Biomedical subjects

J M Palacios

Publications and source records attributed to J M Palacios.

At least 19 recordsLinked to original sources

PubMed1992

Stereoisomerism and muscarinic receptor agonists: synthesis and effects of the stereoisomers of 3-[5-(3-amino-1,2,4-oxadiazol)yl]-1- azabicyclo[2.2.1]heptane.

The preparation and the biological activities of the four stereoisomers of 3-[5-(3-amino-1,2,4-oxadiazol)yl]-1-azabicyclo[2.2.1]heptane are described. The most potent stereoisomer, 3a, has the 3R,4R configuration, and in vitro activities in (pD2(% efficacy): ileum 8.8 (87%), hippocampus 9.8 (116%) and ganglion 10.2 (36%)). 3b (3S,4S) was weaker (ileum 8.1 (121%), hippocampus 8.5 (107%), ganglion 9.0 (63%)). The other two stereoisomers, 4a (3S,4R; ileum 7.1 (108%), hippocampus 8.2 (116%), ganglion 7.3 (31%)) and 4b (3R,4S; ileum 7.0 (100%), hippocampus 7.0 (120%), ganglion 7.2 (67%)) are of comparable activity, with an analogous profile to that of the more potent stereoisomers. Thus, compounds 3a and 4a, possessing the 4R stereochemistry, showed selectivity for the hippocampus over the ileum. Compound 3a was, however, more potent in the ganglion than in the hippocampus. All four stereoisomers were full agonists in the hippocampus, indicating M1 activity; however, they were partial agonists in the depolarisation of the rat superior cervical ganglion, another M1-mediated response. This may be due to M2-mediated hyperpolarization. With 3a (0.01 mg/kg i.p.), expression of c-fos mRNA was observed in the hypothalamus and in brain areas involved in sensory processing; these effects were totally blocked by pretreatment with 2 mg/kg scopolamine. In particular, activation of the superior colliculus is consistent with potent M2 activity.

Animals↗

PubMed1992

Intracerebroventricular application of competitive and non-competitive NMDA antagonists induce similar effects upon rat hippocampal electroencephalogram and local cerebral glucose utilization.

In this study we have used electrophysiological and metabolic markers to investigate the effects of competitive and non-competitive NMDA antagonists in rats after central or peripheral administration. The non-competitive antagonist, MK-801, induced dose-dependent suppression of rat hippocampal EEG energy both after intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) application. Similar effects were observed after i.p. and i.c.v. application of the competitive antagonist, DL-CPP-ene. Whereas the MK-801 was more potent after i.p. application, DL-CPP-ene was more potent after i.c.v. administration. Intracerebroventricular administration of MK-801 and DL-CPP-ene resulted in similar changes in the pattern of local cerebral glucose utilization in the olfactory tubercle and regions of the limbic system such as the anteroventral thalamus, hippocampus and entorhinal cortex. Intravenous (i.v.) administration of MK-801 induced increases in glucose metabolism similar to those observed after i.c.v. application. In contrast, i.v. administration of DL-CPP-ene induced only small decreases of glucose utilization in several regions of the central sensory system. Thus the blockade of glutamatergic (NMDA) transmission results in decreased hippocampal EEG activity which is paralleled by increased metabolic activity in this area. We conclude from EEG recordings and [14C]2-deoxyglucose uptake experiments that both non-competitive and competitive NMDA antagonists produce the same pattern of alterations after i.c.v. administration. Apparent differences in efficacy after peripheral administration may be largely due to differences in bioavailability.

Animals↗

PubMed1992

Characterization of the human 5-hydroxytryptamine1B receptor.

We report the cloning of a human gene encoding the 5-hydroxytryptamine1B receptor. The receptor has the characteristics of a G-protein-linked receptor and is most homologous to the human 5-HT1D receptor. This human 5-HT receptor gene, most abundantly expressed in striatum, is localized on chromosome 6, at 6q13, and the gene encoding the 5-HT1D receptor is localized on chromosome 1. Radioligand studies indicate that the affinity of [3H]5-HT is 16 +/- 2 nM. Drug competition studies indicate that the receptor displays high affinity (i.e. less than 40 nM) for 5-HT, 5-carboxyamidotryptamine, methiothepin, and metergoline.

Amino Acid Sequence↗

PubMed1992

Muscarinic M2-selective ligands also recognize M4 receptors in the rat brain: evidence from combined in situ hybridization and receptor autoradiography.

