Effect of ethanol on dopamine synthesis and release from rat corpus striatum.

The effect of ethanol upon dopamine (DA) synthesis and release from dopaminergic terminals was studied. Slices from rat corpus striatum were incubated in freshly oxygenated Krebs-Ringer phosphate (KRP) media of variable ionic composition containing l-tyrosine-¹⁴C (U) as dopamine precursor and in the presence and absence of ethanol (0.1 to 0.8%, w/v). The addition of ethanol directly to normal KRP media produced no effect on the conversion of ¹⁴C-tyrosine to ¹⁴C-DA. As reported previously, tne absence of Ca²⁺ from the incubation media markedly increased the formation of ¹⁴C-DA. The presence of ethanol in this media was not able either to block or to potentiate the Ca²⁺-free induced formation of ¹⁴C-DA. The presence of K⁺ (55 mM) in the incubation media also increased about 2-fold the formation of ¹⁴C-DA. Ethanol (0.2 to 0.8%, w/v) added directly to the KRP-high K⁺ markedly blocked the K⁺-induced formation of newly synthesized ¹⁴C-DA. The presence of ethanol did not modify the amount of ¹⁴C-tyrosine taken up by striatal slices incubated either in normal KRP or KRP-high K⁺ media. A superfusion system was used to study both spontaneous and K⁺-induced release of labeled DA from striatal slices. The addition of ethanol (0.4 to 0.8%, w/v) to the superfusion system was not able either to block or to potentiate the K⁺-induced release of ³H-DA previously taken up by the slices nor the K⁺-induced release of newly synthesized ³H-DA. The results reported in this work, as well as others recently reported by Murrin et al. (Pharmacologist16, 128, 1974), suggest the existence of another regulatory mechanism of DA synthesis besides the commonly accepted one of feedback inhibition exerted by DA upon the rate-limiting enzyme, tyrosine hydroxylase. The possibility is also raised that the inhibitory effect of ethanol described in this paper might play a role in the intoxicating effect of ethanol in vivo.     

Effect of l-tetrahydropalmatine on dopamine release and metabolism in the rat striatum

In vivo voltammetric measurements of striatal extracellular DOPAC concentrations and of striatal DA release in combination with post-mortem analysis of striatal catechols were performed in the rat to study the effects on the nigro-striatal neurons of a Chinese neuroleptic, l-tetrahydropalmatine (l-THP), which is known to block post-synaptic dopaminergic receptors. l-THP injected at doses that cause sedation in rats and mice (5–10 mg/kg) induced a marked increase in post-mortem DOPAC levels (+250%), while no significant effect was observed on post-mortem DA levels. The extracellular DOPAC concentration was increased to 155±9% of the control value after l-THP administration (1 mg/kg, IP). Further, an injection of l-THP (1 mg/kg, IP) induced an increase in extracellular DA concentration (220% of the basal value), reversed the decrease in extracellular DA concentration induced by apomorphine (0.05 mg/kg, SC) and enhanced the effects of the electrical stimulation of the nigro-striatal pathway. These results confirm that l-THP acts on the nigro-striatal neurons as a dopaminergic antagonist that can block both post-and presynaptic receptors.Visiting scholar from Shanghai, Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200031, China     

Synthesis and human neurotensin receptor binding activities of neurotensin(8-13) analogues containing position 8 alpha-azido-N-alkylated derivatives of ornithine, lysine, and homolysine

A series of neurotensin(8-13) (NT) analogues were synthesized through intermediates in which the N-terminal Arg(8) was replaced by various omega-bromo-2(S)-azido residues spanning 3-5 methylene units in side-chain length. Subsequent nucleophilic substitution of the omega-bromo groups with ammonia, methylamine, dimethylamine, or trimethylamine provided peptides containing N-terminal 2(S)-azido residues containing primary through quaternary N-alkylated side chains corresponding in length to ornithine, Lys, and homolysine. The synthetic procedure appears applicable for incorporation of a wide variety of amine-containing nonnatural amino acids into peptides. The particular modifications were intended to enhance physiochemical properties of NT(8-13) responsible for human NT 1 receptor (hNTR) binding, overall lipophilicity, and stability that may influence the potency of the peptides in vivo. When the peptides were tested for hNTR binding, the affinities in each series followed the order primary > secondary > tertiary > quaternary amine with the homolysine side-chain length being favored. All analogues possess binding affinities between acetyl-NT(8-13) and NT(8-13) indicating that the sterically less bulky alpha-azido may be inherently preferable to the acetyl group for N-terminal protection. This study extends the strategy of modifying amine-containing drugs through alkylations to peptide modification. The set of alkylated side chains also offers a new method of steric selection between receptor subtypes and could be used to modify the properties and biological effects of any peptide that contains cationic residues.     

