentration. Naloxone antagonised all morphine-induced changes with the exception of AA increase and glutamate decrease in dialysate concentrations. Systemic or intrastrial (0.2–2 mM) naloxone increased AA and decreased glutamate dialysate concentrations. When given intranigrally, morphine (1 mM) increased DOPAC+HVA, AA and uric acid and decreased glutamate dialysate concentrations over a 2 h period after morphine; DA and 5-HIAA concentrations were unaffected. These results suggest that: (i) morphine increases striatal DA release and 5-hydroxytryptamine oxidative metabolism by a μ-opioid receptor-mediated mechanism mainly at extranigrostriatal sites; (ii) morphine increases DA and xanthine oxidative metabolism and affects glutamate and AA release by a μ-opioid receptor mediated mechanism acting also at nigral sites; and (iii) a μ-opioid receptor-mediated mechanism tonically controls at striatal sites extracellular AA and glutamate concentrations.     

Lack of autoreceptor-mediated inhibitory control of dopamine release in striatal synaptosomes of D2 receptor-deficient mice

Mouse purified striatal synaptosomes were used to study the release of newly synthesised [³H]-dopamine ([³H]-DA) or of previously taken up [³H]-DA. Quinpirole (QP, 10 μM), a D2/D3 dopaminergic agonist, was found to reduce the release of newly synthesised [³H]-DA with a larger amplitude when 4-aminopyridine (100 μM) instead than veratridine (1 μM) or potassium (25 mM) was used to evoke DA release. Among the different D2/D3 dopaminergic agonists tested R(−)-propylnorapomorphine (NPA) and quinpirole were the most potent. These compounds reduced, in a concentration-dependent manner, the 4-aminopyridine-evoked release of [³H]-DA previously taken up by synaptosomes (50% maximal inhibition). In contrast, the D3 agonist PD-128,907 had little effect even when used at 100 nM. The QP (100 nM)-induced response was completely antagonised by sulpiride (1 μM). Strikingly, the NPA (100 nM) and PD-128,907 (100 nM)-evoked responses were completely suppressed in D2 receptor-deficient mice. This data strongly suggest that only D2 but not D3 receptors are involved in the autoreceptor-mediated inhibition of the evoked release of [³H]-DA. Interestingly, while amphetamine-induced release of [³H]-DA was not modified, a slight reduction of [³H]-DA efflux induced by the dopamine (DA) uptake inhibitor cocaine was observed in D2 receptor-deficient mice.     

活体溶出伏安法测定鼠脑缺血时纹状体单胺神经递质的含量变化

应用活体溶出伏安法（ＩＶＶ）连续测定沙土鼠脑缺血再灌流模型纹状体单胺类神经递质多巴胺（ＤＡ）５－羟吲哚乙酸（５－ＨＩＡＡ），并同期测定鼠脑皮质灌流量、脑电活动及腐胶含量。结果发现：１、脑缺血期纹状体ＤＡ与５－ＨＩＡＡ显著增高；再灌流期ＤＡ明显下降，５－ＨＩＡＡ仅在１５ｍｉｎ时有一过性降低，但两者均明显高于缺血前水平。２、脑缺血时脑皮质灌流量显著下降（下降９５％），相应时间的脑电活动明显抑制；再灌流期皮质灌流量有所恢复，但仍明显低于缺血前（约为其３０％），脑电活动亦无恢复。３、脑缺血时脑皮质腐胺含量下降，而再灌流３０ｍｉｎ时显著增高，在９０ｍｉｎ时恢复至正常水平。     

Ketamine anaesthesia has no effect on striatal dopamine metabolism in rats

Striatal levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid and homovanillic acid in rats were not altered for at least 6 h after a ketamine injection (100 mg/kg). Striatal DA turnover which was measured by giving alpha-methyl-p-tyrosine after ketamine was unchanged. Even the dose regimen of ketamine which anaesthetized animals for approximately 3.5 h (100 mg/kg + 5 maintenance injections of 50 mg/kg at 30 min intervals) produced no alteration in DA turnover for at least 9 h. These results suggest that ketamine anaesthesia will not adversely affect studies investigating central DAergic mechanisms in rats.     

