Effect of phencyclidine on spontaneous and N-methyl-D-aspartate (NMDA)-induced efflux of dopamine from superfused slices of rat striatum.

Phencyclidine (PCP) acts as an indirect dopamine (DA) agonist by inhibiting the neuronal reuptake of DA, while it also works as a N-methyl-D-aspartate (NMDA) antagonist. Aiming to investigate characteristics of these two properties of PCP in the same experimental system, the effects of PCP on spontaneous and NMDA-induced efflux of DA from superfused slices of the striatum of the rat were examined. Dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) in the samples of superfusate were extracted by alumina extraction and measured by high-performance liquid chromatography with electrochemical detection (HPLC-EC). Phencyclidine at concentrations greater than 1 microM, produced a concentration-dependent increase of the spontaneous efflux of DA. The efflux of DOPAC was also concentration-dependently increased by PCP. However, PCP inhibited the efflux of DA induced by NMDA, even at a small concentration (0.1 microM), which did not alter the spontaneous efflux of the transmitter. The mode of the inhibition by PCP was shown to be noncompetitive, with an estimated IC50 value of 280 nM. These results suggest that PCP, at small concentrations, reduces the synaptic levels of DA by blocking the facilitating effect of endogenous glutamate on the release of DA and, at slightly greater concentrations, the drug also works as an indirect DA agonist, to increase the levels of the transmitter in the synaptic clefts. The clinical significance of the dual effects of PCP is discussed in relation with the unique schizophrenomimetic property of PCP.     

Effects of phencyclidine on extracellular levels of dopamine, dihydroxyphenylacetic acid and homovanillic acid in conscious and anesthetized rats

Dose-dependent effects of phencyclidine on extracellular levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the neostriatum were studied in both urethane-anesthetized and conscious rats. In vivo microdialysis was used to collect 10 min samples that were analyzed for levels of DA, DOPAC and HVA, using high-performance liquid chromatography with electrochemical detection (HPLC-EC). In both the anesthetized and conscious preparations, 20 mg/kg of phencyclidine produced an increase in extracellular levels of DA, 10 mg/kg resulted in no change, while 1 mg/kg produced a slow decrease. In the anesthetized animals phencyclidine did not have a significant effect on levels of DOPAC or HVA, but in the conscious animals phencyclidine produced a dose-dependent decrease in levels of DOPAC and HVA. The increase in levels of DA could be the result of increased release of DA or inhibition of the uptake of DA. The decrease in levels of DOPAC and HVA, at the 1 mg/kg dose, could result from a decrease in the synthesis of DA that is offset at the 10 and 20 mg/kg doses by opposing mechanisms.     

Inhibitory effect of NMDA on dopaminergic transmission in a slice preparation of rat globus pallidus.

The effect of N-methyl-D-aspartate (NMDA) on KCl-evoked endogenous dopamine (DA) release from slices of rat globus pallidus (GP) was examined. NMDA inhibited the KCl-evoked DA release in a dose-dependent manner. This inhibition was blocked by CPP, an NMDA antagonist. Tetrodotoxin partially antagonized the effect of NMDA. The NMDA-induced inhibition was also partially antagonized by bicuculline methiodide and was mimicked by muscimol. These results strongly suggest that 1) an activation of NMDA receptors exerts an inhibitory effect on dopaminergic transmission in GP and 2) GABAergic transmission is involved in the effect of NMDA.     

Spinal antinociceptive effects of excitatory amino acid antagonists: quisqualate modulates the action of N-methyl-D-aspartate