Facilitation of brain stimulation reward by mesencephalic injections of neurotensin-(1-13).

The effects on brain stimulation reward of neurotensin-(1-13) microinjected at different concentrations (2.5, 5, 10 and 20 micrograms/0.5 microliters) into the ventral mesencephalic region containing mesocorticolimbic dopamine neurons were tested in 12 male rats. Neurotensin lowered the stimulation frequency required to sustain threshold levels of responding for brain stimulation reward, suggesting that this neuropeptide is involved in modulating the activity of dopamine neurons that mediate behaviors motivated by positive reinforces. The magnitude of the facilitatory effect of neurotensin on brain stimulation reward was dependent on the concentration injected and to a significant extent also on whether the peptide was administered in an ascending or a descending order of concentration. The different effects of neurotensin depending on the order of administration may suggest long-lasting effects on the responsiveness of neurotensin receptors in this region after injection of high concentrations of the peptide. Subsequent injection of morphine (2.5-5 micrograms/0.5 microliter) into the same site produced a weaker facilitation of brain stimulation reward than expected, suggesting that local damage after multiple central injections or prior injections of neurotensin itself reduced the responsiveness of dopamine neurons to opiates. Taken together, the results are consistent with data indicating that activation of neurotensin receptors in the ventral mesencephalon stimulates dopamine cell firing and axonal dopamine release in limbic terminal fields and suggest that endogenous neurotensin is involved in the control of behavior motivated by positive reinforcement.     

Effect of dopamine D-1 and D-2 receptor selective drugs on dopamine release and metabolism in rat striatum in vivo

Summary The effect of the dopamine (DA) D-1 agonist SKF 38393, the D-2 agonist LY 171555 and the mixed D-1/D-2 agonist apomorphine on striatal DA release and metabolism was tested in vivo using an intracerebral dialysis method in halothane-anaesthetized rats. The specificity of responses to these agonists was tested using the selective DA antagonists SCH 23390 (D-1) and sulpiride (D-2).Both LY 171555, 0.01 mg/kg, and SKF 38393, 10 mg/kg, reduced levels of DA in striatal perfusates. Neither SCH 23390, 0.5 and 5 mg/kg, nor sulpiride, 10 mg/kg, affected levels of DA in striatal perfusates, but 250 mg/kg sulpiride caused a DA increase. The decrease of DA levels induced by LY 171555 (0.01 mg/kg) was prevented by pretreatment with sulpiride (10 mg/kg) but not SCH 23390 (0.5 mg/kg). In comparison, pretreatment with SCH 23390 (0.5 mg/kg) completely inhibited the reduction of DA induced by SKF 38393 (10 mg/kg) while sulpiride (10 mg/kg) was without effect. Apomorphine (0.05 mg/kg) also decreased DA in striatal perfusates and this action was partially inhibited by both SCH 23390 (0.5 mg/kg) and sulpiride (10 mg/kg).Levels of the DA metabolite DOPAC in striatal perfusates also significantly decreased following LY 171555 (0.01 mg/kg) and apomorphine (0.05 mg/kg) but not SKF 38393 (10 mg/kg). The antagonist SCH 23390, in a dose, 0.5 mg/kg, that alone did not increase levels of DOPAC, inhibited the reduction of DOPAC induced by both LY 171555 and apomorphine. Sulpiride, 10 mg/kg, caused a marked increase in striatal DOPAC and this was not affected by a subsequent injection of LY 171555, SKF 38393 or apomorphine.We conclude from these data that DA release in rat striatum is autoregulated by independent D-1 and D-2 receptor-linked mechanisms. In contrast, the level of DA metabolism is controlled by a D-2 receptor-coupled mechanism which can be influenced by the D-1 receptor. This study provides further evidence that DA release and DA synthesis/metabolism are able to change independent of each other.     

