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Biomedical subjects

F Artigas

Publications and source records attributed to F Artigas.

At least 55 records · Page 3Linked to original sources
PubMed1997

3-Hydroxybutyrate co-infused with noradrenaline decreases resulting plasma levels of noradrenaline in Wistar rats.

Pentobarbital-anaesthetized male Wistar rats were infused with 6microgkg-1min-1 of noradrenaline. The infusion was supplemented with 8.5 mgkg-1min-1 of D-3-hydroxybutyrate (3-OHB) for 15 min in order to determine its effect on the adrenergic response of the rat. Plasma levels of noradrenaline rose to a plateau of approximately 50 nmoll-1 with infusion. In the group infused with noradrenaline alone, noradrenaline levels were maintained for 1h. Supplementation with 3-OHB induced a decrease in plasma noradrenaline level that was inversely correlated with 3-OHB level. Aortic and interscapular brown adipose tissue temperatures increased with noradrenaline infusion, but the rise was arrested by 3-OHB; replacing 3-OHB with glucose had no effect. Infusion of saline, glucose or 3-OHB in the absence of noradrenaline did not induce a rise in temperature in either tissue. Blood 3-OHB concentration increased to 1.2 mmoll-1 during 3-OHB infusion, decreasing rapidly at the end of infusion. Blood glucose levels increased with noradrenaline infusion; the presence of high 3-OHB levels decreased glucose concentration. The effects observed were transient and dependent on 3-OHB concentration; these effects may help explain most of the other effects of noradrenaline described here. The role of 3-OHB as a regulator of adrenergic responses seems to be part of a complex fail-safe mechanism which prevents wasting.

3-Hydroxybutyric Acid↗
PubMed1996

The 5-HT1A antagonist WAY-100635 selectively potentiates the presynaptic effects of serotonergic antidepressants in rat brain.

The increases in extracellular serotonin (5-hydroxytryptamine; 5-HT) produced by some antidepressent drugs in forebrain are attenuated by the activation of somatodendritic 5-HT1A autoreceptors by the excess 5-HT induced by these agents in the midbrain raphe. Using microdialysis, we have examined the effects of the selective 5-HT1A antagonist WAY-100635 in rats pretreated with the selective 5-HT reuptake inhibitors (SSRIs) citalopram, fluoxetine, fluvoxamine, the tricyclic antidepressants clomipramine and desipramine and the monoamine oxidase inhibitor phenelzine. WAY-100635 markedly potentiated the increases in 5-HT produced by the SSRIs, clomipramine and phenelzine but it did not alter that produced by desipramine. These results indicate that the effects of serotonergic antidepressant drugs (but not those of desipramine, which mainly blocks noradrenaline reuptake) can be potentiated by 5-HT1A autoreceptor blockade.

Animals↗
PubMed1996

Effect of pindolol on the function of pre- and postsynaptic 5-HT1A receptors: in vivo microdialysis and electrophysiological studies in the rat brain.

In microdialysis studies, somatodendritic 5-HT1A receptors in the dorsal raphe nucleus (DRN) were activated by the local infusion of 50 microM citalopram, a selective 5-HT reuptake inhibitor (SSRI). This reduced extracellular 5-HT by about 50% in dorsal striatum, an area receiving 5-HT afferents exclusively from the DRN. (-)Pindolol dose-dependently attenuated this citalopram-induced reduction of striatal extracellular 5-HT. Consistent with its 5-HT reuptake blocking properties, single doses of the SSRI paroxetine (1 and 3 mg/kg IP) and citalopram (1 mg/kg IP) significantly elevated extracellular 5-HT in the dorsal striatum. Pretreatment with (-)pindolol (15 mg/kg IP) potentiated the effect of 3 mg/kg paroxetine and 1 mg/kg citalopram on striatal extracellular 5-HT. A 2-day treatment with 10 mg/kg/day (SC) of paroxetine reduced by 60% the spontaneous activity of 5-HT neurons of the DRN. However, 5-HT neurons displayed normal activity in rats treated with paroxetine and (-)pindolol for 2 days. The inhibitory effect of LSD on 5-HT neuronal firing activity was also markedly attenuated in (-)pindolol-treated rats, indicating that somatodendritic 5-HT1A receptors were blocked by (-)pindolol. To determine whether (-)pindolol also blocked postsynaptic 5-HT1A receptors in hippocampus, 5-HT and the prototypical 5-HT1A agonist 8-OH-DPAT were applied by microiontophoresis onto CA3 pyramidal neurons following the same treatment. (-)Pindolol did not modify the responsiveness of these neurons to 5-HT and 8-OH-DPAT. Taken together, these results indicate that (-)pindolol can potentiate the effects of an SSRI on extracellular 5-HT concentration by preventing the activation of somatodendritic 5-HT1A autoreceptors resulting from the blockade of the 5-HT transporter in the raphe. This presumably leads to enhanced 5-HT neurotransmission because (-)pindolol would not alter the responsiveness of certain postsynaptic 5-HT1A receptors, such as those located on hippocampal CA3 pyramidal neurons. These results provide a neurobiological basis for the reported potentiation of certain antidepressant drugs by pindolol in major depression.