We have used autoradiographic techniques to examine the characteristics and distribution of the binding of reported selective M2 muscarinic ligands and compared them with the distribution of cells expressing mRNAs for the different subtypes of muscarinic receptors. Our results suggest that the M2 ligands used in the present study ([3H]OXO-M, ([3H]OXO-M,[3H]AF-DX384,AF-DX116, methoctramine) also recognize M4 receptors present in regions such as the striatum and olfactory tubercle. This is supported by 1) relative abundances of the different transcripts, with m2 mRNA being very scarce and m4 mRNA very abundant in these regions; 2) comparison of the pharmacological characteristics of M2-ligand binding sites in brain areas selected by their exclusive expression of M2 receptors versus areas enriched in M4 receptors. An important conclusion of these studies is that none of the muscarinic radioligands available at the present time appears to label specifically a single muscarinic receptor subtype population. Areas are suggested where autoradiographic techniques can be helpful in elucidating the subtype selectivity of existing and new ligands.

Animals↗

PubMed1992

Regional distribution of neuropeptide somatostatin gene expression in the human brain.

The regional distribution of mRNA coding for the neuropeptide somatostatin has been studied in the human brain by in situ hybridization histochemistry using 32P-labeled oligonucleotides. We show that somatostatin mRNA-containing neurons are widely distributed in a number of nuclei and grey areas of the human brain, including neocortex, putamen, nucleus caudatus, nucleus accumbens, amygdala, midbrain, medulla oblongata, hippocampal formation, reticular nucleus of the thalamus, and posterior nucleus of the hypothalamus. No significant hybridization signal was observed in the substantia nigra, claustrum, globus pallidus, thalamus, and cerebellum. The topographic localization of neurons containing SOM mRNA in the human brain is in agreement with previous studies using immunocytochemical or radioimmunoassay techniques. These results show that in situ hybridization histochemistry with oligonucleotide probes can be used to map the distribution of neurons expressing SOM mRNA in human postmortem materials.

Adult↗

PubMed1992

Non 5-HT1A/5-HT1C [3H]5-HT binding sites in the hamster, opossum, and rabbit brain show similar regional distribution but different sensitivity to beta-adrenoceptor antagonists.

We have used receptor autoradiography to investigate the distribution and pharmacological profile of non 5-HT1A/5-HT1C[3H]5-hydroxytryptamine binding sites in the brain of rabbits, hamsters and opossums. These data were compared to those found under similar conditions in the brain of rats and guinea pigs, species which are known to possess 5-HT1B and 5-HT1D receptors, respectively. In the presence of 100 nM 8-OH-DPAT and mesulergine, the regional distribution of [3H]5-hydroxytryptamine binding sites was very similar in the brain of all species investigated; densest labelling was observed in the globus pallidus, substantia nigra and superior colliculus. In all species, 5-carboxamidotryptamine competed for the labelled sites in a biphasic manner and metergoline displayed a subnanomolar affinity. In contrast, the beta-adrenoceptor blocking agents (-)propranolol, (-)pindolol, and (+/-)SDZ 21009 were potent displacers only in the rat, hamster and opossum brains. These data indicate that non 5-HT1A/5-HT1C[3H]5-HT binding sites display a high affinity for these agents in a particular rodent suborder as well as in opossum, a phylogenetically unrelated species.

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

PubMed1992

5-HT1D binding sites in various species: similar pharmacological profile in dog, monkey, calf, guinea-pig and human brain membranes.

Radioligand binding studies were performed in membranes of calf caudate, guinea-pig cortex, dog caudate and whole brain, monkey caudate and whole brain, and human caudate using the novel iodinated radioligand, Serotonin-5-O-Carboxymethyl-Glycyl[125I] Tyrosinamide (abbreviated [125I]GTI for the sake of simplicity), a ligand known to label 5-HT1B and 5-HT1D sites. In all membrane preparations tested, [125I]GTI labelled high affinity sites with the following rank order of affinity: 5-carboxamidotryptamine greater than 5-HT = DHE = ergotamine greater than or equal to sumatriptan greater than or equal to metergoline = CGS 12066 greater than or equal to yohimbine = methysergide greater than or equal to methiothepin greater than 8-OH-DPAT greater than or equal to mianserin greater than or equal to CP 93129 greater than or equal to (-)pindolol = ketanserin greater than or equal to isamoltane = mesulergine greater than or equal to corynanthine = spiperone greater than MDL 72222. The affinity profiles were very similar in the membranes of the different species, especially in dog, monkey and human brain. The pharmacological profile of [125I]GTI binding (determined with up to 25 different drugs) was fully comparable to the binding profile reported previously in human substantia nigra (using [125I]GTI) or in a variety of brain preparations known to contain 5-HT1D sites using [3H]5-HT as a radioligand.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

"5-HT1R" or 5-HT1D sites? Evidence for 5-HT1D binding sites in rabbit brain.