Blockade of N-methyl-D-aspartate (NMDA) receptors in the spinal cord of rodents has been shown to produce antinociceptive effects and motor impairment. To find out whether other receptors for excitatory amino acids (EAA) can influence spinal pathways utilizing the NMDA receptors we compared, in mice, the behavioral consequences of intrathecal injection of four EAA antagonists, 2-amino-5-phosphono valerate (APV), kynurenate, gamma-D-glutamyl glycine (DGG) and glutamylaminomethyl sulphonate (GAMS). The selectivity of these antagonists at different concentrations was evaluated behaviorally by assessing their ability to block the biting behavior elicited by intrathecal EAA agonists. Blockade of the NMDA receptor was necessary to elicit antinociceptive effects and motor impairment. Thus, APV produced antinociception at concentrations selective for the action of NMDA. The wide spectrum EAA antagonists, DGG and kynurenate, and the quisqualate/kainate antagonist, GAMS, all produced antinociception and motor impairment at concentrations which also blocked NMDA-induced bites. However, an inhibitory modulation of the action of NMDA by quisqualate-sensitive systems was also observed. Thus, high concentrations of APV (greater than 1 mM), which also blocked quisqualate-elicited bites, produced a surprising, sharp decrease in APV antinociception and motor impairment, effects which were reversed by quisqualate. Furthermore, quisqualate significantly inhibited NMDA-induced bites. Additional evidence for such an inhibitory-modulatory effect of quisqualate can be gathered from the antinociceptive potency of DGG. This antagonist, which blocks the action of both NMDA and quisqualate, was less potent as an antinociceptive agent than APV. No such discrepancy between the ability to inhibit the action of NMDA and to elicit antinociceptive effects and motor impairment was noted for either kynurenate or GAMS. Evidence is provided that these different profiles of action are due to the fact that DGG and high concentrations of APV act at different subpopulations of quisqualate receptors than do kynurenate and GAMS, and that the former subpopulation is involved in the modulation of the action of NMDA.     

Behavioral sensitization to quinpirole is not associated with increased nucleus accumbens dopamine overflow

This study assessed the relationship between extracellular nucleus accumbens (NAc) dopamine (DA) concentrations and sensitized locomotor activation following repeated administration of the DA D2-like receptor agonist quinpirole. Locomotor activity measures and nucleus accumbens microdialysis samples were collected concurrently in response to the first (acute) and tenth (repeated) quinpirole injection (0.5 mg/kg s.c., every other day). Results indicate that acute quinpirole produced locomotor activation and that repeated quinpirole resulted in locomotor sensitization. Acute quinpirole significantly decreased the detection of extracellular concentrations of DA and the DA metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the NAc. Following repeated quinpirole, basal NAc DA levels were decreased, whereas basal DOPAC levels were increased. Nevertheless, quinpirole challenge elicited a significant decrease in DA, DOPAC and HVA following repeated treatment. In addition, although acute quinpirole did not affect NAc levels of the serotonin metabolite 5-hydroxyindolacetic acid (5-HIAA), quinpirole challenge produced a significant increase in 5-HIAA levels following repeated treatment. Taken together, these data indicate that functional DA autoreceptor subsensitivity is not a necessary condition for the expression of behavioral sensitization to quinpirole. Instead, it appears that behavioral sensitization to quinpirole occurs predominantly as a consequence of neuroadaptations that are post-synaptic to DA release.     

Time-course of the effects of ovarian steroids on the activity of limbic and striatal dopaminergic neurons in female rat brain

This paper studies the time-course of the effects of pharmacological administrations of ovarian steroids on the functional state of dopaminergic terminals in the striatum and the limbic forebrain, using the ratio between the contents of dopamine (DA) and its metabolite, L-3,4 dihydroxyphenylacetic acid (DOPAC), as an index of nerve activity. Estradiol produced an increase in the dopaminergic activity of both limbic and striatal neurons, reflected in the high DOPAC/DA ratio observed in both areas. This estrogenic effect was only observed at 4 hours, disappearing in the subsequent times studied. The effect was antagonized by progesterone in both tissues, since a single injection of this steroid to estrogen-pretreated rats restored to control values the estradiol-induced increase, suggesting the existence of negative interactions between both steroids. Furthermore, treatment with progesterone produced also a late decrease of the DOPAC/DA ratio in the striatum, which was observed only in the animals nonpretreated with estrogens.     

