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Recent data indicate that striatal dopamine release induced by stimulation of delta-opioid receptors is a consequence of glutamate release. However, glial cells, which mainly support glutamate uptake and are involved in glutamate signaling and potentially express delta-opioid receptors, could participate to this effect. The present study investigates the contribution of glial cells in the releasing effects of [d-Pen2, d-Pen5]-enkephalin (DPDPE) by using the gliotoxin l-alpha-aminoadipate (l-alpha AA). Initially, we evaluated the early influence of l-alpha AA local infusion (10 microg/microL) on dialysate levels of glutamate and dopamine under basal or DPDPE treatment conditions. l-alpha AA produced a significant increase of glutamate and dopamine in dialysates (+76% and +50% respectively) and the concomitant infusion of DPDPE (10 microM) significantly enhanced this effect in an additive manner (+110% and +44% respectively). Secondly, we assessed the DPDPE effects on striatal glutamate and dopamine dialysate levels, 2 days after an intra-striatal injection of l-alpha AA which produced destruction of glial cells. This lesion, decreasing the basal glutamate dialysate level as well as its tissue content (by 55% and 36% respectively), prevented the increase in glutamate and dopamine extracellular levels induced by DPDPE. This result confirmed that the DPDPE-induced dopamine release requires an initial glutamate release. However, this effect could reflect a major disruption of glutamatergic transmission caused by the toxin, as suggested by the local infusion of glutamine (2.5 mM) which, in lesioned rats, prevented the decrease in the basal extracellular content of glutamate and restored the DPDPE-induced increase in glutamate and dopamine dialysate levels. Therefore, these results indicate that, although glial cells are essential to maintain functional glutamatergic neurotransmission, they are not directly involved in the process by which stimulation of striatal delta-opioid receptors induces extracellular glutamate release and, consecutively, dopamine release.

Background and Purpose: In the present study we investigated, in a range of in vivo tests whether the antidepressant bupropion, and its metabolites shared the dopamine releasing effect of the chemically related dexamphetamine., Experimental Approach: We compared bupropion and dexamphetamine in different neurochemical (microdialysis, DOPAC and HVA contents) and behavioural tests, assessing their effects in animals pretreated with a variety of agents (reserpine, sodium hydroxy-4-butyrate or haloperidol) known to modify dopaminergic transmission., Key Results: In mice, dexamphetamine, like bupropion, increased at low doses and reduced at high doses, locomotor activity. Dexamphetamine restored the locomotor activity in mice made akinetic by either sodium hydroxy-4-butyrate or reserpine, whereas bupropion did not. Moreover, bupropion prevented the dexamphetamine-induced reversal of akinetic effects of reserpine. Haloperidol abolished the locomotor-stimulant effects of dexamphetamine but did not suppress stimulation by bupropion. In microdialysis experiments, in chloral hydrate anesthetized rats, low doses of dexamphetamine (1 mg kg(-1)) markedly increased the extracellular dopamine concentration in striatum (340%), while bupropion (100 mg kg(-1)) produced only a moderate increase (150%). Finally, in rat striatum, as well as in the nucleus accumbens, bupropion increased the effect of haloperidol on DOPAC and HVA concentrations, whereas dexamphetamine reduced these haloperidol effects., Conclusions and Implications: Considering only dopaminergic transmission, our results demonstrated that bupropion and metabolites displayed in vivo, as did bupropion in vitro, an inhibition of dopamine uptake and, contrast to dexamphetamine, were devoid of dopamine releasing effects.

We have previously shown that striatal dopamine release induced locally by a delta-opioid receptor agonist was totally inhibited by a glutamate N-methyl-D-aspartate receptor antagonist, indicating the involvement of glutamatergic receptors in this effect. The aim of the present study was to specify this mechanism. Firstly, we investigated the effect of [D-Pen2,D-Pen5]-enkephalin (DPDPE) on glutamate release in rats by intrastriatal microdialysis. The infusion of DPDPE (10 microm) enhanced the glutamate content in dialysate by approximately 34%, an effect which did not appear to result from inhibition of glutamate uptake. We then considered the consequences of a unilateral thermocoagulation of the frontal cortex on either glutamate or dopamine release induced by stimulation of delta-opioid receptors 2 days later. This lesion, which decreased the glutamate content in ipsilateral striatum by approximately 30%, totally prevented the increase in dialysate levels of glutamate induced by DPDPE. Moreover, whereas DPDPE (10 microm) was found to increase the striatal dopamine release in intact animals by approximately 59%, this effect was also completely suppressed by the cortical lesion. Finally, we studied the effect of the lesion on the [3H]-DPDPE binding to striatal membranes prepared from the whole striatum. In the ipsilateral striatum a significant decrease in this [3H]-DPDPE binding (by approximately 18%) was found 2 days after the lesion. Our results indicate that the increase in striatal dopamine release induced by DPDPE probably depends on glutamate release from corticostriatal glutamatergic afferents in response to the stimulation of delta-opioid receptors located on terminals of these neurons.