Radioligand binding studies were performed in membranes of rabbit whole brain and striatum using the novel iodinated radioligand for 5-hydroxytryptamine 5-HT1B and 5-HT1D sites, Serotonin-5-O-Carboxymethyl-Glycyl[125I]Tyrosinamide ([125I]GTI). [125I]GTI labelled a finite number of high affinity sites in rabbit brain membranes, Bmax = 191 +/- 47 fmol/mg protein, pKD (-log mol/l) = 8.50 +/- 0.13, n = 5. The pharmacological profile of [125I]GTI binding was fully comparable to that reported previously in human and other brain preparations known to possess 5-HT1D sites (using either [3H]5-HT or [125I]GTI) and displayed a characteristic rank order of affinity: 5-carboxamido-tryptamine greater than 5-HT = dihydroergotamine greater than or equal to ergotamine greater than or equal to sumatriptan greater than or equal to CGS 12066 greater than or equal to metergoline greater than yohimbine greater than or equal to methysergide greater than ICYP greater than 8-OH-DPAT greater than or equal to CP 93129 greater than (-)pindolol greater than ketanserin greater than isamoltane greater than mesulergine greater than corynanthine greater than buspirone greater than MDL 72222. Autoradiographic studies were performed on rabbit brain slices using [3H]5-HT in the presence of 100 nmol/l 8-OH-DPAT and mesulergine (in order to mask 5-HT1A and 5-HT1C binding sites) and [125I]CYP (iodocyanopindolol) in the presence of 3 mumol/l isoprenaline and 100 nmol/l 8-OH-DPAT (in order to mask beta adrenoceptor and 5-HT1A binding sites). There was no detectable specific binding of [125I]CYP through the brain, thus excluding the presence of 5-HT1B sites in rabbit brain.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Limbic seizures induce a differential regulation of the expression of nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3, in the rat hippocampus.

Small unilateral electrolytic lesions placed in the hilus of the dentate gyrus produce limbic seizures. We have investigated the effects of these hilar lesions on the levels of the mRNAs encoding for 3 neurotrophic factors (NTF): nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3). 'In situ' hybridization histochemistry with synthetic oligonucleotides was used to analyze their mRNA distribution and levels. In agreement with previously published data (Science, 245 (1989) 758-761), NGF mRNA was found bilaterally, quickly and transiently increased in granule cells of the dentate gyrus. Only 2 h after the onset of limbic seizures, mRNA levels for BDNF were also found to be dramatically elevated in both sides of the hippocampus, reaching a maximum 30-fold increase in the granule cell layer of the dentate gyrus 5 h after the lesion. Moreover, increased levels of this mRNA were also been found in the pyramidal layer of the CA3 (5-fold) and CA1 (15-fold) hippocampal fields. In contrast, NT3 mRNA was found to be clearly and bilaterally decreased in dentate gyrus granule cells, reaching 5- to 6-fold decreased levels at 12 h after lesion. Taken together, these results clearly show a different regulation of neurotrophic factors genes (NGF, BDNF and NT3) expression in the different hippocampal fields, as a consequence of seizure-producing hilar lesions.

Animals↗

PubMed1992

Direct visualization of serotonin1D receptors in the human brain using a new iodinated radioligand.

The development of the new ligand serotonin-5-O-carboxymethyl-glycyl [125I]tyrosinamide (abbreviated [125I]GTI) allows for the direct visualization of serotonin1B and serotonin1D (5-HT1B/1D) sites. Autoradiographic techniques were used to demonstrate the selective binding of this ligand to 5-HT1D sites in human post-mortem brain materials. The distribution of [125I]GTI binding sites was compared to [3H]5-HT sites in the presence of different displacers. The results show the selective binding of [125I]GTI to sites in the basal ganglia and substantia nigra which corresponds to 5-HT1D receptors.

Aged↗

PubMed1992

Beta-amyloid precursor protein localization in the Golgi apparatus in neurons and oligodendrocytes. An immunocytochemical structural and ultrastructural study in normal and axotomized neurons.