Cocaine elevates striatal dopamine efflux in spontaneously hypertensive and Wistar-Fyoto rats

The effects of acute cocaine administration on central dopaminergic systems were examined in the striata of spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats with the use of an in vivo microdialysis technique. Increased extracellular levels of dopamine were observed for 45 to 75 minutes following acute cocaine administration in both halothane-anesthetized and conscious SHR and WKY. However, no significant differences were noted between anesthetized and conscious SHR and WKY in either baseline levels or cocaine-induced changes in extracellular levels of dopamine and its metabolites. A positive, linear correlation between extracellular levels of dopamine and cocaine was demonstrated for the 60-min period following acute cocaine administration in both SHR and WKY. The slopes of the linear regression plots obtained from the data of each 15-min sample was slightly, but significantly, higher in conscious SHR than in conscious WKY. The present results suggest a transient and dose-related stimulation of striatal dopamine release following acute cocaine administration and a linear relationship between striatal extracellular levels of dopamine and cocaine in both SHR and WKY.     

Effects of dopamine depletion on the spontaneous activity of type I striatal neurons: relation to local dopamine concentration and motor behavior

The relation between the electrophysiological activity of Type I striatal neurons, local dopamine (DA) concentration, and motor behavior in rats was investigated using intraventricular administration of the neurotoxin 6-hydroxydopamine (6-HDA) and extracellular single-unit recording. Results are compared with findings of past experiments in which the activity of Type II striatal neurons was examined after comparable 6-HDA-induced lesions. Several differences between the present observations and the earlier results were found. First, although large depletions (greater than 50%) of DA local to the site of the recording were required before the spontaneous firing rate of either cell type was increased, the levels necessary for this effect were found to be less for Type I cells than for Type II neurons. Second, although DA depletions of greater than 50% always were associated with increased Type I cell activity, depletions of greater than 95% resulted in spontaneous firing rates that were lower than those observed after depletions of approximately 90%. Thus, the relation between extent of dopaminergic depletion and Type I cell firing rate was biphasic, whereas that relation previously was found to be monophasic for Type II neurons. Finally, whereas increased Type I cell activity in the lateral striatum was associated with the aphagia, adipsia, and akinesia induced by large DA-depleting brain lesions, increased Type II cell activity in the medial striatum was found to be associated with these impairments. Because accumulating evidence suggests that the functioning of the lateral striatum is more critical for these behaviors, however, it is proposed that the substrate of the behavioral dysfunctions resulting from DA depletion is the Type I cell population in lateral striatum.     

Modulatory action of dopamine on acetylcholine-responsive striatal and accumbal neurons in awake, unrestrained rats

In ambulant rats, iontophoresis of low concentrations of dopamine (DA) enhances the response of neurons in striatum and nucleus accumbens to iontophoretic glutamate. In an extension of this line of investigation, we tested the effects of acetylcholine (ACh), a presumed modulator of neuronal function in these same brain regions, and assessed possible DA-ACh interactions. Data were obtained from spontaneously active neurons known to respond to ACh (5–30 nA) when the animals rested quietly with no overt movement. ACh iontophoresis either excited or inhibited striatal and accumbal activity but excitatory effects predominated in both areas. With multiple applications of ACh, especially at the lowest currents tested, either response often was interspersed with instances of no change in firing rate. Responsiveness to ACh also diminished during periods of spontaneous movement when basal firing showed phasic increases in activity. In fact, neurons with the highest rates of basal activity showed the smallest magnitude response to ACh. Prolonged applications (120–180 s) of DA attenuated basal firing as well as the iontophoretic effects of ACh both during the DA application itself and for up to 1 min after DA ejection offset. The result of these inhibitory effects was no net change in the relative magnitude of the ACh response. Thus, although ACh can modulate striatal and accumbal neuronal activity, DA does not regulate this effect in the same way that it regulates the neuronal responsiveness to glutamate.     

