Emili Martínez

Postsynaptic antagonistic interaction between adenosine A1 and dopamine D1 receptors.

BEHAVIOURAL, AND biochemical evidence for the existence of a powerful specific postsynaptic interaction between adenosine A1, and dopamine D1 receptors in the mammalian brain was found. Behavioural data showed that A1 receptor stimulation induced a decrease in the D1-induced motor activation in reserpinized mice, and a decrease in the D1-dependent oral dyskinesia in rabbits. Biochemical data suggested that A1 receptor stimulation could produce a GTP-independent uncoupling of the rat striatal D1 receptor to the G protein. The A1-D1 receptor-receptor interaction might represent an important additional mechanism of action responsible for the motor depressant effects of adenosine agonists, and for the motor stimulant effects of adenosine antagonists, like the methylxanthines caffeine, and theophylline

Metabotropic glutamate mGlu5 receptor-mediated modulation of the ventral striopallidal GABA pathway in rats. Interactions with adenosine A(2A) and dopamine D(2) receptors.

Interactions between subtypes of dopamine, glutamate and adenosine receptors seem to play an important integrative role in the function of striatal gamma-aminobutyric acid (GABA)ergic efferent neurons. Recent behavioral and biochemical studies suggest the existence of specific interactions between adenosine A2A receptors (A(2A)R), dopamine D2 receptors (D2R) and the group I metabotropic mGlu5 receptors (mGlu5R) in the dorsal striatum. The dual-probe approach in vivo microdialysis technique in freely moving rats was used to study the role of mGlu5R/A2AR/D2R interactions in the modulation of the ventral striopallidal GABA pathway. Perfusion of a selective mGlu5R agonist (CHPG) in the nucleus accumbens facilitated GABA release in the ipsilateral ventral pallidum. This effect was strongly potentiated by co-perfusion with the A2AR agonist CGS 21680. Co-perfusion with the D2R agonist quinpirole counteracted the increase in pallidal GABA levels induced by CGS 21680 and by CGS 21680 plus CHPG. These results demonstrate that mGlu5R/A2AR/D2R interactions play an important modulatory role in the function of the ventral striopallidal GABA pathway, which might have implications for the treatment of schizophrenia and drug addiction.

Working memory deficits in transgenic rats overexpressing human adenosine A2A receptors in the brain

Adenosine receptors in the central nervous system have been implicated in the modulation of different behavioural patterns and cognitive functions although the specific role of A(2A) receptor (A(2A)R) subtype in learning and memory is still unclear. In the present work we establish a novel transgenic rat strain, TGR(NSEhA2A), overexpressing adenosine A(2A)Rs mainly in the cerebral cortex, the hippocampal formation, and the cerebellum. Thereafter, we explore the relevance of this A(2A)Rs overexpression for learning and memory function. Animals were behaviourally assessed in several learning and memory tasks (6-arms radial tunnel maze, T-maze, object recognition, and several Morris water maze paradigms) and other tests for spontaneous motor activity (open field, hexagonal tunnel maze) and anxiety (plus maze) as modification of these behaviours may interfere with the assessment of cognitive function. Neither motor performance and emotional/anxious-like behaviours were altered by overexpression of A(2A)Rs. TGR(NSEhA2A) showed normal hippocampal-dependent learning of spatial reference memory. However, they presented working memory deficits as detected by performance of constant errors in the blind arms of the 6 arm radial tunnel maze, reduced recognition of a novel object and a lack of learning improvement over four trials on the same day which was not observed over consecutive days in a repeated acquisition paradigm in the Morris water maze. Given the interdependence between adenosinic and dopaminergic function, the present results render the novel TGR(NSEhA2A) as a putative animal model for the working memory deficits and cognitive disruptions related to overstimulation of cortical A(2A)Rs or to dopaminergic prefrontal dysfunction as seen in schizophrenic or Parkinsons disease patients.