We have used a polyclonal antibody raised against a synthetic peptide from the carboxyl terminal of the beta-amyloid precursor protein (APP) to examine the cellular and subcellular localization of this protein in the rat brain. Light and electron microscopic immunocytochemical techniques were used. Immunoreactivity was found throughout the brain in all the neurons examined as well as in oligodendrocytes. At the light microscopic level, a perinuclear filamentous distribution was seen in neurons, suggesting a concentration of the protein to the Golgi apparatus. Axotomy of motor neurons of the facial nucleus produced a decrease in choline acetyltransferase (ChAT) activity and an increase in the perineuronal microglial nucleoside diphosphatase (NDPase)-positive cells in addition to a hypertrophy of the GFAP immunoreactive astrocytes. On the other hand, increased APP-like immunoreactivity all over the neuronal cell bodies accompanied by a dispersion ('rete dispersion') of the Golgi apparatus labeling was demonstrated. In contrast, reactive microglia and hypertrophic astrocytes in axotomized facial nucleus were not immunolabeled. Oligodendrocytes showed a punctate APP immunoreactivity corresponding to the Golgi apparatus in both operated and control facial nucleus. This was further demonstrated by electron microscopic immunolabeling. These results show that the main localization of the C-terminal containing forms of the APP in the rat brain is the Golgi apparatus in both neurons and oligodendroglia and further supporting the secretory nature of these proteins. The increased synthesis of this protein after axotomy is suggestive of a role of the APPs in growth and/or regeneration.

Alzheimer Disease↗

PubMed1992

Administration of quinolinic acid in the rat hippocampus induces expression of c-fos and NGFI-A.

We have studied the effect of intrahippocampal administration of quinolinic acid (QUIN) on the temporal expression of mRNAs encoding the immediate early genes (IEGs) c-fos and NGFI-A, by in situ hybridization histochemistry. After administration of QUIN to the left hippocampus, expression of mRNA of both IEGs was transiently stimulated. Maximal expression was found between 1 and 3 h. mRNA of both IEGs was simultaneously expressed in the ipsilateral and contralateral sides in the granule cell layer of the dentate gyrus, the pyramidal cell layer of the CA1 and CA3 fields as well as in the cortex. After pretreatment with the non-competitive NMDA antagonist MK-801 (2 mg/kg i.p. -30 min) the increased expression of both IEGs was partially prevented in the hippocampus and completely in the cortex. No inhibition was observed after treatment with the AMPA antagonist NBQX (30 mg/kg i.p. -15, -5 and +10 min). Additional delayed expression of both IEGs was observed in the ipsilateral hippocampus. This expression was related to cell damage. Twelve h after QUIN administration, c-fos and NGFI-A mRNAs were present in the dentate gyrus. After 4 days, only c-fos mRNA was observed in the dentate gyrus and CA1 field while no NGFI-A mRNA was detected. The present results show that the effect of QUIN is mediated by NMDA and not by AMPA receptors.

Animals↗

PubMed1992

Visualization of dopamine D1, D2 and D3 receptor mRNAs in human and rat brain.

Using 32P-labelled oligonucleotides derived from the coding regions of dopamine D1, D2 and D3 receptor mRNAs we localized cells containing transcripts for these receptors in the human (hD1, hD2) and rat brain (rD1, rD2, rD3). Dopamine D1 receptor mRNA was detected at high levels in neurons of the caudate and putamen as well as in the nucleus accumbens in both human and rat brain. In the rat brain D1 receptor mRNA was also abundant in the olfactory tubercles and several thalamic nuclei. In both species D1 mRNA was absent from the neurons of the substantia nigra and the ventral tegmental area as well as from the globus pallidus medialis in humans and entopeduncular nucleus in rats. In contrast, dopamine D2 receptor mRNA was found in dopaminergic neurons of the substantia nigra pars compacta and of the ventral tegmental area. In addition high levels of D2 mRNA were detected in neurons of the caudate, putamen and accumbens nuclei, the olfactory tubercle and the anterior lobe of pituitary gland. In the rat the highest level of hybridization was found in the intermediate lobe of the pituitary gland. In the rat brain dopamine D3 mRNA was mainly detected in the Islands of Calleja and at lower levels in the anterior nucleus accumbens, the medial mammillary nucleus as well as in the bed nucleus of the stria terminalis. In general, a good agreement was found between the distribution of transcripts and binding sites labelled with the D1 antagonist SCH 23390 or with the D2 ligand SDZ 205-502. For D1 receptors, the main exceptions were the absence of mRNA in the globus pallidus and the substantia nigra despite the high densities of binding sites in these regions. For D2 receptors, regions where binding sites but not mRNA were detected included the olfactory bulb, neocortex, hippocampus and superior colliculus.