3,4-Dihydroxyphenylacetaldehyde (DOPAL) is formed by the oxidative deamination of dopamine (DA) catalyzed by monoamine oxidases (MAO); then, the aldehyde is oxidized to 3,4-dihydroxyphenylacetic acid (DOPAC) by aldehyde dehydrogenases (ALDH) or reduced to 3,4-dihydroxyphenylethanol (DOPET) by aldose/aldehyde reductases. The present work aimed at evaluating the in vitro toxicity of DOPAL on catecholaminergic neuroblastoma SH-SY5Y cells which accumulate DA. DOPAL synthesis was stimulated by incubating cells with DA and blocking DOPAL oxidation by disulfiram, an irreversible inhibitor of ALDH. As evidenced by MTT reduction assays, DA and disulfiram treatments produced cell losses which increased with time. 10(-2)M DA reduced by 40% cell viability after a 1h treatment, when its TC(50) (concentration reducing viability by 50%) value was 7.3 x 10(-5) M after a 24 h treatment. For the same treatment periods, TC(50) values for disulfiram were 8 x 10(-5) and 8.7 x 10 (-7) M, respectively. MTT reduction assay performed after a 24h treatment followed by a 24h incubation in a drug-free medium evidenced that the toxicity of 10(-4)M DA or 10(-6)M disulfiram was potentiated by the second drug. HPLC measurements showed that DOPAL was produced at the early stages of the treatment by DA and disulfiram. This was evidenced by the significant increase in the ((DOPAL + DOPET)/DOPAC ratio observed after a combined 3h treatment by 10(-4)M DA and 10(-6)M disulfiram. Total contents in DA and DOPAL were greatly reduced at the end of a 15 h treatment, and disulfiram did not significantly enhanced the (DOPAL + DOPET)/DOPAC ratio. For both treatment durations, DOPAL and DOPET were detectable only in the extracellular medium. So, these results suggest that an early production of DOPAL could produce delayed toxic effects on SH-SY5Y cells. Production of DOPET and release of DOPAL could be important means for reducing DOPAL concentrations in dopaminergic neurons.

It is well documented that VMAT2 protects nigrostriatal DA neurons against MPP(+) by sequestering it inside vesicles away from its mitochondrial site of neurotoxic action. However, the implication of the VMAT2 in the mechanism of action exerted by 6-OHDA has received little attention. Therefore, the aim of the present study was to determine whether the vesicular sequestration of 6-OHDA would protect dopaminergic neurons from its toxicity similarly to what is observed with MPP(+). We injected mice with 6-OHDA 90 min after TBZ treatment. Since, unexpectedly, TBZ pretreatment prevented 6-OHDA neurotoxicity, we performed a similar experience replacing 6-OHDA with MPP(+) in order to check our experimental protocol. TBZ pretreatment similarly prevented MPP(+) neurotoxicity. This discrepancy with what is commonly describe in the literature, led us to use reserpine. Indeed, the long lasting VMAT2 inhibition induced by reserpine allowed us to inject neurotoxins while mice no longer presented hypothermia. Contrary to TBZ pretreatment, reserpine pretreatment potentiated both 6-OHDA and MPP(+) toxicity on dopaminergic neurons. Hypothermia elicited by TBZ appeared to be responsible, at least in part, for the neuroprotective effect observed. To verify this hypothesis, we investigated the influence of hypothermia on the toxic activity of both neurotoxins. A hypothermia similar to that induced by TBZ was obtained by a forced swimming test of putting mice into cool water (23 degrees C). The hypothermia prevented both 6-OHDA and MPP(+)-induced neurotoxicity. We finally reported that VMAT2 inhibition potentiates both MPP(+) and 6-OHDA neurotoxicity.