Adenosine A1 receptor blockade selectively potentiates the motor effects induced by dopamine D1 receptor stimulation in rodents

An antagonistic interaction between adenosine A1 and dopamine D1 receptors has previously been found in the basal ganglia. However, direct evidence for a selective adenosine A1 antagonist-induced potentiation of dopamine D1-mediated motor activation is lacking. The systemic administration of the adenosine A1 antagonist 8-cyclopentyl-1,3-dimethylxanthine significantly potentiated the motor activating properties of the systemically administered dopamine D1 agonist SKF 38393 in both reserpinized mice and unilaterally 6-hydroxy-dopamine-lesioned rats. However, 8-cyclopentyl-1, 3-dimethylxanthine did not modify the motor effects of the dopamine D2 agonist quinpirole. The present work shows that an antagonistic interaction between adenosine A1 and dopamine D1 receptors may be involved in the motor activating effects of adenosine antagonists, like caffeine.

Changes in polyamine levels in rat brain after systemic kainic acid administration: relationship to convulsant activity and brain damage

Abstract: We have examined the effects of systemic kainic acid (KA) administration (9 mg/kg, i.p.) on rat behavior, brain damage, and polyamine levels and the action of the specific ornithine decarboxylase inhibitor α‐difluoromethylornithine (DFMO) on these effects. KA elicited convulsant activity in 63% of the animals. In the acute convulsant phase (1–3 h after KA), a rapid decline (−39% at 3 h) of spermidine content in frontal cortex was found. After the acute convulsant phase, levels of hippocampal spermidine and spermine were reduced (−70 and −66%, respectively, at 8 h). A dramatic increase of putrescine content (681, 1,382, and 336% at 8h, 24h, and 9 days, respectively, after KA) was found, associated with histological signs of cortical brain damage (ischemia and necrosis). There was a close relationship between the concentration of putrescine and signs of delayed toxicity (body weight losses) 24 h and 9 days after KA. DFMO partially antagonized the convulsant activity and reduced the increased putrescine levels to ∼50% of values in KA‐treated animals at 24 h but did not change the pattern of histological damage. The role of polyamines in the early and late phases of KA‐induced neurotoxicity is discussed.

Seizures and neuronal damage induced in the rat by activation of group I metabotropic glutamate receptors with their selective agonist 3,5-dihydroxyphenylglycine.

While it is well documented that the overactivation of ionotropic glutamate receptors leads to seizures and excitotoxic injury, little is known about the role of metabotropic glutamate receptors (mGluRs) in epileptogenesis and neuronal injury. Intracerebroventricular (i.c.v.) infusion of the group I mGluR specific agonist (R,S)‐3,5‐dihydroxyphenylglycine (3,5‐DHPG) (1.5 μmol) to conscious rats produced severe and delayed seizures (onset at 4 hr) in 70% of the animals. The i.c.v. infusion of the group I mGluR non‐selective agonist 1S,3R‐1‐aminocyclopentane‐1,3‐dicarboxylic acid (1S,3R‐ACPD) (2 μmol) produced a similar rate of severe seizures, but with an early onset (0.6 hr). The analysis of motor activity showed that 3,5‐DHPG elicited higher central stimulatory action than did 1S,3R‐ACPD. Histopathological analysis of the hippocampus showed that 3,5‐DHPG produced severe neuronal damage mainly in the CA1 pyramidal neurons and, to a lesser extent, in the CA3. Although 1S,3R‐ACPD infusion also induced a slight injury of the CA1 and CA3 pyramidal neurons, damage was greater in the CA4 and dentate gyrus cells. In conclusion, the in vivo activation of group I mGluRs with the selective agonist 3,5‐DHPG produces hyperexcitatory effects that lead to seizures and neuronal damage, these effects being more severe than those observed after infusion of the non‐selective agonist 1S,3R‐ACPD. J. Neurosci. Res. 51:339–348, 1998. © 1998 Wiley‐Liss, Inc.