NMDA antagonists block restraint-induced increase in extracellular DOPAC in rat nucleus accumbens

The effects of the N-methyl-D-aspartate (NMDA) receptor antagonists CPP, TCP, PK 26124 and ifenprodil, and of the minor tranquillizer diazepam on stress-induced changes of dopamine metabolism in the nucleus accumbens were investigated in the rat. Dopamine metabolism was assessed by measuring the extracellular levels of 3,4-dihydroxyphenylacetic acid (DOPAC) by means of in vivo differential pulse voltammetry with electrochemically pretreated carbon fiber electrodes. Physical immobilization of the rats for 4 min caused a marked and long-lasting increase in extracellular DOPAC levels in the nucleus accumbens. A similar, though shorter-lasting, augmentation of extracellular DOPAC was observed in the nucleus accumbens after systemic administration of the anxiogenic agent methyl-beta-carboline-3-carboxylate (beta-CCM) (10 mg/kg s.c.). Pretreatment with CPP (1 mg/kg i.p.), TCP (3 mg/kg i.p.), PK 26124 (3 mg/kg i.p.), ifenprodil (3 mg/kg i.p.) or diazepam (2 mg/kg i.p.) totally antagonized the immobilization-induced increase in extracellular DOPAC in the nucleus accumbens. Diazepam and the benzodiazepine (omega 1-2) receptor antagonist flumazenil (30 mg/kg i.p.), but not ifenprodil, also antagonized the beta-CCM-induced activation of dopamine metabolism in the nucleus accumbens. Finally, systemic administration of haloperidol (25 micrograms/kg i.p.) increased the extracellular concentrations of DOPAC in the nucleus accumbens, but pretreatment with ifenprodil (3 mg/kg i.p.) did not modify this response. These data indicate that NMDA receptor antagonists prevent the activation of dopamine metabolism in the nucleus accumbens caused by immobilization stress but not by beta-CCM-induced anxiogenic stimulation. These results suggest that NMDA receptor antagonists may possess an anxiolytic-like action in the rodent, which is exerted via neuroanatomical circuits distinct from those acted upon by diazepam.     

Effects of phencyclidine and dizocilpine on NMDA-, kainate-, and water deprivation-induced drinking in pigeons

The excitatory amino acid (EAA) agonists, N-methyl-D-aspartate (NMDA) and kainate, elicit a copious drinking response in pigeons. NMDA-induced drinking, as compared with kainate- and water deprivation-induced drinking, is selectively antagonized by the competitive, NMDA receptor antagonist CGS 19755, and appears to be mediated by NMDA receptors located in brain. There have been several studies which have reported differences between competitive and non-competitive (PCP-like) NMDA antagonists in blocking various behavioral effects of NMDA, such as discriminative stimulus effects. The present studies examined the effects of the non-competitive antagonists, phencyclidine (PCP) and dizocilpine, on drinking elicited by NMDA, kainate, and water deprivation. PCP and dizocilpine were effective antagonists of NMDA-induced drinking, resulting in surmountable shifts to the right in agonist dose-response functions. These compounds had little effect on drinking evoked by either kainate or water deprivation. These results support the notion that the dipsogenic effects of NMDA are mediated by NMDA-type receptors, and also provide important information as to the characteristics of non-competitive NMDA antagonists. EAA-induced drinking provides a useful tool for the examination of the behavioral pharmacology of EAA agonists and antagonists.     

The importance of dopaminergic neurotransmission in the hypermotility response produced by the administration of N-methyl-D-aspartic acid into the nucleus accumbens

The bilateral injection of N-methyl-D-aspartic acid (NMA) into the nucleus accumbens of rats has been shown to stimulate locomotor activity. This response is antagonized by drugs that interfere with dopaminergic neurotransmission, such as reserpine, alpha-methyl-p-tyrosine (AMPT) and haloperidol, suggesting that NMA may exert its effects by stimulating the release of dopamine (DA) from nerve terminals. To test this hypothesis, the ability of NMA to release endogenous DA from slices of nucleus accumbens, which were incubated in magnesium-free medium was evaluated. It was found that NMA, at concentrations of 0.1 and 1 mM, did not stimulate the release of endogenous DA from slices in magnesium-free normal medium, medium containing pargyline (to inhibit monoamine oxidase) or medium containing methylphenidate (to block the reuptake of released DA). In contrast, both amphetamine (10(-5) M) and a high potassium (20 and 40 mM) stimulated the release of endogenous dopamine. The lack of effect of NMA on the release of endogenous DA was supported by in vivo studies which showed that the injection of NMA into the nucleus accumbens, in a dose that stimulated locomotor activity, did not increase the turnover of dopamine as reflected by an increase in the concentration of DOPAC. In contrast, the direct administration of haloperidol (13 nmol) into the nucleus accumbens produced a marked increase in the concentration of DOPAC. To determine the role of activation of DA receptors in the hypermotility response to NMA, NMA was administered together with subthreshold doses of either DA or apomorphine into the nucleus accumbens of rats pretreated with AMPT.(ABSTRACT TRUNCATED AT 250 WORDS)     