Animals↗
PubMed1996

Acceleration of the effect of selected antidepressant drugs in major depression by 5-HT1A antagonists.

At clinically relevant doses, selective serotonin (5-HT) reuptake inhibitors (SSRIs) and MAO inhibitors (MAOIs) increase the extracellular concentration of 5-HT in the midbrain raphé nuclei, thereby activating inhibitory somatodendritic 5-HT1A autoreceptors. Consequently, the firing activity of 5-HT neurons is reduced and the enhancement of extracellular 5-HT concentration in forebrain is dampened. Overriding this feedback by using antagonists of 5-HT1A autoreceptors permits SSRIs to produce a marked increase of extracellular 5-HT in the forebrain. Hence, combined treatment with an SSRI and a 5-HT1A antagonist increases the extracellular concentration of 5-HT more so than the former drug alone. The treatment of patients with major depression using an SSRI and pindolol, a 5-HT1A/ beta-adrenoceptor antagonist, markedly reduced the latency of the antidepressant response in previously untreated patients and induced a rapid improvement in treatment-resistant patients.

Antidepressive Agents↗
PubMed1996

Reduction of serotonergic function in rat brain by tryptophan depletion: effects in control and fluvoxamine-treated rats.

The administration of tryptophan (Trp)-free amino acid mixtures to depressed patients responding to serotonin [5-hydroxytryptamine (5-HT)] uptake inhibitors (SSRIs) worsens their clinical state. This procedure reduces Trp availability to brain and thus impairs 5-HT synthesis. We have examined the influence of Trp depletion on extracellular 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) concentrations in the rat brain using in vivo microdialysis. The treatment with the SSRI fluvoxamine significantly increased 5-HT content in dialysates from frontal cortex, as compared with control rats (10.2 +/- 2.7 vs. 3.1 +/- 0.4 fmol per fraction), whereas 5-HIAA was unaffected. Food deprivation for 20 h reduced dialysate 5-HT content to almost control values in fluvoxamine-treated rats (10.2 +/- 2.7 vs. 4.3 +/- 0.6 fmol per fraction) but did not alter dialysate 5-HIAA content (7.8 +/- 0.4 vs. 7.2 +/- 0.5 pmol per fraction). The administration of Trp-free amino acid mixtures to fluvoxamine-treated rats significantly attenuated the release of 5-HT in frontal cortex (approximately 50%) and, to a lesser extent, in the midbrain raphe nuclei. This effect was more marked in rats not deprived from food before the experiments (67% reduction of dialysate 5-HT content in frontal cortex) and was absent in control rats (treated with saline). In contrast, dialysate 5-HIAA was markedly affected by Trp depletion in all groups, including controls (65-75% reductions). These data show that the administration of an amino acid mixture with the same composition and dose (in milligrams per kilogram of body weight) as those inducing a severe mood impairment in depressed patients reduces 5-HT and 5-HIAA concentrations in brain dialysates. The reduction of 5-HT release, however, occurs only in animals previously treated with the antidepressant fluvoxamine for 2 weeks, which would be consistent with a marked reduction of 5-HT-mediated transmission in treated depressed patients but not in healthy controls.

Animals↗
PubMed1996

Differential effects of ipsapirone on 5-hydroxytryptamine release in the dorsal and median raphe neuronal pathways.