Effect of cholecystokinin on acetylcholine turnover and dopamine release in the rat striatum and cortex

The effect of sulfated cholecystokinin (CCK-8S) on acetylcholine turnover (TRACh) and dopamine (DA) release in the rat cerebral cortex and striatum was studied in unanaesthetized animals in vivo. CCK-8S (1 mg/kg s.c.) decreased TRACh in the fronto-parietal cortex but not in the striatum. This effect was prevented by peripheral (10 mg/kg i.p.) but not central (1 microgram i.v.t.) administration of the peripheral CCK receptor antagonist CR 1409. In a separate study, CCK-8S decreased 3-methoxytyramine (3-MT) levels (an index of DA release) in the fronto-parietal cortex and in the striatum. CR 1409 appeared to have a partial agonist action, reducing cortical and striatal 3-MT levels, and only partially reversing the effect of CCK-8S in the striatum. These data indicate that peripheral administration of CCK-8S decrease TRACh in the cortex but not in the striatum and that this action is mediated by peripheral-type CCK receptors possibly located outside the CNS. CCK-8S also reduces DA release in the cortex and in the striatum, and this effect appears to be mediated by a mechanism of action different from that modulating cortical TRACh.     

Effects of adenosine A1- and A2A-receptor agonists on enhancement of dopamine release from the striatum in methamphetamine-sensitized rats.

We report here both adenosine A1- and A2A-receptor agonists inhibit the expression of methamphetamine (MAP)-induced behavioral sensitization in rats. Animals were treated with MAP (1.0 mg/kg, i.p.) every 3 days with a total of 5 administrations. The augmentation of dopamine release from the striatum was demonstrated by MAP re-administration (0.5 mg/kg, i.p.) after 7-day withdrawal by microdialysis. The augmentation of dopamine release was inhibited by pre-treatment not with N6-cyclohexyladenosine (0.01 mg/kg, i.p.) but by with 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxy-amide adenosine (0.1 mg/kg, i.p.). These results suggested that adenosine A1 and A2A receptors play an inhibitory role in sensitization via different mechanisms.     

Release of endogenous dopamine from rat isolated striatum: effect of clorgyline and (-)-deprenyl

High performance liquid chromatography with electrochemical detection was used to measure the release and content of dopamine and dihydroxyphenylacetic acid (DOPAC) from rat isolated striatum. The effects of the monoamine oxidase (MAO) inhibitors clorgyline and (-)-deprenyl on dopamine and DOPAC release and contents, and the IC50 values of these compounds for inhibition of dopamine deamination in rat striatum were determined. Dopamine release was significantly increased by elevated KCl (22 mM) in a Ca2+-dependent manner, and by ouabain (20 muM), whereas the release of DOPAC remained constant. The loss in striatal dopamine content during the incubation period (67% of initial content) was far greater than the amount of dopamine recovered in the incubation fluid (16% of initial content), suggesting that much of the DOPAC, released during incubation originated from the conversion of dopamine to DOPAC within the striatum. A concentration-dependent decrease in DOPAC efflux, both during rest and stimulation periods, was observed in the presence of clorgyline (10(-8)M-10(-7)M) and (-)-deprenyl (10(-5)M-10(-4)M). Higher concentrations of clorgyline (10(-7)M) and (-)-deprenyl (10(-4)M), which inhibited dopamine deamination by 85-90%, enhanced both the resting and KCl-induced release of dopamine. The total amount of dopamine plus DOPAC that was released in the presence of clorgyline or (-)-deprenyl did not differ from control values, suggesting that the increase in dopamine release elicited by MAO inhibitors might result from reduced degradation of dopamine to DOPAC.(ABSTRACT TRUNCATED AT 250 WORDS)     