Analysis of extracellular DOPAC, HVA and 5-HIAA in rat striatum in vivo by differential pulse voltammetry: effect of phencyclidine, haloperidol and their coadministration

Phencyclidine (PCP, 10 mg/kg s.c.) produced a marked reduction in the extracellular concentrations of DOPAC and HVA in the rat striatum in vivo, as measured by differential pulse voltammetry. In contrast, extracellular 5-HIAA levels were significantly elevated. Haloperidol (1 mg/kg i.p.) increased DOPAC and HVA, and reduced 5-HIAA, in agreement with previous studies. When PCP and haloperidol were injected together, the effects of PCP were abolished. These results suggest that PCP administration leads to increased activation of dopamine receptors, which results in a decrease in striatal dopamine turnover and an increase in striatal serotonin turnover.     

Involvement of opioid mu1-receptors in opioid-induced acceleration of striatal and limbic dopaminergic transmission.

The role of mu1-opioid receptors in the acceleration of cerebral dopaminergic transmission induced by morphine and the putative mu1-opioid agonist, etonitazene, was studied in rats by measuring the tissue levels of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the dorsal striatum and nucleus accumbens. The striatal extracellular concentrations of DA and its metabolites in freely moving rats were estimated as well. Morphine (3 mg/kg) and etonitazene (2.5 microg/kg) increased the striatal and accumbal dopamine metabolism as measured by the tissue ratios of DOPAC/DA and HVA/DA. The mu1-opioid receptor antagonist, naloxonazine (15 mg/kg), significantly antagonized these elevations except the morphine-induced elevation of striatal HVA/DA ratio. Both morphine (3 mg/kg) and etonitazene (1, 2.5, and 5 microg/kg) elevated the striatal extracellular DA, DOPAC, and HVA. Naloxonazine antagonized the effects of morphine and etonitazene on striatal extracellular DA concentration as well as etonitazene's effects on DOPAC and HVA, but not morphine's effects on DOPAC and HVA. As we previously showed concerning morphine, the conditioned place preference induced by etonitazene was inhibited by naloxonazine. These findings emphasize the role of mu1-opioid receptors in opioid reward, in which the mesolimbic dopaminergic system is considered to be importantly involved. Our results clearly show that in addition to the mesolimbic dopaminergic system the mu1-opioid receptors are also involved in the control of nigrostriatal DA release and metabolism. However, the effects of etonitazene on the striatal DA differ from those of morphine, suggesting that the opioid mechanisms regulating these two DA systems differ.     

The release of dopamine from nerve terminals and dendrites of nigrostriatal neurons induced by excitatory amino acids in the conscious rat

Summary The possible localization of excitatory amino acid (EAA) receptors on dopaminergic neurons was studied by microdialysis in conscious male rats. Varying concentrations of 3 specific EAA agonists, N-methyl-D-aspartate (NMDA), kainate and amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), were infused into the striatum or into the substantia nigra, and the extracellular dopamine (DA) was recorded by the same probe. All 3 compounds induced a dose-dependent increase in both striatal and nigral extracellular DA. Kainate and AMPA were more potent than NMDA. Nigral DA release was stimulated by lower concentrations of kainate and AMPA than striatal DA release.The effects of two concentrations of NMDA and kainate on the release of DA were analyzed in terms of tetrodotoxin (TTX) dependency and sensitivity to ibotenic acid-induced striatal lesion. It appeared that NMDA and kainate stimulated DA release by 3 different mechanisms. The first mechanism is seen at low concentrations of kainate, it fulfills the criteria for a functional receptor-interaction: it is TTX-sensitive and independent of the ibotenic acid lesion. The second mechanism was observed when relatively low concentrations of NMDA stimulate the release of DA; in this effect postsynaptic structures are involved. The third mechanism lacks specificity as it is seen after high concentrations of kainate as well as of NMDA. The latter mechanism is TTX-independent and is probably of a toxic nature. Finally NMDA and kainate were infused into the nigra, whereas DA was recorded with a second probe implanted into the striatum. Kainate and NMDA induced an increase of striatal DA, but kainate was about 100 times more potent in this model than NMDA.The present data therefore support localization of kainate and (probably) AMPA-receptors on nigrostriatal dopaminergic neurons. The receptors on the somatoden-dritic sites were observed to be more sensitive than those on the nerve terminals. Send offprint requests to B. H. C. Westerink at the above address     

