Biomedical subjects

D Martínez-Fong

Publications and source records attributed to D Martínez-Fong.

13 recordsLinked to original sources

PubMed1999

Expression of dopamine receptors in the subthalamic nucleus of the rat: characterization using reverse transcriptase-polymerase chain reaction and autoradiography.

We analysed the expression of dopamine receptor subtypes in the subthalamic nucleus by means of reverse transcriptase-polymerase chain reaction. We also studied, using autoradiography, all pharmacologically characterized dopamine receptors in four subregions of the subthalamic nucleus. For comparison, dopamine receptor subtypes were also evaluated in brain regions where they are more abundant and well characterized. The radioligands used were: [3H]SCH-23390, [3H]emonapride and [3H]2-dipropylamino-7-hydroxy-1,2,3,4-tetrahydronaphthalene for dopamine D1, D2 and D3 receptors, respectively; and [3H]YM-09151-2 in the presence of raclopride for dopamine D4 receptors. Finally, we also evaluated the effect of unilateral 6-hydroxydopamine injection into the medial forebrain bundle on dopamine receptor levels expressed in the ipsilateral subthalamic nucleus. The lesion was estimated by decrease in the binding of [3H]WIN-35428, a specific dopamine transporter label. D1, D2 and D3 receptor messenger RNAs and binding sites were present in the subthalamic nucleus, but no messenger RNA for D4 receptors was found, although specific binding sites for these receptors were observed. As compared to the intact side, the 6-hydroxydopamine lesion did not change D1 receptors, increased D2 receptors, and decreased D3 receptors and the dopamine transporter. The results suggest that postsynaptic D1, D2 or D3 receptors can mediate the effect of dopamine on subthalamic nucleus neuronal activity. D4 receptors would mediate exclusively presynaptic effects. These results reinforce the idea that dopamine receptors in the subthalamic nucleus may play an important role in the physiology of the basal ganglia and in the pathophysiology of Parkinson's disease.

Animals↗

PubMed1996

Muscarinic antagonists microinjected into the subthalamic nucleus decrease muscular rigidity in reserpinized rats.

The ability of anticholinergic agents microinjected into the subthalamic nucleus to reduce reserpine-induced muscular rigidity was assessed in rats. The electromyographical activity of the gastrocnemius-soleus muscle was used as a parameter of muscular rigidity. Reserpine (5 mg/kg i.p.) produced the appearance of electromyographical activity. The muscarinic antagonists M3 (1.27 nmol of 4-DAMP) and M1 (2.36 nmol of pirenzepine) markedly reduced the reserpine-induced electromyographical activity, whereas the M2 antagonist AFDX-116 (2.37 nmol) had no effect. These results suggest that a high cholinergic tone in the subthalamic nucleus is associated with the reserpine-induced muscular rigidity. Moreover, the M3 muscarinic antagonist is more effective than the M1 muscarinic antagonist in reducing the muscular rigidity in reserpinized rats, a model of Parkinson's disease, by blocking the high cholinergic tone in the subthalamic nucleus.

Anesthetics, Intravenous↗

PubMed1996

Circling behavior elicited by cholinergic transmission in the substantia nigra pars compacta: involvement of nicotinic and muscarinic receptors.

The influence of cholinergic transmission within the substantia nigra pars compacta on circling behavior was assessed in male rats. Microinjection of physostigmine (6-37 nmol) into the caudal part of the substantia nigra pars compacta elicited a dose-dependent contralateral circling. The circling was inhibited 93 +/- 3% by the dopamine antagonist haloperidol (53 nmol) injected into the neostriatum 90 min before the injection of physostigmine (37 nmol) into the ipsilateral substantia nigra pars compacta. The effect of haloperidol was reversible, since the circling behavior was fully restored when physostigmine was applied to the same animals 24 h later. The circling was completely blocked when physostigmine (37 nmol) was applied simultaneously with the muscarinic M1 antagonist pirenzepine (2 nmol). The M2 antagonist AF-DX 116 (2 nmol) only partially blocked the circling induced by a lower dose of physostigmine (12 nmol). The nicotinic antagonist mecamylamine (5 nmol) also inhibited the circling, but only during the 5 min following co-injection of the drugs. These results indicate that endogenous acetylcholine stimulates muscarinic and nicotinic receptors of nigrostriatal dopaminergic neurons which, in turn, increase their firing rate and cause the circling behavior. We conclude that the pedunculopontine cholinergic neurons, which innervate the substantia nigra pars compacta, modulate the motor behavior by increasing the activity of dopaminergic nigrostriatal pathway.

Animals↗

PubMed1994

Activation of subthalamic neurons produces NMDA receptor-mediated dendritic dopamine release in substantia nigra pars reticulata: a microdialysis study in the rat.

