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M Herkenham

Publications and source records attributed to M Herkenham.

At least 73 records · Page 4Linked to original sources
PubMed1990

Cannabinoid receptor localization in brain.

[3H]CP 55,940, a radiolabeled synthetic cannabinoid, which is 10-100 times more potent in vivo than delta 9-tetrahydrocannabinol, was used to characterize and localize a specific cannabinoid receptor in brain sections. The potencies of a series of natural and synthetic cannabinoids as competitors of [3H]CP 55,940 binding correlated closely with their relative potencies in several biological assays, suggesting that the receptor characterized in our in vitro assay is the same receptor that mediates behavioral and pharmacological effects of cannabinoids, including human subjective experience. Autoradiography of cannabinoid receptors in brain sections from several mammalian species, including human, reveals a unique and conserved distribution; binding is most dense in outflow nuclei of the basal ganglia--the substantia nigra pars reticulata and globus pallidus--and in the hippocampus and cerebellum. Generally high densities in forebrain and cerebellum implicate roles for cannabinoids in cognition and movement. Sparse densities in lower brainstem areas controlling cardiovascular and respiratory functions may explain why high doses of delta 9-tetrahydrocannabinol are not lethal.

Animals↗
PubMed1990

Altered expression of hypothalamic neuropeptide mRNAs in food-restricted and food-deprived rats.

Hypothalamic neuropeptides play a role in appetite and weight regulation. Food restriction for 2 weeks and food deprivation for 4 days were used as models to characterize the effects of weight loss on hypothalamic peptide gene expression in male and female rats. We used in situ hybridization to examine the mRNA levels of hypothalamic peptides which stimulate and inhibit food intake and found selective effects primarily in the arcuate nucleus. Neuropeptide Y (NPY) mRNA was increased and pro-opiomelanocortin (POMC) and galanin (GAL) mRNA were decreased in the hypothalamic arcuate nucleus and corticotropin-releasing hormone (CRH) mRNA was decreased in the hypothalamic paraventricular nucleus in male and female food-restricted and food-deprived rats. Food restriction produced larger changes in peptide mRNA expression than did food deprivation. Changes in NPY, POMC and CRH gene expression induced by food restriction were greater in male than female rats. Elevated NPY and reduced CRH gene expression may be a compensatory physiological response to restore food intake in food-restricted and food-deprived animals. The discrete changes in NPY, POMC, GAL and CRH gene expression in food-restricted and food-deprived animals suggest the involvement of these peptides in abnormal appetitive behavior and weight loss associated with human eating disorders.

Adrenocorticotropic Hormone↗
PubMed1989

Chronic morphine increases mu-opiate receptor binding in rat brain: a quantitative autoradiographic study.

Quantitative autoradiography was used to show the locations of mu-opiate receptor binding sites which are upregulated following chronic morphine treatment in rats. A saturating concentration of the mu-specific ligand [3H]D-ala2-N-methyl-Phe4,Gly-ol5-enkephalin was used to label sites in slide-mounted sections through one level of the thalamus in rats implanted subcutaneously with morphine pellets for 5 days. In vitro binding and autoradiography showed the largest increase in binding in the hypothalamus, especially the ventromedial nucleus (155%), with smaller increases in the basolateral and medial amygdaloid nuclei and the striatum. The set of structures showing the upregulation appears to be a subset of those upregulated by opiate antagonists, but there appears to be no correlation of the mu-sites showing upregulation with other anatomical features of the brain opiate system. The physiological significance of the upregulation is not known at present.

Animals↗
PubMed1988

Physiological regulation of neurohypophyseal kappa-opiate receptors.

Quantitative autoradiography was used to examine the characteristics of kappa-opiate receptor binding in neural lobe sections from dehydrated rats and water-sated homozygous Brattleboro rats. The density of kappa-sites was decreased by 40% and 44%, respectively, after 5 days of water deprivation or hypertonic saline. Both the density and affinity of kappa-receptor sites were lower in homozygous Brattleboro rats. We suggest that kappa-receptor down-regulation occurs as a result of elevated release of opioid peptides induced by chronic osmotic stimulation.

Analgesics↗
PubMed1987

Dehydration reduces kappa-opiate receptor binding in the neurohypophysis of the rat.