(-)-1-(Benzofuran-2-yl)-2-propylaminopentane enhances locomotor activity in rats due to its ability to induce dopamine release

"Catecholaminergic and serotoninergic activity enhancer" effects are newly found mechanisms of action of a class of compound that enhance impulse propagation-mediated release of catecholamines and serotonin in the brain. In the present study, (-)-1-(benzofuran-2-yl)-2-propylaminopentane hydrochloride [(-)-BPAP HCl], a compound with selective and potent "catecholaminergic and serotoninergic activity enhancer" effects, was tested for its efficacy to potentiate locomotor activity in normal rats and to attenuate hypolocomotion in reserpine-treated rats. (-)-BPAP HCl potentiated locomotor activity in non-habituated rats during a 2-h observation period dose-dependently (0.3-10 mg/kg). (-)-BPAP HCl (1-3 mg/kg) was also effective to reverse reserpine-induced hypolocomotion. The effects of (-)-BPAP HCl in normal and reserpine-treated rats were attenuated by the dopamine D1 receptor antagonist, R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH 23390), suggesting that the effects of (-)-BPAP HCl were mediated by activation of the dopaminergic system. In addition, the administration of (-)-BPAP HCl increased ipsilateral turning in unilaterally 6-hydroxydopamine-lesioned rats, implying presynaptic activation of nigrostriatal dopaminergic terminals by (-)-BPAP HCl. Furthermore, although antiparkinsonian agents, such as apomorphine and amantadine, failed to improve reserpine-induced ptosis, (-)-BPAP HCl significantly improved ptosis. These findings suggested that a "catecholaminergic and serotoninergic activity enhancer" compound, (-)-BPAP, stimulates motor function in rats and improves motor deficits in animal models of Parkinson's disease due to its ability to induce dopamine release.     

Dynorphin-(1-13), dopamine and feeding in rats

Intraventricular administration of the dopamine agonist, bromergocryptine, reliably induces feeding over a narrow dose range with a bell-shaped curve. Bromergocryptine (80 micrograms) induced feeding is inhibited by the dopamine antagonist, haloperidol (0.5 mg/kg) and the opiate antagonist, naloxone (10 and 1 mg/kg). The leucine-enkephalin containing opioid peptide, dynorphin-(1-13) induces feeding which is inhibited by haloperidol (0.5 and 0.1 mg/kg) and by naloxone (1 mg/kg). Of the common satiety factors tested only bombesin (10 micrograms/kg subcutaneously) inhibited both dynorphin-(1-13) and bromergocryptine induced feeding. Cholecystokinin-octapeptide (10 and 20 micrograms/kg, subcutaneously), thyrotropin-releasing hormone (10 and 20 micrograms), ICV) and calcitonin (1 unit, ICV) all failed to inhibit dynorphin-(1-13)-induced feeding. Calcitonin and CCK-8 but not TRH inhibited bromergocryptine-induced feeding. These studies have demonstrated the close interaction between dopaminergic an dopiate systems in the regulation of food intake. The concept of dopamine being primarily responsible for the initiation of chewing behavior and the opiates regulating food ingestion is compatible with the observations reported here.     

多巴胺受体激动剂对乙醇引起大鼠纹状体抗坏血酸释放的影响

目的　研究多巴胺受体激动剂对乙醇引起大鼠纹状体抗坏血酸 (AA)释放的影响。方法　应用脑内透析技术结合高效液相电化学检测的方法。结果　乙醇 (3 0 g·kg-1,ip)显著增加纹状体抗坏血酸释放 ,高于基础水平的 2 0 0 %左右。多巴胺D1受体激动剂SKF 38393(10mg·kg-1,ip)对纹状体AA释放及乙醇引起纹状体AA释放均无显著影响。多巴胺D2 受体激动剂LY 1715 5 5 (0 5 ,1 0mg·kg-1,ip)显著增加纹状体AA释放及乙醇引起纹状体AA释放 ,但LY1715 5 5与乙醇对纹状体抗坏血酸释放的增加没有协同作用。具有多巴胺D1受体强拮抗剂和D2 受体强激动剂特性的溴隐亭 (10mg·kg-1,ip)在给药后 6 0min内对纹状体AA释放及乙醇引起纹状体AA释放均有显著的增加作用 ,且两者有协同作用。非选择性多巴胺受体激动剂阿扑吗啡也能增加纹状体AA释放及乙醇引起纹状体AA释放 ,而 0 2mg·kg-1的阿扑吗啡与乙醇有协同作用 ,0 4,0 8mg·kg-1的阿扑吗啡与乙醇没有协同作用。结论　多巴胺D2 受体的兴奋参与调节纹状体AA的释放 ,兴奋D2 受体同时抑制D1受体能够协同乙醇引起的大鼠纹状体抗坏血酸释放的作用。     