Lateralized changes in behavior and striatal dopamine release following unilateral tactile stimulation of the perioral region: a microdialysis study

Intracranial microdialysis was used to measure dopamine (DA) release in the ventrolateral neostriatum of freely moving rats before and after unilateral tactile stimulation was applied to the orofacial region. Several behavioral parameters which have been linked to changes in nigrostriatal DA transmission (scanning, or snout contact with the walls of the observation chamber, turning and locomotion) were measured as well. Orofacial stimulation was followed by an asymmetrical increase in DA release with concentrations of transmitter higher in the neostriatum ipsilateral to the side of stimulation. Asymmetrical scanning behavior was observed during the time period when DA release was asymmetric, with rats favoring use of the side of the face contralateral to increased DA release. Increase in the DA metabolites DOPAC and HVA were found in the striatum ipsilateral to stimulation, but were delayed 40 min following the increase in DA.     

Dopamine release and uptake rates both decrease in the partially denervated striatum in proportion to the loss of dopamine terminals

The present study tested the hypothesis that normal concentrations of extracellular dopamine are preserved in the partially denervated striatum without active compensatory changes in dopamine uptake or release. One to four weeks after adult rats were unilaterally lesioned with 6-hydroxydopamine, fast-scan cyclic voltammetry at Nafion-coated, carbon-fiber microelectrodes was used to monitor extracellular dopamine levels in vivo, under urethane anesthesia. Simultaneous voltammetric recordings were collected in the lesioned and contralateral control striata. Extracellular dopamine was elicited by bilateral electrical stimulation of the medial forebrain bundle. A 20 Hz stimulation evoked similar concentrations of extracellular dopamine in both lesioned and control striata, although tissue dopamine was decreased 30–70% in lesioned striata, as determined subsequently by HPLC-EC. However, kinetic analysis of the voltammetric recordings revealed that the concentration of dopamine released per stimulus pulse and V_max for dopamine uptake decreased in proportion to the magnitude of the lesion. These data support the hypothesis that normal extracellular dopamine levels can be generated in the partially lesioned striatum in the absence of active neuronal compensation. These results also suggest that passive mechanisms involved in the regulation of extracellular dopamine play an important role in maintaining function during the preclinical or presymptomatic phase of Parkinson's disease.© 1997 Elsevier Science B.V. All rights reserved.     

Pre- and postsynaptic neurochemical alterations following estrogen-induced striatal dopamine hypo- and hypersensitivity

The administration of pharmacologic doses of estrogen results in a biphasic response in striatal dopamine sensitivity, as measured by apomorphine-induced stereotypy. At 24 hr after the last dose of estradiol benzoate (EB) there is a suppression of apomorphine-induced stereotypy, which is followed by an increased sensitivity to apomorphine at 48 hr. The dopamine hyposensitivity is reflected postsynaptically by an increased KD (i.e., decreased affinity) for 3H-spiroperidol binding to striatal membranes, while the hypersensitive phase is reflected by an increased Bmax for 3H-spiroperidol binding to striatal membranes. Presynaptically during the hyposensitive phase the tyrosine hydroxylase displayed a decreased KM for the pterine cofactor. The decreased KM for the cofactor was retained in the hypersensitive animals, however the Vmax for tyrosine hydroxylase was decreased during the hypersensitive phase of the EB-induced changes in dopamine sensitivity. The presynaptic or autoreceptor sensitivity of the dopamine neurons projecting to the striatum was assessed by determining the apomorphine IC50 value for the inhibition of synaptosomal tyrosine hydroxylase activity. Utilizing this assay the animals that were hyposensitive to dopamine showed a normal presynaptic sensitivity, while those animals that had developed a hypersensitivity to dopamine following EB were also hypersensitive to dopamine presynaptically.