Quantitative autoradiography was used to examine the effects of dehydration on kappa-opiate receptor binding in the neural lobe of the pituitary in rats. Dehydration was produced by 5 days of water deprivation or ingestion of 2% saline. Brattleboro rats homozygous for diabetes insipidus were used as a model of chronically disturbed water balance. Slide-mounted pituitary sections were incubated with [3H]bremazocine using kappa-receptor-selective assay conditions. Binding in the neural lobe was quantified by densitometry of film autoradiographs. Specific [3H]bremazocine binding in neural lobe sections of control rats was 45.4 fmol/mg wet weight. In contrast, binding in neural lobe sections of water-deprived, saline-treated, and water-sated homozygous Brattleboro rats was lower by 50%, 35% and 37%, respectively. We suggest that chronic dehydration elevates levels of endogenous neurohypophyseal dynorphin and produces a down-regulation of kappa-opiate receptors in the neurohypophysis, a change in affinity of the receptors for kappa-agonists, or both.

Animals↗
PubMed1987

Distribution of opiate receptor subtypes and enkephalin and dynorphin immunoreactivity in the hippocampus of squirrel, guinea pig, rat, and hamster.

The distribution of enkephalin and dynorphin immunoreactivity in the hippocampus of four rodent species (gray squirrel, guinea pig, rat, and hamster) is compared with the pattern of opiate receptor subtypes (mu, delta, and kappa). The distribution of opioid peptides is fairly consistent in the anterior hippocampus of these four species. Intense immunoreactivity for dynorphin and enkephalin is found in the hilus of the dentate gyrus and in the mossy fiber system. Occasional immunoreactive processes are seen in the dentate molecular layer and scattered throughout the CA1 and CA3 fields. In the rat and hamster, an additional plexus of enkephalinergic fibers straddles both sides of the hippocampal fissure. Cells immunoreactive for both opioid peptides are located in and just superficial to the dentate granule cell layer. Opiate receptors are variably distributed in these rodent species. In the squirrel, guinea pig, and hamster, mu and kappa binding is dense in the stratum lucidum of CA3 and the molecular layer of the dentate gyrus. In the rat, dense mu and kappa binding is localized within and adjacent to the pyramidal and granule cell layers. Delta receptor patterns show additional species differences. In the rat, the delta distribution is similar to the mu and kappa patterns. In the other species, the delta binding pattern is generally the inverse of the mu/kappa pattern: most areas of the hippocampus are enriched in delta sites, whereas the stratum lucidum and the pyramidal cell layer are receptor-sparse. Thus, the stratum lucidum--site of dense terminations of mossy fibers containing opioid peptides--is characterized by selectively sparse delta receptors in four species and by selectively dense kappa receptors in three species. The three receptor subtypes, taken either individually or together and compared to the peptides, are more variably and more widely distributed throughout the hippocampus and fail to show a correspondence with opioid-peptide-containing terminals. The mismatches suggest that receptor locations and densities are organized without relation to the sites of relevant transmitter release.

Animals↗
PubMed1987

The neostriatal mosaic: II. Patch- and matrix-directed mesostriatal dopaminergic and non-dopaminergic systems.

Mesostriatal projections, which arise from dopaminergic and non-dopaminergic neurons in the ventral tegmental area, substantia nigra, and retrorubral area, are compartmentally organized in the striatum. Anterograde axonal tract tracing with Phaseolus vulgaris-leucoagglutinin (PHA-L), combined with immunohistochemical localization of tyrosine hydroxylase (TH) and autoradiographic localization of mu-opiate receptor binding sites, shows that midbrain projections to the striatum are distributed to either the mu-opiate receptor-rich "patch" or the receptor-poor "matrix" striatal compartments. Three morphologically distinct mesostriatal afferent fiber types are labeled. The first type, type A, forms a plexus of relatively thin (0.1-0.4 micron), smooth fibers with small varicosities (0.3-0.6 micron). A second type, type B, is similar to the first in forming a plexus of fibers, but is slightly thicker (0.2-0.6 micron), with more frequent varicosities (0.4-1.0 micron) that give this fiber type a crinkled appearance. The third type, type C, constitutes a minority of striatal afferents and is characterized by its large caliber (0.4-0.7 micron) with large bulbous varicosities (1.2-2.0 micron). Projections of the ventral tegmental area (A10 cell group) are primarily dopaminergic type A fibers directed to the matrix of the ventromedial striatum, including the nucleus accumbens. The retrorubral area (A8 cell group) also provides predominantly dopaminergic type A fibers to the striatal matrix, but these are distributed dorsally. The substantia nigra contains a mixed population of neurons that project to the striatum. Some, located in the dorsal tier of the pars compacta (dorsal A9 cell group), provide dopaminergic type A fibers to the striatal matrix. Others, in the ventral tier of the pars compacta (ventral A9 cell group) and in the ventral tier of the pars reticulata (displaced A9 cells), provide dopaminergic type B fibers to the striatal patches. An additional set of substantia nigra neurons that are non-dopaminergic is the source of type C fibers to the striatal matrix. Thus, distinct dorsal and ventral sets of midbrain dopaminergic neurons project, respectively, to striatal matrix and patches, and there is a non-dopaminergic mesostriatal projection to the matrix.