Serotonergic neurons of the dorsal and median raphe nuclei are morphologically dissimilar. Recent results challenge previous evidence indicating a greater inhibition of dorsal raphe neurons after 5-hydroxytryptamine1A (5-HT1A) autoreceptor activation. As both nuclei innervate different forebrain territories, this issue is critical to understanding the changes in brain function induced by anxiolytic and antidepressant drugs. Using microdialysis, we examined the modifications of 5-HT release induced by the selective 5-HT1A agonist ipsapirone in both neuronal pathways. Maximal and minimal basal 5-HT values (in the presence of 1 microM citalopram) were 45.0 +/- 4.8 fmol/fraction in the median raphe nucleus and 8.4 +/- 0.4 fmol/fraction in the dorsal hippocampus. Ipsapirone (0.3, 3, and 10 mg/kg s.c.) reduced dose-dependently 5-HT in the two raphe nuclei and four forebrain areas. Maximal reductions (to approximately 25% of predrug values) were observed in cortex and striatum and in median raphe nucleus. The effects were more moderate in dorsal and ventral hippocampus (to 66 and 50% of baseline, respectively). These results are consistent with a higher sensitivity of dorsal raphe neurons to 5-HT1A autoreceptor activation. Yet the differential reduction of 5-HT release in the median raphe nucleus and hippocampus suggests the presence of complex mechanisms of control of 5-HT release in these neurons.

Animals↗
PubMed1996

Role of 5-HT1A autoreceptors in the mechanism of action of serotoninergic antidepressant drugs: recent findings from in vivo microdialysis studies.

Although a new generation of selective serotonin reuptake inhibitors (SSRIs) has been introduced in therapeutics as antidepressant drugs, a two to four week lag period still occurs between starting treatment with SSRIs and the onset of therapeutic effects in man. In vivo cerebral microdialysis can be used to measure extracellular concentrations of serotonin (5-hydroxytryptamine, 5-HT), which reflect intrasynaptic events. With the coupling of this new experimental method to very sensitive analytical assays such as liquid chromatography with electrochemical detection, it has recently been possible to obtain two major arguments supporting the hypothesis that somatodendritic 5-HT1A autoreceptors situated in the raphe nuclei play an important role in the mechanism of action of SSRIs. First, in the rat, single administration of SSRIs at low doses comparable to those used therapeutically increases extracellular 5-HT concentrations in the vicinity of the cell body and the dendrites of serotoninergic neurones of the raphe nuclei. This effect is more marked than that observed in regions rich in nerve endings (frontal cortex). The magnitude of the activation of the serotoninergic neurotransmission depends on the brain area studied and the dose of the SSRIs administered to rats. This could be explained by simultaneous activation of somatodendritic 5-HT1A autoreceptors by endogenous 5-HT in the raphe nuclei, thereby limiting the corticofrontal effects of the antidepressant. Second, SSRIs cause a larger increase in extracellular 5-HT concentrations in the nerve endings when administered chronically: 5-HT autoreceptors may have gradually desensitized during the 2-4 weeks of treatment with SSRIs. Preliminary studies of patients with depression appear to confirm these experimental results, as co-administration of a 5-HT1A autoreceptor antagonist and a SSRI accelerated the onset of the antidepressant effect (< 1 week).

Animals↗
PubMed1996

In vivo effects of the simultaneous blockade of serotonin and norepinephrine transporters on serotonergic function. Microdialysis studies.