Inhibition by phencyclidine of excitatory amino acid-stimulated release of neurotransmitter in the nucleus accumbens

The effects of phencyclidine (PCP) on the release of acetylcholine and dopamine, stimulated by excitatory amino acid agonists was examined in slices of nucleus accumbens of the rat. In slices incubated in [3H]choline or [3H]dopamine, the amount of tritium efflux produced by 1 mM N-methyl-D-aspartate (NMDA), kainic acid (KA) or quisqualic acid (QA) was compared with that produced in the presence of varying concentrations of phencyclidine. N-Methyl-D-aspartate stimulated the calcium-dependent release of both ACh and DA, which was completely inhibited by physiological concentrations of magnesium and inhibited by 2-aminophosphonovalerate (2-APV). Kainic acid- and quisqualic acid-stimulated release of ACh and DA was partially inhibited by magnesium or by 2-APV. Phencyclidine inhibited NMDA-stimulated release of ACh and DA with IC50's around 100 nM. Phencyclidine (0.1 microM) also significantly inhibited kainic acid and quisqualic acid-induced release of ACh in magnesium-free but not magnesium-containing buffer, suggesting that the effect of PCP on kainic acid- and possibly quisqualic acid-stimulated release of ACh is on that part of the response which is mediated by NMDA receptors. The results suggest that the inhibition by PCP of the release of ACh and DA in the nucleus accumbens is selective for NMDA-type receptors.     

盐酸苯环壬酯对最大电休克发作及戊四氮惊厥模型的抗惊作用

目的评价盐酸苯环壬酯抗癫痫疗效，探讨其抗癫痫作用机制。方法建立不同癫痫发作模型，评价盐酸苯环壬酯等药物抗癫痫疗效；观察盐酸苯环壬酯等药物对致死剂量NMDA中毒小鼠、NMDA诱导的原代培养大鼠海马神经细胞损伤及NMDA诱发电流的影响。结果盐酸苯环壬酯在不同癫痫发作模型上均具明显抗惊作用；并可显著对抗致死剂量NMDA中毒，浓度依赖性抑制NMDA诱导原代培养大鼠海马神经细胞损伤及NMDA诱发电流。结论盐酸苯环壬酯在经典癫痫模型上均具显著抗惊作用，其作用机制可能与其对NMDA受体的拮抗作用有关。     

Analysis of S-nitroso-N-acetylpenicillamine effects on dopamine release in the striatum of freely moving rats: role of endogenous ascorbic acid and oxidative stress