Increased plasma free serotonin but unchanged platelet serotonin in bipolar patients treated chronically with lithium

The effect of lithium salts administered chronically to bipolar patients on peripheral measures of the serotoninergic system has been studied. Plasma free serotonin (5HT), whole blood 5HT, plasma 5-hydroxyindoleacetic acid (5HIAA) and plasma total tryptophan (TP) have been analyzed in 22 patients treated with lithium carbonate (mean daily dose: 1280 mg, mean serum concentration: 0.73 mmol/l) and compared to 14 healthy controls and 11 patients treated chronically with antipsychotic drugs. Lithium salts induced significant increases in plasma free 5HT (+159% with respect to control values) and in plasma 5HIAA (+39%) without affecting 5HT contained in platelets. Plasma TP was also unchanged by chronic lithium treatment. The ratio between 5HT stored in platelets and 5HT free in plasma, a variable reduced after uptake inhibitors like clomipramine, was decreased in lithium-treated patients (-50%). These results are compatible with an enhanced synthesis of 5HT in the periphery (mainly enterochromaffin cells) as well as with an inhibition of platelet 5HT uptake (or increased 5HT efflux from intracellular stores) induced by lithium. The lack of effect of several antipsychotic drugs upon these variables is consistent with their predominant effect on the dopaminergic system and reinforces the specificity of the effect observed with lithium salts. Taken together, these results support the usefulness of using this “in vivo” 5HT peripheral model for the study of the actions elicited by drugs acting on the presynaptic components of the 5HT system.

Effect of N-methyl-d-aspartate on motor activity and in vivo adenosine striatal outflow in the rat

It has been previously found that the systemic administration of low doses of N-methyl-D-aspartate (NMDA) in mice induces motor depression. The effects of the systemic administration of different doses of NMDA (10, 30 and 60 mg/kg s.c.) on the motor activity and on the in vivo extracellular levels of adenosine in the striatum was studied in Sprague-Dawley rats. The adenosine concentration in samples of perfusate was determined 24 h after implantation of a transverse microdialysis probe. At 30 and 60 mg/kg, but not 10 mg/kg, NMDA induced both a significant motor depression (motility and rearing) and a significant increase in the striatal extracellular levels of adenosine. Both the motor depression and the changes in the extracellular levels of adenosine were only evident during the first 30 min after NMDA administration. The non-competitive NMDA receptor antagonist MK-801 (0.1 mg/kg s.c.) completely counteracted the effects of NMDA (30 mg/kg s.c.) on motor activity (motility) and on the striatal extracellular levels of adenosine. The correlation between the behavioural and the biochemical data strongly support the hypothesis that adenosine release in the striatum is a main mechanism responsible for the motor depressant effects produced by the systemic administration of NMDA.

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.

Dopamine-independent and adenosine-dependent mechanisms involved in the effects of N-methyl-d-aspartate on motor activity in mice

The involvement of dopamine and adenosine mechanisms in the motor effects of systemically administered N-methyl-D-aspartate (NMDA) was studied in non-reserpinized and in reserpinized mice. In non-reserpinized mice NMDA induced motor depression (with 8, 25 and 75 mg/kg i.p.) during the first hour and motor activation (with 25 and 75 mg/kg i.p.) during the second hour after its administration. The non-selective adenosine antagonist, theophylline (3, 10 and 30 mg/kg i.p) induced motor activation during both 1-h periods of observation. NMDA-induced motor depression in non-reserpinized mice was antagonized by theophylline. Higher doses of theophylline were needed to counteract the motor depressant effect induced by higher doses of NMDA. The motor activation induced by NMDA and theophylline in non-reserpinized mice was not additive and theophylline did not enhance the motor activation induced by high doses of NMDA. Both NMDA (25 and 75 mg/kg i.p.) and theophylline (10 and 30 mg/kg) induced motor activation in reserpinized mice and, when coadministered, NMDA counteracted the effect of theophylline. NMDA (8 and 25 mg/kg i.p.) antagonized and theophylline (3, 10 and 30 mg/kg i.p.) potentiated the motor activation induced by the non-selective dopamine agonist, apomorphine (0.1 mg/kg s.c.), in reserpinized mice. In reserpinized mice, the non-selective dopamine antagonist, haloperidol (0.5 mg/kg s.c.) antagonized the motor activation induced by apomorphine (0.1 mg/kg s.c.) and the induced by theophylline (10 mg/kg i.p.) and did not modify NMDA-induced motor activation.(ABSTRACT TRUNCATED AT 250 WORDS)