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Biomedical subjects

A Pazos

Publications and source records attributed to A Pazos.

108 records · Page 6Linked to original sources
PubMed1985

Quantitative autoradiographic mapping of serotonin receptors in the rat brain. II. Serotonin-2 receptors.

The distribution of serotonin-2 (5-HT2) receptors in the rat brain was studied by light microscopic quantitative autoradiography. Receptors were labeled with four ligands: [3H]ketanserin, [3H]mesulergine, [3H]LSD and [3H]spiperone, which are reported to show high affinity for 5-HT2 receptors. Co-incubation with increasing concentrations of several well-known 5-HT2-selective drugs, such as pirenperone, cinanserin and ketanserin, resulted in an inhibition of the binding of the four 3H-labeled ligands to the same areas. However, all of them recognized, in addition to 5-HT2 sites, other populations of binding sites. Receptor densities were quantified by microdensitometry with the aid of a computer-assisted image-analysis system. Our results reveal a heterogeneous distribution of 5-HT2 receptor densities in the rat brain. Very high concentrations were localized in the claustrum, olfactory tubercle and layer IV of the neocortex. The anterior olfactory nucleus, piriform cortex and layer I of neocortex were also rich in 5-HT2 receptors. Intermediate concentrations of receptors were found in caudate putamen, nucleus accumbens, layer V of neocortex, ventral dentate gyrus and mammillary bodies. Areas containing only low concentrations of receptors included the thalamus, hippocampus, brainstem, medulla, cerebellum and spinal cord. The specificity of the different ligands used is discussed in terms of the other populations of sites recognized by them. The distribution of 5-HT2 receptors here reported is discussed in correlation with (a) the known distribution of serotoninergic terminals, (b) the specific anatomical systems and (c) the central effects reported to be mediated by 5-HT2-selective drugs.

Animals↗
PubMed1985

beta-Adrenoceptor blocking agents recognize a subpopulation of serotonin receptors in brain.

The interaction of beta-adrenoceptor blocking agents with serotonin receptors in rat brain was analyzed by quantitative light microscopic autoradiography using (-) [125I]cyanopindolol (ICYP) as a ligand. In some brain areas such as the globus pallidus and dorsal subiculum, binding of ICYP was blocked with high affinity by some serotoninergic ligands, RU-24969 and serotonin, but not by lysergic acid diethylamide and 8-hydroxy-2-(N,N-di-n-propylamino)tetralin. Some beta-blockers also showed high affinity for these sites. These results supply direct evidence for the labeling of a subclass of serotonin receptors, the 5-HT-1B class, providing anatomical and pharmacological basis for some known serotonin-related effects of beta-adrenoceptor drugs.

Adrenergic beta-Antagonists↗
PubMed1985

Autoradiographic studies on dopamine D2 receptors in rat pituitary: influence of hormonal states.

The influence of the estrous cycle on the density of dopamine D2 sites in the rat pituitary was studied by quantitative autoradiography using [3H]spiperone. While no significant changes were found in the neural and intermediate lobes during the cycle, a lower number of D2 receptors in the anterior lobe was observed in the proestrus when compared to the diestrus. The difference in the density of [3H]spiperone binding in the pituitary between male and female rats was also analysed. A significantly lower number of receptors in the three lobes of the male pituitary, as compared to those of the female, was found. Finally, no significant variation in the number of binding sites in the 3 pituitary lobes was observed between lactating and separated mothers.

Animals↗
PubMed1985

Thyrotropin-releasing hormone receptor binding sites: autoradiographic distribution in the rat and guinea pig brain.

Thyrotropin-releasing hormone (TRH) binding sites were labeled in vitro in mounted brain tissue sections from rat and guinea pig brains with [3H]methyl TRH and localized autoradiographically using 3H-sensitive film. Regional densities of TRH binding sites were measured by computer-assisted microdensitometry. The distribution of sites in both species was highly heterogeneous. In both guinea pig and rat brains, the highest densities of binding sites were seen in the amygdaloid nuclei and the perirhinal cortex. In contrast, in other brain areas, a clear difference between the distribution of sites in rat and guinea pig was found. The temporal cortex, pontine nuclei, and interpeduncular nucleus, which contained high densities of binding in the guinea pig, were scarcely labeled in the rat. The accessory olfactory bulb and the septohippocampal area presented in the rat higher concentrations of binding sites than in the guinea pig. Other brain areas showing intermediate to low densities in both species were accumbens nucleus, bed nucleus of the stria terminalis, dentate gyrus, facial and hypoglossal nuclei, and gelatinosus subnucleus of the trigeminal nerve, among others. The anterior pituitary also presented low to intermediate concentrations of receptors. The distribution of TRH sites here described does not completely correlate with that of endogenous TRH, but is in good agreement with previous biochemical data. The results are discussed in correlation to the physiological effects that appear to be mediated by TRH.