Previously established dose-response curves indicated that modafinil 20-40 mg/kg i.p. elicited in mice an obvious stimulation of locomotor activity roughly similar to that induced by (+)amphetamine 2-4 mg/kg. The effects of various agents modifying dopamine transmission were compared on the locomotor response to both drugs. The preferential D2 dopamine receptor antagonist haloperidol 37.5-150 micrograms/kg i.p. suppressed the stimulant effect of (+)amphetamine in a dose dependent manner, but not that of modafinil. The D1 dopamine receptor antagonist SCH 23390 (7.5-30 micrograms/kg s.c.) reversed the (+)amphetamine but not the modafinil induced hyperactivity. The tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (200 mg/kg) suppressed the hyperactivity induced by 4 mg/kg dexamphetamine but not that induced by 20 mg/kg modafinil. Associating L-DOPA 150 mg/kg and benserazide 37.5 mg/kg with (+)amphetamine 2 mg/kg resulted in stereotyped climbing behavior, that was not observed with modafinil 10-80 mg/kg. The profound akinesia induced by reserpine (4 mg/kg s.c.; 5 h before testing) was reversed by (+)amphetamine 2 mg/kg but not by modafinil 40 mg/kg. Finally, on synaptosomes prepared from mouse striata preloaded with [3H]dopamine, modafinil 10(-5) M did not increase the spontaneous [3H]dopamine release whereas (+)amphetamine, at the same concentration, doubled it. From all these differences between the two drugs, it is concluded that the mechanism underlying the modafinil induced stimulant locomotor effect differs completely from that of (+)amphetamine.

The long-term effects of a unique injection of reserpine (5 mg/kg s.c.) on the vesicular monoamine transporter and dopamine uptake complex have been investigated, in parallel with behavioral and neurochemical effects. Early after treatment, a dramatic decrease in locomotor activity, as well as a marked depletion in striatal dopamine (DA), associated with a prominent enhancement in dopaminergic turnover were observed in reserpine-treated rats. From 2 to 60 days after reserpine injection, a recovery in locomotor activity occurred, in parallel with an increased DA content in the striatum, reaching about 50% of controls at day 60. At this time, the dopamine turnover was quite normal. The density of the dopamine uptake sites in the striatum, studied with 3H GBR12783, was unchanged after reserpine treatment at any time studied up to 60 days. By contrast, the density of binding sites for 3H dihydrotetrabenazine (3H TBZOH), a marker for the vesicular monoamine transporter, remained dramatically decreased in the striatum all over the time of the study (> -90% of controls at day 2 and -80% at day 30 and 60). A lesser decrease (-60%) was observed in the substantia nigra pars compacta (SNc), 2 and 30 days after reserpine treatment. This suggests that at least 60% of the vesicular monoamine transporter is sensitive to reserpine in this cell bodies region, indicating that this proportion of the transporter is integrated in functional vesicles, a prerequisite for reserpine binding.(ABSTRACT TRUNCATED AT 250 WORDS)

The dopamine carrier (dopamine uptake complex) is located on the membrane of dopaminergic neurons in a diffuse pattern. It is involved in the uptake of the dopamine released into the synaptic cleft. Considered at the level of nigro-striatal dopaminergic neurons, whose degeneration is responsible for the Parkinson's disease, this carrier seems to constitute a major target. It could be involved in the nigro-striatal neurodegeneration by concentrating neurotoxins. Its in vivo labelling by position emitting agents should allow evidencing of a partial striatal dopaminergic denervation, before the occurrence of extrapyramidal troubles. Its blockable by pure dopamine uptake inhibitors, by preventing the neuronal concentration of toxins, could stop the neurodegeneration process. These agents by inhibiting the dopamine reuptake, could also lessen extrapyramidal troubles as well as the depressive manifestations which are frequently associated to Parkinson's disease.

When mice are introduced into an open-field, they are inclined to explore mainly the peripheral zone of this open-field. This tendency to remain close the walls, called thigmotaxis, decreases gradually during the first minutes of exploration. We have considered the degree of thigmotaxis during this period of decrease as an index of anxiety in mice. This hypothesis has been validated with several reference anxiogenic drugs (dexamphetamine, pentylenetetrazole, yohimbine, idazoxan) which increased thigmotaxis; and with anxiolytic drugs (buspirone, phenobarbital), which reduced it. On this test the selective or non-selective indirect dopamine agonists GBR 12783, dexamphetamine and cocaine induced an increase of thigmotaxis. Finally, the simultaneous involvement of D1 and D2 dopamine receptors has been evidenced in the anxiogenic-like effect associated with an increase of dopaminergic transmissions.