Here we have studied whether the activation of the subthalamic neurons induces the release of dopamine (DA) from dopaminergic dendrites in the pars reticulata of the substantia nigra. Subthalamic neurons were activated by carbachol microinjected into the subthalamic nucleus. A microdialysis probe was implanted in the medial aspect of the pars reticulata to collect samples of the perfusate. Carbachol (1 microgram/0.25 microliter saline) enhanced (58 +/- 8% over basal values) nigral DA release. The enhancement was fully blocked by the NMDA antagonist AP5 added to the microdialysis medium perfusing the pars reticulata. Perfusion of the pars reticulata with NMDA also increased (125 +/- 25% over basal) nigral DA release. Again, AP5 reversed the effect. These results suggest that activation of the glutamatergic subthalamonigral pathway enhances dendritic DA release by activating NMDA receptors present on dopaminergic dendrites.

Animals↗

PubMed1994

Cholinergic stimulation of rostral and caudal substantia nigra pars compacta produces opposite effects on circling behavior and striatal dopamine release measured by brain microdialysis.

Turning in circles is among the behaviors elicited by unilateral cholinergic stimulation of the substantia nigra. Recent studies have shown that microinjection of cholinergic agonists into the substantia nigra pars compacta increases dopamine release and turnover in the striatum of anesthetized rats [Hernández-López et al. (1992) Brain. Res. 598, 114-120; Blaha and Winn (1993) J. Neurosci, 13, 1035-1044]. In this study, the relationship between circling behavior and striatal dopamine release following cholinergic stimulation of the substantia nigra pars compacta neurons was assessed by brain microdialysis in awake rats. The results indicate that cholinergic stimulation of the substantia nigra pars compacta with the mixed nicotinic-muscarinic cholinergic agonist carbachol modulates striatal dopamine release, and this effect is accompanied by circling behavior and stereotypies. Microinjection of carbachol (109 nmol) in the caudal portions of the substantia nigra pars compacta induced contralateral circling associated with an increase of dopamine release in neostriatum. On the contrary, ipsilateral circling and reduction of striatal dopamine release was elicited when the same dose of the drug was applied in the rostral portions of the substantia nigra pars compacta. The above findings are in accordance with recent electrophysiological studies suggesting the existence of sub-populations of nigrostriatal dopaminergic neurons, and indicate that the substantia nigra pars compacta is functionally compartmentalized. We conclude that the cholinergic input to the substantia nigra pars compacta could modulate the motor behavior through regulating the firing rate of nigrostriatal dopaminergic neurons and dopamine release in the neostriatum.

Animals↗

PubMed1992

A cholinergic input to the substantia nigra pars compacta increases striatal dopamine metabolism measured by in vivo voltammetry.

3,4-Dihydroxyphenylacetic acid (DOPAC) and ascorbic acid (AA) were measured by differential pulse voltammetry in the neostriatum of anesthetized rats. Physostigmine (2.3 nmol) applied into the substantia nigra pars compacta (SNc), increased DOPAC concentration in the ipsilateral neostriatum, but did not modify AA levels. The largest increase of striatal DOPAC (37 +/- 8% above basal) was observed when physostigmine was applied at less than 0.5 mm from SNc, and decreased with increasing distance of the injection site from the pars compacta region. Chemical stimulation of the pedunculopontine tegmental nucleus (PPN) with kainic acid (2.3 nmol) increased both DOPAC and AA concentration in the ipsilateral neostriatum. Pretreatment with the muscarinic antagonist scopolamine (5 mg/kg, i.p.) inhibited the increase of striatal DOPAC from 20 to 70 min after kainic acid injection into the PPN, whereas the increase of AA was reduced from 90 to 160 min. By contrast, the nicotinic antagonist mecamylamine (4 mg/kg, i.p.) did not inhibit neither DOPAC nor AA increase elicited by the chemical stimulation of PPN. These results support the existence of cholinergic neurotransmission within the SNc that increases the firing rate of nigrostriatal dopaminergic neurons, enhancing dopamine turnover in neostriatum without changes in AA release. They also suggest that the PPN could be the origin of cholinergic afferents to the SNc that modulate the activity of dopaminergic neurons, through activation of muscarinic cholinergic receptors. Finally, the activation of a multisynaptic loop involving a cholinergic pathway which modulates the activity of the glutamatergic corticostriatal neurons is postulated to explain the increase of AA in neostriatum observed after PPN stimulation.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1992

NMDA receptor mediates dopamine release in the striatum of unanesthetized rats as measured by brain microdialysis.

We have studied the characteristics associated with the activation of the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor on the release of dopamine (DA) in the striatum of awake rats as measured by brain microdialysis technique. NMDA dose-dependently stimulated the striatal DA release in Mg(2+)-free Ringer's solution. The stimulation was significant at 90 microM and the maximum observed effect was at the highest concentration tested (800 microM). The selective NMDA receptor antagonist, 2-amino-5-phosphonovalerate (AP5; 300 microM), blocked the stimulatory effect of NMDA. The NMDA-induced release of DA was reduced by 1.2 mM Mg2+ and totally blocked by 2.5 mM of the cation. Glycine (200 microM) potentiated the response evoked by 300 microM NMDA while 7-chloro-kynurenate (100 microM), an antagonist of the glycine site, reduced markedly this response. Neither atropine (100 microM) nor tetrodotoxin (TTX) (5 microM) prevented the stimulatory effect of NMDA. These results suggest that glutamate released from corticostriatal terminals presynaptically stimulates the release of DA via an NMDA receptor.