Animals↗
PubMed1984

Mesulergine, a selective serotonin-2 ligand in the rat cortex, does not label these receptors in porcine and human cortex: evidence for species differences in brain serotonin-2 receptors.

The kinetic and pharmacological characteristics of the binding of [3H]ketanserin and [3H]mesulergine to frontal cortical brain membranes from rat, pig and human were studied. In the 3 species [3H]ketanserin labeled sites with the characteristics of the 5-HT2 receptors previously described in the rat. In contrast, [3H]mesulergine labeled 5-HT2 receptors in rat, but not in pig and human cortices. The characteristics of the sites labeled by [3H]mesulergine in pig cortex were similar to those of sites in the choroid plexus of rats, pigs and humans. While several reputed 5-HT2 ligands presented a similar affinity for the [3H]ketanserin binding sites in the 3 species, other such ligands, e.g. mesulergine, methysergide, cinanserin and LSD which displaced these sites with high affinity in rat brain, had lower affinities in pig and human brain. These results indicate that 5-HT2 receptors show different pharmacological profiles in different species. Caution should thus be exerted in extrapolating data from laboratory animals to humans.

Animals↗
PubMed1984

The binding of serotonergic ligands to the porcine choroid plexus: characterization of a new type of serotonin recognition site.

The kinetic and pharmacological characteristics of the binding of [3H]5-HT (serotonin), [3H]8-OH-DPAT (8-OH-2-di-n-propylaminotetraline), [3H]LSD, [3H]ketanserin and [3H]mesulergine to membranes from frontal cortex, hippocampus and choroid plexus of pig brain were studied. The binding of these ligands to frontal cortex and hippocampus demonstrated the presence of 5-HT1 and 5-HT2 sites in both tissues, although hippocampus was richer in 5-HT1 (subtype 5-HT1A) sites. [3H]5-HT, [3H]mesulergine and [3H]LSD labeled the pig choroid plexus with high affinity. The pharmacological profiles of [3H]5-HT and [3H]mesulergine binding to this tissue were closely comparable. Ligands reported as selective for 5-HT1A, 5-HT1B or 5-HT2 subtypes did not show high affinity for these binding sites. Therefore, these 5-HT binding sites in pig choroid plexus could be named 5-HT1C. Other drugs with a high affinity for these sites were methysergide and mianserine. In pig frontal cortex, [3H]5-HT labeled the different subtypes of 5-HT1 sites. In contrast, [3H]mesulergine bound in pig frontal cortex to a small population of sites with pharmacological properties similar to those of the choroid plexus 5-HT1C sites. Possible physiological functions in which these sites might be involved are discussed.

Animals↗
PubMed1984

A comparative study in rats of the respiratory depression and analgesia induced by mu- and delta-opioid agonists.

A comparison was made in awake rats between the analgesic and the respiratory depressant actions induced by the mu-opiate agonists morphine and Tyr-D-Ala-Gly-N-Me-Phe-Met-(O)-ol (FK-33824), and the delta-agonists Tyr-D-Ala-Gly-Phe-D-Leu ( DADLE ) and Tyr-D-Ser-Gly-Phe-D-Leu-Thr (D-Ser2- Thr6 ), injected into the cerebral ventricles. The four opioids caused a dose-dependent analgesia (tail-flick); FK-33824 was the most potent, followed by morphine, DADLE and D-Ser2- Thr6 , and the duration of the analgesic effect of D-Ser2- Thr6 was very short. Respiratory frequency was dose-dependently depressed by FK-33824 and DADLE ; dose-response curves with morphine and D-Ser2- Thr6 could not be obtained for technical reasons. The in vivo apparent pA2 values for naloxone against the mu-agonist FK-33824 and the delta-agonist DADLE were similar in analgesia suggesting an interaction with the same type of receptor. On the other hand, in respiration studies the pA2 value for the interaction of naloxone with DADLE was significantly higher than with FK-33824. The ratio between the ED50 required to induce respiratory depression and analgesia was 1,500 times higher for FK-33824 than for DADLE . It was concluded that agonist interaction with mu-receptors can result in antinociceptive effect in the tail-flick test, whereas respiratory depression seems to require a prominent, but non-exclusive, interaction with delta-receptors.