Afferent Pathways↗
PubMed1986

A comparative autoradiographic study of the distributions of substance P and eledoisin binding sites in rat brain.

The relative potencies of tachykinin peptide analogs competing for binding of [125I]Bolton Hunter-conjugated substance P ([125I]BH-SP) or [125I]Bolton Hunter-conjugated eledoisin ([125I]BH-ED) in slide-mounted rat brain sections are very different, indicating the presence of two distinct tachykinin binding sites. The structure-activity profiles resemble those described in peripheral bioassay studies in which two tachykinin receptors have been postulated. Autoradiography of the two iodinated ligands bound with selective and one-site in vitro incubation conditions shows two discrete and distinctly different distribution patterns in brain. Binding sites for [125I]BH-ED are densely distributed in the accessory olfactory bulb, intermediate layers of the cerebral neocortex, portions of the hippocampal CA fields, hypothalamic supraoptic and paraventricular nuclei, central portions of the interpeduncular nucleus, sphenoid nucleus, medial subdivision of the solitary tract complex, and the substantia gelatinosa of the spinal cord. Binding sites for [125I]BH-SP are present in many of these same structures, but the densities and distribution patterns are different. In addition, [125I]BH-SP binds in numerous structures not labeled by [125I]BH-ED. Neither pattern matches the locations of terminations of endogenous tachykinin pathways marked by immunohistochemistry. The results suggest that it would be inappropriate to name brain tachykinin receptors according to the endogenous ligand which binds with highest affinity.

Animals↗
PubMed1986

Opiate receptors in rat pituitary are confined to the neural lobe and are exclusively kappa.

The distribution and density of opiate receptor subtypes in rat pituitary were examined by quantitative autoradiography of tritiated ligand-binding to slide-mounted sections under conditions optimized to label mu, delta, or kappa opiate receptors. Mu and delta receptor-binding was virtually undetectable in the pituitary. Kappa receptor-binding was confined to the neural lobe where it was densest in the external rim. Autoradiographic silver grains in emulsion-coated, Nissl-stained sections were preferentially located between cells, suggesting kappa receptor localization on nerve terminals and/or processes of pituicytes.

Animals↗
PubMed1986

Autoradiographic localization of mu- and delta-opiate receptors in the forebrain of the rat.

The autoradiographic distributions of mu opiate receptors, labeled in vitro by [125I]D-Ala2-MePhe4-Met(o)5-ol-enkephalin (FK), and delta-opiate receptors, labeled by [3H]D-Ala2-D-Leu5-enkephalin (DADLE) in the presence of oxymorphone to block high affinity binding to the mu site, were examined and compared in the forebrain of the rat. The mu- and delta-receptors were differentially distributed in most structures. mu Binding sites were found in nearly all gray matter structures and showed heterogeneous patterns of density that were correlated with cytoarchitecture and neuronal connections. Laminar density profiles were seen in laminated structures such as olfactory bulb, cerebral cortex and hippocampus. Highest mu binding densities were in striatal patches and the habenular streak. delta Sites had distinct laminar patterns in the main olfactory bulb and cortex which differed from the mu patterns. The external plexiform layer of the main olfactory bulb had the greatest density of delta binding sites; cortex and striatum were also densely labeled. The septum, globus pallidus, preoptic area and hypothalamus were lightly labeled by both ligands. The magnocellular hypothalamic nuclei had negligible mu and delta labeling. The thalamus had dense mu but sparse delta sites. mu And delta binding sites were both present in the amygdala but had different distributions. Two fiber tracts--optic tract and fasciculus retroflexus--had FK labeling. In contrast, a portion of the corpus callosum was labeled by DADLE and not by FK. The results suggest an association of mu-opiate receptors with sensory, especially olfactory, and limbic projections in the forebrain, and delta-opiate receptors with intrinsic and commissural forebrain pathways.