Intracerebroventricular (i.c.v.) administration of [D-Trp11]neurotensin to rats decreased locomotor activity at a low dose (30 ng) and increased it at a high dose (750 ng). Only this high dose increased the dopamine turnover in the nucleus accumbens. The locomotor stimulant effect elicited by this high dose was potentiated by the dopamine uptake inhibitor, GBR 12783 (1-[2-(diphenyl-methoxy)ethyl]4-(3-phenyl-2-propenyl) piperazine) (5 mg/kg, i.p.), and reduced by the dopamine releaser, dexamphetamine (1.5 mg/kg). It was suppressed by the bilateral injection of 6-hydroxydopamine (8 micrograms/2 microliters) into the nucleus accumbens when rats were tested 4 days after the lesion. Fifteen days after the lesion, the i.c.v. administration of 750 ng of [D-Trp11]neurotensin induced hypolocomotion during the first hour of the test, and hyperlocomotion during the second hour. This latter locomotor stimulant effect was suppressed by the dopamine antagonist, haloperidol (50 micrograms/kg, i.p.). Thus, the hypokinetic effect of 30 ng [D-Trp11]neurotensin is independent of dopamine transmission, whereas the hyperkinesia elicited by 750 ng proceeds via an increase in dopamine transmission in the nucleus accumbens.

In anesthetized rats, the intrastriatal infusion of the delta-opioid receptor agonist, [D-Pen2,D-Pen5]enkephalin, increased the extracellular concentration of dopamine. This effect was abolished by the NMDA receptor antagonist, 3-[(+/-)-2-carboxypiperazine-4-yl]propyl-1-phosphonate, but was unchanged by the AMPA (D,L-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate) and kainate receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione. This suggests that the dopamine release induced by the delta-opioid agonist depends critically on the involvement of glutamatergic transmission via NMDA receptors.

A chronic treatment (10 mg/kg, twice daily during 9 days) with the dopamine uptake inhibitor GBR 12783 was performed in rats at a dose increasing their locomotor activity. Forty-eight hours after the last administration, animals were sacrificed and 3H mazindol binding was performed on brain slices. Autoradiographic analysis revealed no change in this binding relatively to control animals in regions with high dopamine contents: striatum, nucleus accumbens, olfactory tubercle, substantia nigra and ventral tegmentum area. The treatment did not either modify the levels of dopamine (DA) and metabolites (HVA, DOPAC) both in the striatum and the nucleus accumbens. Thus, early after the end of the treatment, the chronic blockade of the dopamine uptake complex regulates neither the dopamine uptake complex nor the dopamine metabolism.

Prolonged incubation of synaptosomes in Krebs-Ringer oxygenated medium in the presence of ascorbic acid (10(-4) M) led, after 20 min, to a decrease in [3H]dopamine (DA) (synaptosomes prepared from the striatum) and [3H]serotonin (5HT) (synaptosomes prepared from the cortex) uptake. The decrease was progressive and uptake was virtually abolished after a 60 min incubation period. A concentration-dependent (from 5 x 10(-6) M) role of ascorbic acid in the decrease of [3H]DA or [3H]5HT uptake was demonstrated. This decrease was potentiated by Fe2+ ions and prevented by the ferrous chelating agent desferrioxamine. Thus, the progressive decrease in synaptosomal uptake of either [3H]DA or [3H]5HT could depend on the generation of free radicals by the association of ascorbic acid with Fe2+ ions. The decrease in synaptosomal uptake was prevented, in a concentration-dependent manner, by the Ginkgo biloba extract EGb 761 (4-16 micrograms/mL) and the vitamin E analog trolox C (10(-4) M). The terpenic fraction of EGb 761, Bn 52063 (up to 0.5 microgram/mL), did not prevent the reduction of [3H]amine uptake. In contrast, the flavonoidic fraction, Cp 202, was effective (from 1 microgram/mL) and its efficacy was shared by the flavonoid quercetin (from 0.1 microgram/mL). The prolongation of the ability of synaptosomes to take up [3H]amine elicited by EGb 761, in particular its flavonoidic fraction, as well as by trolox C could be due to their free radical scavenger properties.