Animals↗

PubMed1992

Mesostriatal and mesolimbic dopamine uptake binding sites are reduced in Parkinson's disease and progressive supranuclear palsy: a quantitative autoradiographic study using [3H]mazindol.

It has been suggested that not only mesostriatal but also mesolimbic pathways are involved in the degeneration of dopaminergic neurons in Parkinson's disease. Using quantitative ligand autoradiography we have investigated dopamine transporter sites in basal ganglia of patients affected by Huntington's chorea, Parkinson's disease and progressive supranuclear palsy. [3H]Mazindol, a ligand for catecholamine uptake, was used in the presence of desipramine to block the binding to norepinephrine uptake sites. Schizophrenic cases were entered in the study to take into account the effects of neuroleptics, commonly administered also to Huntington's disease patients, on dopamine uptake sites. In control cases high densities of [3H]mazindol binding sites were found in the caudate nucleus, putamen and nucleus accumbens, whereas very low densities were present in substantia nigra and ventral tegmental area. In Huntington's chorea the density of [3H]mazindol binding sites was slightly decreased in the caudate nucleus, an area severely affected by the neurodegenerative process. In schizophrenic patients the density of dopamine uptake sites in the basal ganglia was slightly reduced, mainly in the middle third of putamen. Both Parkinson's disease and progressive supranuclear palsy populations were characterized by a marked loss of [3H]mazindol binding sites in the neostriatum (about 75%) and in the nucleus accumbens (about 65%). These results suggest that in Parkinson's disease and progressive supranuclear palsy severe decreases of dopamine uptake sites occur not only in the mesostriatal pathway but also in the mesolimbic tract.

Aged↗

PubMed1992

Muscarinic M2 receptor mRNA expression and receptor binding in cholinergic and non-cholinergic cells in the rat brain: a correlative study using in situ hybridization histochemistry and receptor autoradiography.

The goal of the present study was to identify the cells containing mRNA coding for the m2 subtype of muscarinic cholinergic receptors in the rat brain. In situ hybridization histochemistry was used, with oligonucleotides as hybridization probes. The distribution of cholinergic cells was examined in consecutive sections with probes complementary to choline acetyltransferase mRNA. Furthermore, the microscopic distribution of muscarinic cholinergic binding sites was examined with a non-selective ligand ([3H]N-methylscopolamine) and with ligands proposed to be M1-selective ([3H]pirenzepine) or M2-selective ([3H]oxotremorine-M). The majority of choline acetyltransferase mRNA-rich (i.e. cholinergic) cell groups (medial septum-diagonal band complex, nucleus basalis, pedunculopontine and laterodorsal tegmental nuclei, nucleus parabigeminalis, several motor nuclei of the brainstem, motoneurons of the spinal cord), also contained m2 mRNA, strongly suggesting that at least a fraction of these receptors may be presynaptic autoreceptors. A few groups of cholinergic cells were an exception to this fact: the medial habenula and some cranial nerve nuclei (principal oculomotor, trochlear, abducens, dorsal motor nucleus of the vagus). Furthermore, m2 mRNA was not restricted to cholinergic cells but was also present in many other cells throughout the rat brain. The distribution of m2 mRNA was in good, although not complete, agreement with that of binding sites for the M2 preferential agonist [3H]oxotremorine-M, but not with [3H]pirenzepine binding sites. Regions where the presence of [3H]oxotremorine-M binding sites was not correlated with that of m2 mRNA are the caudate-putamen, nucleus accumbens, olfactory tubercle and islands of Calleja. The present results strongly suggest that the M2 receptor is expressed by a majority of cholinergic cells, where it probably plays a role as autoreceptor. However, many non-cholinergic neurons also express this receptor, which would be, presumably, postsynaptically located. Finally, comparison between the distribution of m2 mRNA and that of the proposed M2-selective ligand [3H]oxotremorine-M indicates that this ligand, in addition to M2 receptors, may also recognize in certain brain areas other muscarinic receptor populations, particularly M4.

Acetylcholinesterase↗

PubMed1992

In situ hybridization histochemistry in the human hypothalamus.