The effects of the blockade of serotonin (5-HT) and norepinephrine (NE) transporters on extracellular 5-HT (5-HText) have been examined using in vivo microdialysis in conscious rats. Locally infused, imipramine increased 5-HText dose-dependently in raphe nuclei and frontal cortex. The potency was identical (ED50 11 microM), although greater elevations were noted in the raphe nuclei (e.g., 74.5 +/- 16.9 vs. 41.1 +/- 4.5 fmol/fraction in the frontal cortex at 33 microM imipramine). The i.p. administration of imipramine at 4, 10 and 20 mg/kg increased 5-HText dose-dependently in the frontal cortex to concentrations as high as 390% of basal values. The lowest dose of imipramine significantly increased 5-HText in the raphe, but not in the frontal cortex (187 vs. 120% of basal values, respectively), but higher doses did not cause substantially greater increases in the raphe. The lowest dose affected 5-HText in a manner comparable to 1 mg/kg of the selective 5-HT reuptake inhibitors citalopram and fluvoxamine. The noradrenergic system may participate in the cortical elevations seen after 10 and 20 mg/kg of imipramine, because 10 mg/kg of desipramine significantly increased 5-HText in the frontal cortex, but not the raphe nuclei, of fluoxetine-treated rats (from 8.6 +/- 1.4 to 13.3 +/- 1.9 fmol/fraction; prefluoxetine values: 4.3 +/- 0.6 fmol/fraction, n = 11). Desipramine alone (10 mg/kg i.p.) did not modify 5-HText in the frontal cortex. The elevation induced by desipramine in fluoxetine-treated rats does not seem to involve changes in the activation of alpha-2 adrenoceptors, as it was still present in rats pretreated with 0.2 mg/kg i.p. of RX-821002, a selective antagonist of alpha-2 adrenoceptors. Moreover, clonidine, an alpha-2 adrenoceptor agonist, significantly reduced 5-HText in fluoxetine-treated rats when infused locally in the cortex, but it did not modify the effects of the systemic administration of desipramine, providing a further indication that alpha-2 heteroreceptors in 5-HT terminals do not participate in the effects of desipramine. When given for 2 weeks, 4 mg/kg day of imipramine significantly elevated 5-HText in the frontal cortex (from 7.7 +/- 1.2 to 20.0 +/- 5.8 fmol/fraction), but not in the raphe nuclei. These results are consistent with previous data suggesting that low doses of antidepressants with serotonergic action enhance 5-HText in the frontal cortex only after repeated treatment. The elevations noted in the frontal cortex after the higher doses of imipramine may reflect the involvement of the noradrenergic system.

Adrenergic Uptake Inhibitors↗
PubMed1996

Biochemical markers of neurotoxicity. A review of mechanistic studies and applications.

Neurotoxicology presents major challenges to the development of biological markers in accordance to conventional research strategies. Because of the inaccessibility of the nervous system, one of the proposed alternatives is the study of biochemical signals in peripheral tissues which can easily and ethically be obtained in humans, and which could represent surrogate indicators of equivalent parameters in the nervous tissue. Considerable scientific support to this approach is provided by the results of recent investigations in major areas of pharmacology and psychobiology. Studies examining parameters of neurotransmission and second messenger systems in peripheral blood cells, and variations in the peripheral body fluid content of endogenous substances reflecting nervous tissue dysfunction or damage are presented in this paper as examples of efforts toward rational development and validation of novel indicators of nervous system toxicity. Cholinergic muscarinic receptors and calcium signalling in peripheral blood lymphocytes, myelin basic protein in cerebrospinal fluid, and blood polyamines are discussed as potential surrogate indicators based on the results of in vitro or in vivo animal studies of neurotoxic metals (mercury, triethyltin), pesticides (disulfoton), drugs of abuse (d-fenfluramine) and model epileptogenic compounds (kainic acid). Data from investigations examining serum prolactin, type B monoamine oxidase (MAO-B) and dopamine beta-hydroxylase (DBH) in workers occupationally exposed to manganese, lead or styrene are also presented. Although research in this field is still at its very early stage, current evidence suggests that (i) certain neurochemical markers may be valuably used in animal studies as a complement to conventional laboratory tests to augment their sensitivity or predictivity; (ii) a mechanistic research approach is required to establish which markers offer the greatest promise for application in human biomonitoring.

Animals↗
PubMed1996

Two actions are better than one: avoiding self-inhibition of serotonergic neurones enhances the effects of serotonin uptake inhibitors.

The serotonin (5-HT)-increasing action of 5-HT uptake or monoamine oxidase inhibitors is limited by a negative feedback at somatodendritic level. The excess 5-HT produced by these antidepressant drugs in the interstitial space of the midbrain raphe activates somatodendritic 5-HT1A autoreceptors, thereby attenuating terminal 5-HT release. This effect is maximal in forebrain areas innervated by the dorsal raphe nucleus and can be prevented by the administration of non-selective [(-)pindolol, (-)tertatolol] and selective (WAY-100635) 5-HT1A antagonists. In keeping with these observations, the combined administration of selective serotonin reuptake inhibitors (SSRIs) and 5-HT1A antagonists increase the cortical and striatal extracellular 5-HT concentration more than the former alone. Also, concurrent inhibition of the 5-HT and noradrenaline transporters with 20 mg/kg imipramine increases cortical extracellular 5-HT concentration more than SSRI doses which maximally block the 5-HT transporter. Moreover, the effects of fluoxetine on frontal cortex 5-HT are potentiated by a dose of desipramine that does not modify extracellular 5-HT by itself. Given the relevance of increased serotonergic transmission in the treatment of depression, these experimental data indicate that dual-action antidepressant treatments may be more effective than those which selectively inhibit the 5-HT transporter.