2-Amino-5-phosphonovalerate↗

PubMed1992

GABAB receptor activation partially inhibits N-methyl-D-aspartate-mediated tyrosine hydroxylase stimulation in rat striatal slices.

The effect of the GABAB agonist, (+/-)-baclofen, on the N-methyl-D-aspartate (NMDA)-mediated stimulation of tyrosine hydroxylase activity was investigated in slices of rat striatum. Tyrosine hydroxylase activity was stimulated by NMDA in a concentration-dependent manner (EC50, 1.3 +/- 0.3 microM; maximum stimulation 194 +/- 7% of basal activity). The action of NMDA was reversed by the NMDA antagonist, 2-amino-5-phosphonovalerate (AP-5). (+/-)-Baclofen (100 microM) decreased the maximum effect of NMDA by 24 +/- 2% without significantly modifying its EC50. The IC50 for the inhibitory action of (+/-)-baclofen was 4.2 +/- 1.2 microM. These results show that GABAB receptor activation modulates NMDA-stimulated tyrosine hydroxylase activity, further supporting the possibility of a role of GABA in the regulation of striatal dopaminergic neurotransmission.

Animals↗

PubMed1992

Glutamate stimulation of tyrosine hydroxylase is mediated by NMDA receptors in the rat striatum.

We have studied the action of glutamate on striatal tyrosine hydroxylase activity and determined which type of glutamate receptors are involved. Glutamate stimulated (EC50 = 4 +/- 2 microM) the activity of tyrosine hydroxylase in slices of rat neostriatum. The selective N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonovalerate (10 microM) blocked the stimulation; however, both the non-NMDA receptor antagonist glutamate diethyl ester (10 microM) and the general excitatory amino acid antagonist kynurenate (10 microM) had no effect. NMDA was even more potent than glutamate in stimulating tyrosine hydroxylase activity. Quisqualate (100 microM) only slightly stimulated the enzyme, and kainate had practically no effect. Omission of Mg2+ from the incubation medium potentiated the glutamate stimulation. Neither tetrodotoxin nor atropine prevented the stimulation. These results suggest that glutamate stimulates striatal tyrosine hydroxylase activity via NMDA receptors. The lack of effect of tetrodotoxin and atropine suggests that glutamate acts on NMDA receptors located on the dopaminergic nigrostriatal terminal. The stimulation may involve the entry of Ca2+ into the terminal through the NMDA receptor ionophore, since a Ca(2+)-free medium or cadmium totally blocked the stimulation of the enzyme by glutamate.

2-Amino-5-phosphonovalerate↗

PubMed1991

Activation of nigral M1 and M2 muscarinic receptors produces opposing effects on striatal 3,4-dihydroxyphenylacetic acid measured by in vivo voltammetry.

3,4-dihydroxyphenylacetic acid (DOPAC) was measured by differential pulse voltammetry in the neostriatum of anesthetized rats. DL-Muscarine (2.9 nmol) applied into the substantia nigra pars compacta, increased DOPAC concentration in the ipsilateral neostriatum. This effect was blocked by pirenzepine (2.8 nmol), and potentiated by AF-DX 116 (2.8 nmol). These results indicate the existence of two types of muscarinic receptors on dopaminergic neurons, whose activation produces opposing effects on dopamine metabolism in neostriatum.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1991

Gamma-aminobutyric acid (GABAB) receptor-mediated inhibition of tyrosine hydroxylase activity in the striatum of rat.

The effects of GABA and GABA agonists on calcium and depolarization-dependent stimulation of tyrosine hydroxylase activity in striatal slices were studied. gamma-Aminobutyric acid and (-)baclofen inhibited, while muscimol and (+)baclofen did not affect, the stimulation of tyrosine hydroxylase. The inhibitory effect of GABA and (-)baclofen was blocked by the GABAB antagonist, phaclofen but not by the GABAA antagonist, picrotoxin. The data suggest that the activity of tyrosine hydroxylase on dopaminergic nigrostriatal terminals may be modulated by GABA via GABAB receptors.

Animals↗

PubMed1990

Effect of chronic lead exposure on biopterin metabolism in the rat neostriatum.

Chronic (3 months) lead exposure increased the quinonoid dihydropteridine reductase activity and the tetrahydrobiopterin content but did not affect the GTP-cyclohydrolase activity and the dihydrobiopterin content. These results suggest that lead intoxication may enhance dopamine metabolism in neostriatum by increasing the content of tetrahydrobiopterin, the regulating cofactor of tyrosine hydroxylase activity.

Animals↗

PubMed1987

Spontaneous synaptic potentials in dopamine-denervated neostriatal neurons.

Intracellular spontaneous activity was recorded in neostriatal slices from rats with 6-hydroxydopamine-induced lesion of the left nigrostriatal dopaminergic system. Recordings were made at different times after denervation. Dopaminergic denervation caused the appearance of spontaneous synaptic potentials, which were present even after 8 months. The results suggest a tonic inhibitory influence of the dopaminergic innervation on the synaptic input of neostriatal neurons.

Action Potentials↗