Amygdala↗
PubMed1986

Neostriatal projections from individual cortical fields conform to histochemically distinct striatal compartments in the rat.

A number of recent studies have demonstrated two chemically distinct compartments in the neostriatum: opiate receptor-rich patches and a surrounding matrix. Using axonal transport and receptor localization techniques in the rat brain, we have found that striatal projections from architectonically distinct cortical fields conform to this compartmentalized plan. The prelimbic cortex has bilateral projections that concentrate within the striatal patches. In contrast, the agranular motor cortex and cingulate cortex have bilateral projections to the matrix, while the somatic sensory cortex and visual cortex have ipsilateral matrix projections. Each matrix input occupies a characteristic striatal district. The projection to the patches distributes prelimbic input throughout the striatum, which may allow for prelimbic interactions with input from all other cortical areas.

Animals↗
PubMed1986

Neuromodulators and transmitters in respiratory control.

The respiratory control system is influenced by classical neurotransmitters and by neuromodulators. The neuromodulators are neuroactive substances that can be secreted at a distance from their receptors and must diffuse to their site of action. Their function can be nonsynaptic and long lasting, and their effect can be direct or indirect via other neuroactive substances. In the central nervous system, a variable degree of mismatch exists between sites of neuromodulator secretion and reception. The assignment of a natural role for a neuromodulator in respiratory control is strengthened by evidence from a variety of experimental approaches, including localization of receptor sites in respiratory-related areas and evidence for natural binding of neuromodulators to these receptors, neurophysiological and respiratory responses to the neuromodulators and their antagonists, and, finally, modulation of specific respiratory responses by neuromodulator antagonists to document the role of the endogenous modulator in eliciting the original response. Neuromodulators that are considered seriously as natural participants in respiratory control include dopamine in peripheral chemoreception and adenosine, endorphins (including enkephalins), serotonin, and substance P in central respiratory regulation.

Adenosine↗
PubMed1985

Evidence that the delta-selective alkylating agent, fit, alters the mu-noncompetitive opiate delta binding site.

Considerable evidence supports the notion that the prototypic delta agonist [3H]D-ala2-D-leu5-enkephalin labels two binding sites on brain membranes in vitro. Recent studies have demonstrated that treatment of brain membranes with the delta-selective, site-directed, alkylating agent, FIT (Rice et al., Science 220, 314-316, 1983) results in a membrane preparation devoid of detectable higher affinity [3H]D-ala2-D-leu5-enkephalin binding sites, but contain residual lower affinity binding sites at which mu-ligands are apparent noncompetitive inhibitors (Rothman et al., Neuropeptides 4:210-215, 1984). In this paper we extend these data by showing that although FIT eliminates the higher affinity binding site, it also alters the properties of the residual lower affinity binding sites.

Affinity Labels↗
PubMed1985

Preparation of rat brain membranes highly enriched with opiate kappa binding sites using site-directed acylating agents: optimization of assay conditions.

The goal of this study was to determine optimal conditions with which to measure opiate kappa binding sites in rat brain. Membranes were pretreated with mu-selective (BIT) and delta-selective (FIT) site-directed acylating agents (Rice et al., Science 220, 314-316), and the binding of [3H]bremazocine to the residual binding sites was defined as the kappa binding site. The binding of [3H]bremazocine to BIT/FIT-treated membranes was greatly increased by conducting the assay at 0 degrees C in the presence of 0.4 M NaCl. Using this 0 degrees C/NaCl assay condition, the binding of [3H]bremazocine was best described by a one-site binding model with a KD of 0.45 nM and a Bmax of 378 fmol/mg protein. Autoradiographic studies demonstrated that, using this assay condition, [3H]bremazocine densely labeled the deep layers of guinea pig cortex, an area known to be enriched with kappa binding sites. These and additional data suggest that the binding of [3H]bremazocine to the kappa binding site of rat brain is optimally assayed at 0 degrees C in the presence of 0.4 M NaCl using BIT/FIT-treated membranes and that rat brain is endowed with a high level of kappa binding sites.

Alkylating Agents↗