Analgesia↗
PubMed1984

Different mechanisms are involved in the respiratory depression and analgesia induced by neurotensin in rats.

The tridecapeptide neurotensin (NT), injected intracerebroventricularly in rats, induced a naloxone-insensitive and dose-dependent analgesia (tail-flick test), the ED50 being 3.22 nmol/animal. Higher doses induced a dose-dependent respiratory depression, mostly accounted for by a reduction of frequency; the ED50 for this action was 144.6 nmol/animal. In contrast to analgesia, the respiratory depression was antagonized by naloxone, suggesting the possibility that NT and opioid systems might interact at the level of respiration-related nuclei.

Analgesia↗
PubMed1984

Quantitative receptor autoradiography: application to the characterization of multiple receptor subtypes.

In vitro autoradiographic techniques combined with computer assisted microdensitometry were used to analyze the characteristics and distribution of multiple recognition sites for the neurotransmitters acetylcholine (M1 and M2) and serotonin (5-HT1A and 5-HT1B). For this purpose, binding competition experiments were performed using non-subtype selective 3H-labeled ligands and selective unlabeled compounds. Consecutive tissue sections were incubated in the presence of increasing concentrations of displacers. By using this approach, maximal densities of binding sites, as well as competition profiles of several drugs could be analyzed and quantified in microscopic brain areas. Our results reveal the presence of brain structures enriched in one class of muscarinic or serotonergic-1 recognition sites. This provides a tool for better characterization of the proposed "subtype-selective" ligands and suggests physiological functions for these receptor subtypes. It is concluded that quantitative autoradiographic techniques provide a level of anatomical and pharmacological information on neurotransmitter receptor subtypes, which is difficult to attain using membrane binding studies.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1983

Interaction of naloxone with mu- and delta-opioid agonists on the respiration of rats.

The respiratory depression induced by two mu-opiate agonists morphine and Tyr-D-Ala-Gly-N-Me-Phe-Met(O)-ol (FK-33824), and two delta-agonists Tyr-D-Ala-Gly-Phe-D-Leu (DADLE) and Tyr-D-Ser-Gly-Phe-Leu-Thr (D-Ser2-Thr6) was studied in rats by using the intracerebroventricular route. The four opioids caused a dose-dependent depression of respiratory frequency down to apnea but high doses of morphine elicited motor activation and seizure activity. FK-33824 was the most potent, followed by DADLE, D-Ser2-Thr6 and morphine. The in vivo apparent pA2 values were determined for naloxone against FK-33824, DADLE and D-Ser2-Thr6. The pA2 value of naloxone interacting with the mu-agonist FK-33824 was significantly lower than those obtained against the two delta-agonists. It is proposed that different types of opiate receptors are involved in the opiate-induced respiratory depression.

Animals↗
PubMed1983

A comparative study of the respiratory depressant and analgesic effects of bremazocine, a kappa-agonist.

The respiratory depression and analgesia induced by a kappa-agonist, bremazocine, were studied by the ED50 ratios and the apparent pA2 values of the interaction with naloxone. The ratio between the ED50 in respiratory depression and analgesia (i.c.v.) was very high compared to that of other mu- and delta-agonists, indicating its small activity on the respiratory center. pA2 values were 7.33 and 7.20 for analgesia and respiratory depression, respectively, after i.c.v. administration. After s.c. injection, the pA2 value for analgesia was 6.16. The results confirm the involvement of different opiate receptors in the mediation of supraspinal and spinal analgesia. The results suggest that bremazocine may induce analgesia by interacting with different types of receptors located at different levels of the CNS. This property and the low activity on the respiratory center make drugs like bremazocine good candidates in the search for safer opiate analgesics.

Analgesia↗
PubMed1982

Cardiovascular effects of intracerebroventricular injection of dopamine after selective MAO inhibition in rats.

Intracerebroventricular injection of dopamine (30-300 micrograms) caused a dose-dependent reduction in the blood pressure and cardiac rate of anaesthetized rats. Inhibition of MAO-type A with clorgyline enhanced the vasodepressant effect while it reversed the bradycardiac effect. Deprenyl, a MAO-type B inhibitor, did not modify the cardiovascular effects of dopamine injected into the cerebral ventricles. The persistent hypotensive action of dopamine in clorgyline-pretreated rats was abolished by the central blockade of alpha-adrenoreceptors with intracerebroventricular injection of phentolamine, whereas haloperidol given by the same route did not affect the hypotensive response. The results suggest that dopamine centrally affects cardiovascular regulation, either after conversion into noradrenaline, or through a direct stimulation of central alpha-adrenoceptors.