Animals↗
PubMed1995

Clozapine decreases serotonin extracellular levels in the nucleus accumbens by a dopamine receptor-independent mechanism.

By using brain microdialysis, clear differences in the effects of the systemic administration of clozapine and haloperidol on the extracellular concentration of dopamine (DA) and serotonin (5-HT) were found in the nucleus accumbens of freely moving rats. Haloperidol (0.5 mg/kg s.c.) significantly increased DA (ca. 40%) but did not modify 5-HT extracellular concentration, while clozapine (5 mg/kg s.c.) significantly decreased 5-HT (ca. 40%) but did not change DA concentration. Locally infused, clozapine (10(-5) M) significantly increased DA (75%) and reduced 5-HT extracellular concentration (50%). The reduction of 5-HT cannot be explained by a clozapine-induced blockade of DA receptors, because the local infusion (10(-5) M) of the DA D2-like antagonist raclopride and the DA D1-like antagonist SCH 23390 significantly increased DA (ca. 300% and 200%, respectively) but did not modify 5-HT extracellular concentration. Conversely, the DA D2-like agonist quinpirole and the DA D1-like agonist SKF-38393 significantly decreased (ca. 60% in both cases) DA extracellular concentration without affecting that of 5-HT. The present results indicate that clozapine displays a powerful anti-serotoninergic effect by inhibiting 5-HT release in the nucleus accumbens, an effect probably derived from the reduction of firing activity at the dorsal raphe and by local mechanisms that may involve some 5-HT receptor subtype(s).

Animals↗
PubMed1995

In vivo evidence for the reversible action of the monoamine oxidase inhibitor brofaromine on 5-hydroxytryptamine release in rat brain.

We have used intracerebral microdialysis to examine the reversibility of the action of brofaromine, a selective inhibitor of monoamine oxidase-A (MAO, E.C. 1.4.3.4.), on 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) output in rat frontal cortex. Brofaromine significantly increased the 5-HT output to about 200% of basal values 4 h after the s.c. administration of 10 and 30 mg/kg (but not 3 mg/kg) and reduced the concentration of 5-HIAA in the dialysate dose-dependently (61%, 53% and 41% of basal value with doses of 3, 10 and 30 mg/kg, respectively). At this time, cortical 5-HT concentration was increased and cortical 5-HIAA concentration was decreased in a dose-dependent manner. Treatment of rats with 10 mg/kg brofaromine plus 2.5 mg/kg of the irreversible MAO-B inhibitor L-deprenyl increased the concentration of 5-HT in the dialysate more than did brofaromine alone (503% vs 206% of the basal value, 4h after administration). Similarly, clorgyline (5 mg/kg) plus L-deprenyl (2.5 mg/kg) increased the concentration of 5-HT in the dialysate to 461% of the control value. This indicates that the concurrent inhibition of both types of MAO increases 5-HT output more than the selective blockade of either enzyme subtype. We have used this characteristic to examine, in vivo, the reversibility of the interaction of brofaromine with MAO-A. The output of 5-HT and 5-HIAA was examined 19-21 h after treatment with L-deprenyl plus clorgyline or L-deprenyl plus brofaromine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Reduction of in vivo striatal 5-hydroxytryptamine release by 8-OH-DPAT after inactivation of Gi/G(o) proteins in dorsal raphe nucleus.