左旋千金藤立定加强尾核脑片多巴胺释放(英文)

观察左旋千金藤立定((-)-stepholidine,SPD)对家兔尾核脑片多巴胺(DA)释放的影响.方法:以[~3H]DA预孵脑片,测定DA放射性.结果:选择性D_2受体激动剂LY171555以剂量依赖方式抑制电诱发的兔尾核脑片[~3H]DA释放.SPD可翻转LY 171555对[~3H]DA释放的抑制作用,并以剂量依赖方式加强[~3H]DA释放,在无电刺激条件下,SPD诱发大鼠尾核[~3H]DA释放被蛋白激酶C(protein kinase C,PKC)激活剂咐波酯所加强.结论:SPD对突触前D_2自身受体是阻滞剂.     

Effect of buflomedil [4-(1-pyrrolidinyl)-1-(2,4,6-trimethoxyphenyl)-1-butanone hydrochloride] on neurotransmitters in the striatum and substantia nigra

Effect of buflomedil [4-(1-pyrrolidinyl)-1-(2,4,6-trimethoxyphenyl)-1-butanone hydrochloride] administration on central monoaminergic systems was investigated using male Wistar rats. Single administration of buflomedil (300 mg/kg, p.o.) induced a significant increase in the content of homovanillic acid without altering the content of dopamine (DA) and also caused a significant decrease in choline acetyltransferase (ChAT) activity in the corpus striatum. In addition, both L-glutamic acid decarboxylase activity (GAD) and gamma-aminobutyric acid (GABA) content showed a significant decrease in the substantia nigra following a single administration of buflomedil. These results indicate that buflomedil enhances DA turnover in the nigro-striatal DA pathway, possibly by activating nigro-striatal DA neurons, or by suppressing striatal cholinergic interneurons and/or striato-nigral GABAergic neurons.     

Effect of gamma-hydroxybutyrate on dopamine and dopamine metabolites in the rat striatum

Gamma-butyrolactone (GBL), a precursor for the naturally occurring central nervous system depressant, gamma-hydroxybutyrate (GHB), administered in anesthetic doses, produces an increase in rat corpus striatum dopamine levels without affecting norepinephrine or serotonin levels. The rise and fall of the dopamine levels coincide with the changes of brain GHB levels and the behavioral effects of the drug. The specific activity of striatal dopamine was found to be greater in rats injected with ³H-tyrosine shortly before or shortly after GBL, as compared with controls, which were not treated with GBL. The specific activity of cortical norepinephrine in GBL-treated rats was not significantly different from that observed in untreated controls. No significant difference was observed in blood or striatal tyrosine specific activity of GBL-treated rats. Levels of dopamine metabolites, dihydroxyphenylacetic acid and homovanillic acid, also increased in the corpus stratium after GBL, but the increase did not occur until after brain levels of GHB began to fall. These results suggest that the drug either increases dopamine synthesis and or blocks the release of dopamine from a rapidly turning over functional compartment within the neurons, or both. Perhaps as a result of the ability of GHB to block the release of dopamine, this drug also interferes with the metabolism of dopamine for a certain period of time after administration.     