Interactions between dopamine and neurotensin can occur at various levels of the dopaminergic pathways. By using different approaches in vitro, we investigated the proposed hypothesis that neurotensin might bind to dopamine in the synaptic cleft. Nuclear magnetic resonance spectra of neurotensin were not modified by the addition of dopamine, and no nuclear Overhauser effect was detected. Synaptosomal uptake of [3H]dopamine in the presence of neurotensin did not lead to any modifications of the kinetic constants of the uptake. Neurotensin binding was not modified by the addition of dopamine. These results did not confirm the suggestion that neurotensin can form a complex with dopamine.

Intrastriatal kainic acid injection destroys the neurons originating from the striatum, including those on which terminals of the nigro- and meso-striatal dopaminergic neurons project. We have studied at various times the consequences of this lesion on dopamine metabolism and on the neuronal and vesicular transporters. Two and 15 days after kainic acid injection, whereas dopamine turnover was increased and the dopamine content unchanged, there was no modification in the binding of [3H]GBR 12783, a marker of the neuronal uptake complex, but the binding of [3H]dihydrotetrabenazine, a marker of the vesicular transporter, was significantly decreased. At later times (30 and 60 days) when the dopamine turnover was decreased as well as the dopamine content, the binding of [3H]dihydrotetrabenazine was more dramatically decreased (about 30% of controls) than that of [3H]GBR 12783. In addition autoradiography showed an increase in the density of [3H]dihydrotetrabenazine binding sites in the substantia nigra. Thus it appears that the long-term (60 days) repercussions of a kainic acid lesion affect simultaneously the dopamine turnover (which is decreased) and the vesicular transporter whereas the dopamine uptake complex is little affected.

Kainic acid lesion of the striatum leads to the disruption of the striatonigral regulatory loop. Although microdialysis showed an increase in dopamine release, two days after kainic acid injection, 3-methoxytyramine levels are dramatically decreased. This suggests that the postsynaptic membrane-bound catechol-O-methyltransferase (COMT), but not the glial COMT, is responsible for the formation of measured 3-methoxytyramine.

The present study investigated the effects of a striatal lesion induced by kainic acid on the striatal modulation of dopamine (DA) release by mu- and delta-opioid peptides. The effects of [D-Pen2,D-Pen5]-enkephalin (DPDPE) and [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAGO), two highly selective delta- and mu-opioid agonists, respectively, were studied by microdialysis in anesthetized rats. In control animals both opioid peptides, administered locally, significantly increased extracellular DA levels. The effects of DPDPE were also observed in animals whose striatum had been previously lesioned with kainic acid. In contrast to the effects of the delta agonist, the significant increase induced by DAGO was no longer observed in lesioned animals. These results suggest that delta-opioid receptors modulating the striatal DA release, in contrast to mu receptors, are not located on neurons that may be lesioned by kainic acid.

Various characteristics of the in vivo striatal binding of [3H]GBR 12783 (1-[2-(diphenylmethoxy)-ethyl]-4-(3-phenyl-1[3H]-2-propenyl)pipera zine), a specific ligand of the neuronal dopamine uptake complex, were determined in mice. Increasing doses of the ligand revealed the saturability of the binding at a single site with half-maximal saturation at a dose of approximately 7 mumol/kg and an apparent maximal number of binding sites (Bmax) of 12.8 pmol/mg protein in striatum. Specific binding was prevented by various dopamine uptake blockers, pyrovalerone, GBR 13069, GBR 12783, N-[1-2-benzo(b)thiophenyl)cyclohexyl] piperidine, cocaine, methylphenidate and was inhibited in a stereoselective manner by the enantiomers of nomifensine. Other drugs which are not dopamine uptake blockers either did not modify [3H]GBR 12783 binding (the diphenylbutylpiperazine derivative flupenthixol) or increased it (the diphenylpiperazine derivative flunarizine or the chemically unrelated compounds fenfluramine and SKF 525A). A close correlation was found between occupancy of the striatal [3H]GBR 12783 binding site and the stimulant locomotor effect of the drug. A similar specific striatal binding of [3H]GBR 12783 was evidenced in both NMRI and CD1 strains. It was concluded that [3H]GBR 12783 administered in vivo provides a measure of the density of dopamine uptake sites in mouse striatum.