Animals↗
PubMed1980

Respiratory effects of beta-endorphin, D-Ala2-met-enkephalinamide, and Met-enkephalin injected into the lateral ventricle and the pontomedullary subarachnoid space.

The respiratory effects of Met-enkephalin (900 microgram), D-Ala2-Met-enkephalinamide (10 microgram), and beta-endorphin (10 microgram) were studied and compared in lightly anesthetized cats, after injection into the lateral ventricle and into the pontomedullary subarachnoid space. The 3 peptides injected into the lateral ventricle induced equidepressant effects on respiration, but the duration of action and the involvement of either frequency or tidal volume varied considerably. Met-enkephalin was shorter-acting (45 min) than both D-Ala2-Met-enkephalinamide and beta-endorphin (over 5 h). The depression induced by beta-endorphin was preceded by a long-lasting stimulation of frequency. The effects were antagonized by i.v. naloxone, but the antagonism was not complete in one third of the animals. In the pontomedullary subarachnoid space, beta-endorphin failed to depress respiration significantly whereas Met-enkephalin induced an immediate and short-acting depression (15 min), and D-Ala2-Met-enkephalinamide depressed respiration for 2-4 h in a biphasic pattern. It is concluded that: (1) respiration is depressed by the 3 opiate peptides; (2) the effects of beta-endorphin on respiration, at the dose used in this study, are secondary to other actions on higher brain structures; and (3) Met-enkephalin and D-Ala2-Met-enkephalinamide seem to affect pontomedullary areas located near the ventral surface, although they may also interact with respiratory structures located more deeply in the brain stem.

Animals↗
PubMedDate not supplied

Comparative effects of opioid peptides on respiration and analgesia in rats.

Receptor mechanisms for opiate induced respiratory depression and analgesia (tail-flick) were studied by the ED50 ratios and the apparent pA2 values of the interactions of naloxone with the mu-agonists morphine and D-ala2-me-phe4-met (O)ol5-enkephalin (FK-33824), and the delta-agonists D-ala2-D-leu5-enkephalin (DADL) and tyr-D-ser-gly-phe-leu-thr. The apparent pA2 values of morphine, FK-33824 and DADL for analgesia were similar, whereas the apparent pA2 values of the mu-agonists for respiratory depression were significantly lower than those of the delta-agonists. The ratio between the ED50 of FK-33824 in analgesia and respiratory depression was much lower than that of DADL. It is concluded that different receptors mediate the opiate-induced respiratory depression. One difficulty with the delta-receptors being maximally involved in this action is the high degree of antagonism shown by naloxone on the respiratory effects of the delta-agonists.

Analgesia↗
PubMedDate not supplied

Differential distribution of [3H]sumatriptan binding sites (5-HT1B, 5-HT1D and 5-HT1F receptors) in human brain: focus on brainstem and spinal cord.

We report on the autoradiographic distribution of 5-HT1B, 5-HT1D and 5-HT1F receptor subtypes in human brain, focusing on the brainstem and cervical spinal cord. We have used [3H]sumatriptan as a radioligand in the presence of suitable concentrations of 5-CT (5-carboxamidotryptamine) to define 5-HT1F receptors, and ketanserin, to discriminate between 5-HT1B and 5-HT1D receptors. In the brainstem the highest concentrations of [3H]sumatriptan binding sites were seen in substantia nigra. The spinal trigeminal nucleus, substantia gelatinosa of the spinal cord, nucleus of the tractus solitarius and periaqueductal grey, also showed significant levels of [3H]sumatriptan binding sites. In the brainstem and spinal cord the total population of 5-CT-insensitive receptors, corresponding to 5-HT1F receptors, ranged from 9.8% in the periaqueductal grey to 53.4% in the substantia gelatinosa. This population represented 67.0% of binding in layer V of the frontal cortex. The decrease in [3H]sumatriptan binding in the presence of 200 nM ketanserin, indicative of the presence of 5-HT1D receptors, was very limited throughout the human brain, only reaching 20% of total specific binding over the periaqueductal grey. The proportion of [3H]sumatriptan binding sites displaced by 5-CT and insensitive to ketanserin, corresponding to 5-HT1B receptors, was, in general, the most abundant, ranging from 43.8% in substantia gelatinosa to 69.9% in the periaqueductal grey. Significant levels of 5-HT1B and 5-HT1D receptors found in migraine control pain areas suggest their involvement in antinociceptive mechanisms.

Aged↗