5-HT1A receptor agonists reduce firing-dependent terminal 5-HT synthesis and release by activating somatodendritic 5-HT1A receptors. We have examined the effects of 8-hydroxy-2-(di-n- propylamino)tetralin (8-OH-DPAT, 0.1 mg/kg s.c.) on in vivo striatal 5-HT release in conscious rats with somatodendritic 5-HT1A receptors inactivated by the application of pertussis toxin in the dorsal raphe nucleus. The uncoupling of 5-HT1A receptors from hyperpolarizing potassium channels was demonstrated by the inability of the intra-raphe application of citalopram to reduce striatal release (control animals had a 47% reduction, an effect prevented by previous treatment with the 5-HT1A antagonist (-)-tertatolol). Yet 8-OH-DPAT (0.1 mg/kg s.c.) decreased striatal 5-HT release by 66% (peak effect) in pertussis toxin-treated rats, a value comparable to that found in naive animals (74%). This raises the possibility that other 8-OH-DPAT-sensitive serotonergic receptors different from 5-HT1A autoreceptors may be involved in the control of terminal 5-HT release.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1994

Effects of single and chronic treatment with tranylcypromine on extracellular serotonin in rat brain.

We have examined the effects of tranylcypromine, a monoamine oxidase inhibitor used as antidepressant, on the tissue and extracellular concentration of serotonin (5-hydroxytryptamine, 5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in frontal cortex and dorsal raphe nucleus using microdialysis in conscious rats. Single treatment with tranylcypromine sulphate (0.5, 3 and 15 mg/kg, i.p.) dose dependently elevated dialysate 5-HT in both areas but more markedly in the DRN. Extracellular and tissue 5-HT concentrations were affected by the drug in a different manner. The former increased sharply when tissue 5-HT reached a plateau. This may have reflected saturation of intracellular stores and overflow of the amine. In contrast, tissue and extracellular 5-HIAA concentrations--that indicate metabolic effects of tranylcypromine--were affected similarly. A 2-week treatment with 0.5 mg/kg.day of tranylcypromine sulphate increased basal extracellular 5-HT in frontal cortex and dorsal raphe nucleus (ca. 220%) whereas a further injection of 0.5 mg/kg was without effect in both areas. Thus, chronic, but not acute, treatment with low doses of tranylcypromine increases extracellular 5-HT concentration, suggesting that clinical effects of this monoamine oxidase inhibitor are related to its capacity to enhance serotonergic transmission.

Analysis of Variance↗
PubMed1994

Motor activation in short- and long-term reserpinized mice: role of N-methyl-D-aspartate, dopamine D1 and dopamine D2 receptors.

The effects of dopamine D1 and dopamine D2 receptor agonists and of subconvulsant doses of N-methyl-D-aspartate (NMDA) and the non-competitive NMDA receptor antagonist, dizocilpine (MK-801), alone and in combination, on the motor activity of short- and long-term reserpinized mice (mice pretreated with 5 mg/kg reserpine 4 h or 20 h before, respectively) were analyzed. With short-term reserpinization, the dopamine D2 receptor agonist, quinpirole (1.5 mg/kg), but not the dopamine D1 receptor agonist, SKF-38393 (15 mg/kg), increased motor activity. The effect of quinpirole in short-term reserpinized mice was potentiated by the simultaneous administration of SKF-38393 (15 mg/kg) and was counteracted by the previous administration of the dopamine D2 receptor antagonist, raclopride (1 mg/kg), or by the simultaneous administration of NMDA (25 mg/kg) or MK-801 (0.5 mg/kg). Neither NMDA (25-100 mg/kg) nor MK-801 (0.5-3 mg/kg) induced motor activation in short-term reserpinized mice. With long-term reserpinization, either quinpirole (1.5 mg/kg) or SKF-38393 (15 mg/kg) increased motor activity. The effect of quinpirole in long-term reserpinized mice was not potentiated by the concurrent administration of SKF-38393 (15 mg/kg), was inhibited by the simultaneous administration of MK-801 (0.5 mg/kg) and was not modified by NMDA (25 mg/kg). The effect of SKF-38393 (15 mg/kg) in long-term reserpinized mice was inhibited by the concomitant administration of MK-801 (0.5 mg/kg) and was slightly antagonized by NMDA (25 mg/kg). NMDA induced motor activation in long-term reserpinized mice at doses which were similar to those causing motor activation in non-reserpinized mice (75 and 100 mg/kg), while MK-801 induced motor activation at a dose which was associated with motor depression in non-reserpinized mice (2 mg/kg). The NMDA-induced motor activation in long-term reserpinized mice was counteracted by the previous administration of a low dose of MK-801 (0.5 mg/kg) and was still present when a stronger dopamine-depleting pretreatment was used. These results are interpreted on the basis of changes in sensitivity of the direct striatal efferent pathway after long-term reserpinization.

Animals↗