A possible mechanism of action of thyrotropin-releasing hormone (TRH) and its analog DN-1417 on the release of dopamine from the nucleus accumbens and striatum in rats

Slices of the nucleus accumbens, the terminus of the mesolimbic dopaminergic system and the striatum, the terminus of the nigrostriatal dopaminergic system obtained from rats, were used for analyzing the dopamine releasing effects of TRH and its analog DN-1417 (gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-prolinamide citrate). (1) Dopamine release: The addition of DN-1417 (5 X 10(-5) M) or TRH (5 X 10(-4) M) stimulated the release of prelabelled [3H]-dopamine (DA) from the superfused nucleus accumbens slices, and 100 or 20 times higher concentrations of each compound stimulated DA release from the striatal slices. The omission of Ca2+ from the superfusion medium or the addition of ouabain (5 X 10(-3) M), a (Na+ + K+) stimulated adenosine triphosphate (ATP) phosphohydrolase [(Na+ + K+)-ATPase] inhibitor, almost completely abolished the DN-1417- or TRH-induced DA releasing effect. (2) 45Ca2+ uptake: The addition of DN-1417 (10(-4) M) or TRH (10(-4) M) stimulated 45Ca2+ uptake into the nucleus accumbens slices in a time-dependent manner from 1 to 5 min at 30 degrees C. On the other hand, both drugs (10(-4) M) had no effect on 45Ca2+ uptake into the striatal slices. A Ca2+ ionophore, A-23187 (10(-6) M), stimulated 45Ca2+ uptake into slices of the nucleus accumbens and striatum. Ouabain abolished the DN-1417-, TRH- and A-23187-induced effects. (3) Cyclic AMP formation: The addition of DN-1417 (10(-4) M) or TRH (10(-4) and 10(-3) M) accelerated cyclic AMP formation in the nucleus accumbens, but not in the striatal slices. A Ca2+ antagonist, methoxyverapamil (D-600, 10(-6) M) almost completely abolished the DN-1417- and TRH-effects. (4) (Na+ + K+)-ATPase activity: The addition of DN-1417 (10(-5) and 10(-4) M) or TRH (10(-4) M) activated (Na+ + K+)-ATPase in the P1 fraction (cell debris, nuclei) of the nucleus accumbens, but had little effect on the same activity in the striatum. (5) [3H]-TRH binding: The addition of 10(-6) to 10(-4) M of DN-1417 and TRH inhibited concentration-dependently [3H]-TRH binding in the nucleus accumbens and striatal slices. Ouabain (5 X 10(-3) M) almost completely abolished [3H]-TRH binding in both types of slices.(ABSTRACT TRUNCATED AT 400 WORDS)     

Evaluation of lactam-bridged neurotensin analogues adjusting psi(Pro10) close to the experimentally derived bioactive conformation of NT(8-13)

The neurotensin C-terminal hexapeptide, NT(8-13), which has been found to adopt a beta-strand-like conformation while bound to the NT1 receptor, was modified by the introduction of conformational constraints. Synthesis of the four stereoisomeric 4.4-spirolactams 1-4 and subsequent NT1 receptor binding studies showed that the restriction of psi(Pro10) to approximately 130 degrees leads to a more than 1000-fold increase of binding affinity for 1 (Ki = 12 nM) when compared to the more flexible analogue [NMeTyr11]NT(8-13).     

Effect of ethanol on GABA uptake and release from hypothalamic fragments

A study was performed on the effect of ethanol on the basal and K⁺-evoked efflux of endogenous GABA from rat hypothalamic fragments. The amount of GABA present in the medium and in the tissue was measured by radioreceptor assay. In vitro addition of ethanol (50 and 100 mM) enhanced the K⁺-evoked efflux of GABA in a Ca⁺⁺-dependent manner, and increased tissue GABA content. Since K⁺-evoked outflow induced by ethanol was not affected by the presence of nipecotic acid, ethanol appears to alter the uptake of endogenous GABA. An inhibitory effect of ethanol on ³H-GABA uptake was observed under K⁺ depolarization. On the other hand, acute ethanol administration produced a decrease in basal and K⁺-evoked efflux from hypothalamic fragments and in tissue GABA concentration. Changes in GABA efflux may lie behind some of the neuropharmacological effects of ethanol.     

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.