1. We showed previously that interaction between NO and iron(II), both released following decomposition of sodium nitroprusside (SNP), accounted for the late SNP-induced dopamine (DA) increase in dialysates from the striatum of freely moving rats. 2. In this study, intrastriatal infusion of the NO-donor S-nitroso-N-acetylpenicillamine (SNAP) (0.2 mM for 180 min) induced a moderate increase in dialysate DA and decreases in ascorbic acid dialysate concentrations; in contrast, SNAP 1 mM infusion induced a long-lasting decrease in both DA and ascorbic acid dialysate concentrations. 3-Methoxy-tyramine (3-MT), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and uric acid levels were unaffected. 3. Co-infusion of ferrous sulphate [iron(II), 1 mM for 40 min] with SNAP either 1 or 0.2 mM (for 180 min), produced a significant increase in both DA and 3-MT dialysate concentrations, but it did not affect decreases in dialysate ascorbic acid levels. All other dialysate neurochemicals were unaffected. 4. Co-infusion of ascorbic acid (0.1 mM) with SNAP (1 mM) for 180 min did not modify SNAP-induced decreases in dialysate DA levels. In contrast, co-infusion of uric acid (1 mM) reversed SNAP-induced decreases in dialysate DA; co-infusion of a superoxide dismutase mimetic delayed SNAP-induced DA decreases for a short period, while co-infusion of the antioxidant N-acetylcysteine (NAC, 0.1 mM) significantly increased dialysate DA. 5. The results of this study show that SNAP induces concentration-related changes in DA dialysate levels. At higher concentrations, SNAP induces non-enzymatic DA oxidation, which is inhibited by uric acid and NAC; ascorbic acid failed to protect dialysate DA from oxidation, probably owing to its promoting effect on SNAP decomposition; exogenous iron(II) may react with NO generated from SNAP decomposition, with a consequent increase in dialysate DA and 3-MT, therefore mimicking SNP effects on striatal DA release.     

Neurochemical and behavioural changes induced by ascorbic acid and d-amphetamine in the rat

In male Wistar rats, ascorbic acid (AA) (1 gr/kg i.p.) significantly (P less than 0.05) decreased the rate of CAR in the shuttle box avoidance test and antagonized the d-amphetamine (d-A) (1 mg/kg s.c.)-induced increase of CAR. Shuttle box test reduced striatal dopamine (DA) levels by about 86% (with a consistent 2-3 fold increase of DOPAC levels). DA levels were greatly reduced also in hypothalamus (HYP) and in hippocampus (HIP). AA further decreased striatal DA but significantly antagonized the reduction of DA levels in HYP and HIP. d-A antagonized the reduction of DA levels in all the above brain regions. Shuttle box test reduced noradrenaline (NA) levels mainly in HIP (-52%) and again d-A showed a significant protective effect in all regions; AA did not interfere with NA level reduction in striatum (ST) and HYP, but antagonized it in HIP. It is concluded that striatal DA system plays an important role in rat operant active avoidance behaviour. AA seems to exert a negative modulatory activity which can be counteracted by d-A.     

Comparison of changes in extracellular dopamine concentrations in the nucleus accumbens during intravenous self-administration of cocaine or d-amphetamine

Changes in extracellular concentrations of dopamine (DA) were measured in vivo in the nucleus accumbens of the rat during intravenous self-administration of either cocaine (0.25, 0.5, 1.0mg/infusion) or d-amphetamine (0.05, 0.1, 0.2mg/infusion). Drug intake was limited to 12 self-administered infusions per session for each drug/dose combination. Changes in extra-cellular DA concentrations were measured by two different techniques: chronoamperometry in conjunction with chronically-implanted stearate-modified carbon paste electrodes, or intracerebral microdialysis with off-line analyses using high performance liquid chromatography with electrochemical detection (HPLC-ED). Significant increases in extracellular DA concentrations were observed with both in vivo techniques during self-administration of each dose of cocaine or d-amphetamine. For each drug, the magnitude of change during the first hour of the test session was comparable across doses. However, the change observed over the first 2h period, as measured by microdialysis and HPLC-ED, revealed a dose effect for cocaine, but no dose-response effect for d-amphetamine. The duration of the drug-induced elevation was increased significantly as a function of dose with both cocaine and d-amphetamine. Data from the microdialysis experiments indicated that the high dose of d-amphetamine (0.2mg/infusion) produced a significantly greater increase in extracellular DA concentrations in the nucleus accumbens than did the high dose of cocaine (1.0mg/infusion), but that comparable changes were induced by doses of 0.1mg/infusion of d-amphetamine and 1.0mg/infusion of cocaine, respectively. Each dose of both psychostimulant drugs also produced a significant decrease in dihydroxyphenylacetic acid (DOPAC) levels. The latter finding indicated that the electrochemical signal measured in these studies was not due to the oxidation of DOPAC. These results confirm that self-administration of cocaine or d-amphetamine by the rat is accompanied by a significant increase in extracellular DA concentrations in the nucleus accumbens. The fact that two different psychomotor stimulant drugs of abuse have qualitatively similar neurochemical correlates when self-administered, adds credence to the hypothesis that their reinforcing properties are related to dynamic changes in DA concentrations in the ventral striatal region of the brain.     