In aggregated mice the lethal dose 50% (LD50) of (+)amphetamine was found to be clearly lower than in isolated animals (dose ratio: 6:1), whereas with the pure dopamine uptake inhibitor GBR 12783, the ratio was only 2. Pretreatment of mice with GBR 12783 (20 or 40 mg/kg ip) did not reduce the lethality of (+)amphetamine (10 mg/kg) in aggregated mice. Taking into account their relative affinity for D1 and D2 dopamine receptors, various DA antagonists were opposed to (+)amphetamine (20 mg/kg) in aggregated mice. The specific D1 antagonist SCH 23390 was especially effective (ID50 10 micrograms/kg). The specific D2 antagonists (+/-) sulpiride and metoclopramide were effective for high doses (ID50 = 43 and 19 mg/kg respectively). The dopamine antagonists haloperidol and alpha-flupenthixol, less specific as regards D1 vs D2 receptors, had an ID50 of 66 and 186 micrograms/kg respectively. Association of the D1 antagonist SCH 23390 with the D2 antagonist (+/-) sulpiride resulted in an apparent additive effect for reducing the (+)amphetamine-induced lethality. A semi-chronic treatment with either the D1 agonist SKF 38393 (7 x 20 mg/kg) or (+)amphetamine (6 x 10 mg/kg) performed in isolated mice did not reduce the lethality induced by (+)amphetamine (20 mg/kg) in aggregated mice. The antagonism of the (+)amphetamine-induced lethality in aggregated mice, frequently used to screen meuroleptics, reveals their antagonistic activity towards D1 or D2 dopamine receptor types.

The neurotoxin 6-hydroxydopamine (6-OHDA) was intracerebroventricularly injected (50 micrograms per mouse) in mice submitted to various oxygenation conditions and the striatal levels of dopamine (DA) and its metabolites were determined by HPLC 7 days later. In normoxic conditions the striatal depletion in DA reached 50%. This effect was not modified by a normobaric hypoxia (10% O2) applied 30 min before and 30 min after the 6-OHDA injection. On the contrary, the neurotoxic effect was reduced when the hypoxia was prolonged up to 11 h after the drug administration. When a normobaric hyperoxia (60% O2) was applied 30 min before and 11 h after the 6-OHDA injection, the neurotoxic effects of the latter were not modified. These data, as well as other results obtained from ex vivo experiments showing that normobaric hypoxia or hyperoxia did not modify the striatal synaptosomal [3H]DA uptake, indicate that oxygen availability does not exert a critical influence on the efficiency of the neuronal dopamine uptake complex.

The present study focuses on the changes of two biochemical markers of the striatal dopaminergic innervation evaluated after different postmortem storage periods of rat heads either at room temperature (21 degrees C) or at 4 degrees C: (i) the uptake of [3H]dopamine (DA) into striatal synaptosomes and (ii) the specific binding of [3H]GBR 12783, a selective ligand for the neuronal dopamine uptake sites, to a striatal membrane fraction. The uptake of [3H]DA was completely abolished after 24 and 72 h storage of the tissue at 21 degrees C and 4 degrees C, respectively, whereas in the same conditions, the binding of [3H]GBR 12783 was slightly decreased. The Km and Kd of these two processes were virtually unchanged after the different storage periods considered, whereas the Vmax and Bmax were markedly decreased.

DBA2 mice show an erratic spontaneous climbing which is reduced by increasing doses of direct dopamine agonists (apomorphine up to 5 mg/kg, piribedil up to 20 mg/kg). Sustained stereotyped climbing occurs when animals are treated with L-dopa plus benserazide and dexamphetamine. In this strain, which is spontaneously insensitive to apomorphine-induced climbing, this behaviour progressively appeared in a stereotyped manner after repeated administrations of apomorphine (5 mg/kg). The sensitization to apomorphine-induced climbing is long-lasting (more than 15 days). A similar sensitization may be induced by repeated administrations of either piribedil or of the dopamine uptake inhibitor GBR 12783. The semichronic reduction in dopaminergic transmission induced by four administrations of haloperidol (2 mg/kg at 2-day intervals) or by pretreatment with reserpine (3 mg/kg) induced sensitization to apomorphine-induced climbing. These results are discussed in terms of modifications in the sensitivity of two types of dopamine receptors exerting opposite effects on climbing behaviour.

Labelling of central dopaminergic systems with the dopamine uptake inhibitor [3H]GBR12783 was performed in vivo in mice by i.v. injection of a tracer dose of the ligand (40 microCi) 1 h before sacrifice. Autoradiographic pictures obtained from these experiments were quantified. The data were compared to those obtained by in vitro labelling of rat brain slices with this ligand. Significant specific labelling was observed both in vivo and in vitro in the striatum, the nucleus accumbens, the olfactory tubercle and the substantia nigra.