We have seen that mRNA for several neuropeptides can be visualized at the microscopic level in human post-mortem brain tissues using in situ hybridization histochemistry and oligonucleotides as probes. The specificity of the hybridization signal detected in each case is supported by several criteria such as Northern blot analysis, use of at least two oligonucleotides complementary to different regions of the same target mRNA, cohybridization of labeled and excess unlabeled oligonucleotide probes, and melting curve analysis of the formed hybrids. Furthermore, factors such as age, post-mortem delay or gender did not show a significant effect in the levels of hybridization in the control population studied. Hybridization signals comparable to those found in the control population were obtained in frozen tissues, stored for up to 6 years before analysis. The results obtained for the different neuropeptides examined are, in general, in good agreement with the available information on their distribution and cellular localization as determined by radioimmunoassay or immunohistochemistry. The use of in situ hybridization histochemistry has clearly revealed the location of neurons synthesizing these neuropeptides, adding important information to that provided by radioimmunoassay or immunohistochemistry. A typical example is the identification of peptide synthesizing neuronal cell bodies by immunohistochemistry. This requires, in some cases, the use of treatments such as colchicine, obviously impossible with human brain tissues. The abundance of mRNA could be further related to transcriptional activity and, when compared with peptide levels, can provide some clues on peptide turnover rates. Thus in the hypothalamus, the paraventricular and supraoptic nuclei were found to contain cells expressing arginine-vasopressin and oxytocin mRNAs. Their distribution was in good agreement with that determined by immunohistochemistry (Dierickx and Vandesande, 1977). We have also found that these nuclei contain transcripts for neuropeptide genes such as preproenkephalin A, neuropeptide Y and somatostatin, in agreement with previously reported immunohistochemical data (Agid and Javoy-Agid, 1985; Emson et al., 1986). In the basal ganglia, numerous cells heterogeneously distributed throughout the caudate and putamen nuclei were found to contain preproenkephalin A mRNA.(ABSTRACT TRUNCATED AT 400 WORDS)

Basal Ganglia↗

PubMed1992

Receptor localization in the human hypothalamus.

In summary, we have illustrated and discussed the applicability of different techniques to the study of neurotransmitter receptors in the human brain. Because of the availability of these techniques it is possible today to examine in detail the alterations in density produced by different physiological or pathological conditions. The use of these techniques will in the future, without any doubt, be of help in understanding the chemical neuroanatomy of the human hypothalamus.

Aging↗

PubMed1992

Pharmacological characterization and autoradiographic localization of histamine H2 receptors in human brain identified with [125I]iodoaminopotentidine.

125I-Aminopotentidine (125I-APT), a reversible probe of high specific radioactivity and high affinity and selectivity for the H2 receptor, was used to characterize and localize this histamine receptor subtype in human brain samples obtained at autopsy. On membranes of human caudate nucleus, specific 125I-APT binding at equilibrium revealed a single component, with a dissociation constant of 0.3 nM and maximal capacity of about 100 fmol/mg of protein. At 0.2 nM, 125I-APT specific binding, as defined with tiotidine, an H2-receptor antagonist chemically unrelated to iodoaminopotentidine, represented 40-50% of the total. Specific 125I-APT binding was inhibited by a series of typical H2-receptor antagonists that displayed apparent dissociation constants closely similar to corresponding values at the reference biological system, i.e., guinea pig atrium. This indicates that the pharmacology of the H2 receptor is the same in the human brain as on this reference system. However, histamine was about 10-fold more potent in inhibiting 125I-APT binding to membranes of human brain than of guinea pig brain. 125I-APT binding was also inhibited by amitriptyline and mianserin, two antidepressant drugs, in micromolar concentrations corresponding to effective plasma concentrations of treated patients. The distribution of H2 receptors was established autoradiographically with 125I-APT on a series of coronal sections of human brain after assessing the pharmacological specificity of the labeling. The highest density of 125I-APT sites was found in the basal ganglia, various parts of the limbic system, e.g., hippocampus or amygdaloid complex, and the cerebral cortex. H2 receptors displayed a laminar distribution in cerebral cortex and hippocampal formation. A low density of sites was found in cerebellum as well as in hypothalamus, the brain area where all the perikarya and the largest number of axons of histaminergic neurons are found. The widespread distribution of H2 receptors in the human brain is consistent with the alleged modulatory role of histamine mediated by this subtype of receptor.

Autoradiography↗