The effect of sodium γ-hydroxybutyrate on the metabolism of dopamine in the brain

1. Sodium gamma hydroxybutyrate (GHB-Na), when given to rats and mice, caused a sleep-like state and a fall in body temperature of about 10 degrees C.2. GHB-Na produced a dose-dependent increase in the concentration of dopamine (DA) in the brains of mice kept at an environmental temperature of 18-20 degrees C or 30-32 degrees C.3. The concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) and 4-hydroxy-3-methoxyphenylacetic acid (HVA), the metabolites of DA, were increased in the striatal tissues of rats and mice, after the administration of GHB-Na. However there was a delay of 60 min before the concentration of HVA increased whereas there appeared to be little delay before the concentration of DOPAC increased.4. When GHB-Na was administered to reserpine-treated animals, no increase occurred in the concentration of dopamine in the brains of mice or rats, or of DOPAC in the rat brain.5. Reserpine did not prevent the induction of the sleep-like state by GHB-Na.6. The results presented suggest that the effect of GHB-Na in increasing the concentration of DA requires unimpaired storage mechanisms for the amine.     

Effects of competitive N-methyl-D-aspartate antagonists on midbrain dopamine neurons: an electrophysiological and behavioral comparison to phencyclidine.

Electrophysiological and behavioral methods were used to evaluate and compare the effects of the competitive N-methyl-D-aspartate (NMDA) receptor blocker, NPC 12626, with the non-competitive NMDA antagonist, phencyclidine (PCP), on the activity of mesolimbic dopamine neurons. NPC 12626 (50 mg/kg, i.p.) produced a degree of locomotor hyperactivity comparable to that seen with PCP (5 mg/kg). However, 6-hydroxydopamine lesions of the nucleus accumbens blocked the PCP-induced hyperactivity but not the behavioral activation evoked by NPC 12626. Single-unit extracellular recordings from ventral tegmental A10 dopamine neurons also found marked differences between the competitive and non-competitive NMDA antagonists. Intravenous injections of NPC 12626 and CGS 19755 in doses up to 60 mg/kg failed to change A10 activity. This was in contrast to the striking bimodal dose-dependent increase-decrease in firing rate elicited by PCP. The absence of an effect of NPC 12626 on A10 neurons was not evidently related to a lack of access to central sites since NPC pretreatment (40 mg/kg, i.v.) completely antagonized the neurotoxicity caused by intrastriatal injection of quinolinic acid, an NMDA agonist, but not that caused by the non-NMDA compound, kainic acid. Thus, competitive NMDA antagonists do not share PCP's properties of activating mesolimbic dopaminergic systems, and as such they may be devoid of the potent psychotomimetic effects or the abuse liability associated with non-competitive NMDA receptor blockers such as PCP.     

Keyword index

The effects of intranigral injection of gamma-aminobutyric acid (GABA) (dose range: 10.0-300.0 nmol), dynorphin A (0.005-0.5 nmol) and substance P (0.00007-7.0 nmol) on striatal dopamine (DA) release, and dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) formation were studied by microdialysis. It was found that both GABA and dynorphin A produced a dose-dependent decrease in the release of striatal DA following injection into the ipsilateral substantia nigra, the pars reticulata. In contrast, intranigral injection of substance P produced an increase in DA release. However, the dose-response curve for the substance P effect had a biphasic shape. The maximum effect was produced by 0.007 nmol, whereas higher doses (0.07-0.7 nmol) produced less pronounced effects. At the highest dose (7.0 nmol), substance P produced a strong decrease of DA release. Striatal levels of DOPAC and HVA were enhanced by GABA, dynorphin A and substance P. The present results support the concept that substance P, directly or indirectly, provides a positive feed-back regulation for the release of striatal DA, whereas GABA and dynorphin exert a negative feed-back regulation.