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Biomedical subjects

F E Bloom

Publications and source records attributed to F E Bloom.

At least 217 records · Page 12Linked to original sources

Hypotensive response of ethanol in rats pretreated with disulfiram or nitrefazole.

The effect of disulfiram or nitrefazole pretreatment on ethanol induced hypotension was examined in urethane anesthetized rats. A relatively low dose of ethanol (150 mg/kg; i.p.) produced a characteristic hypotensive response in rats pretreated for various periods with disulfiram or nitrefazole. This hypotensive episode started 5-10 minutes following ethanol administration and lasted 40-60 minutes. The hypotensive response was not seen unless disulfiram or nitrefazole treatment preceded ethanol administration by a least 6-8 hours. The low dose of ethanol produced a plasma ethanol concentration of 10mg/100ml or less. One treatment with nitrefazole (200 mg/kg) rendered rats vulnerable to ethanol-induced hypotension for 6 but not 8 days. One treatment with disulfiram (200 mg/kg) lasted 4 but not 6 days. In addition, the hypotensive response was greater in rats treated with nitrefazole than in rats treated with an equal dose (200 mg/kg) of disulfiram.

Animals↗

Antagonism of effects of vasopressin (AVP) on inhibitory avoidance by a vasopressin antagonist peptide [dPtyr(Me)AVP].

After training in two different passive avoidance tasks, the platform box of Ader and De Wied (1972) and the Jarvik box of Jarvik and Kopp (1967), rats injected with vasopressin immediately following the training trial showed a significant enhancement of retention 24 hours later. This vasopressin effect was reversed by high doses of the vasopressor antagonist, dPtyr(Me) AVP. These results support the hypothesis that the visceral afferent signals may be involved in the apparent memory-enhancing effects of AVP, but the high doses of antagonist required suggest that factors other than a simple reversal of the pressor effects of AVP may be important.

Animals↗

The organization of projections from the cortex, amygdala, and hypothalamus to the nucleus of the solitary tract in rat.

Direct projections from the forebrain to the nucleus of the solitary tract (NTS) and dorsal motor nucleus of the vagus in the rat medulla were mapped in detail using both retrograde axonal transport of the fluorescent tracer True Blue and anterograde axonal transport of wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP). In the retrograde tracing studies, cell groups in the medial prefrontal cortex, lateral prefrontal cortex (primarily ventral and posterior agranular insular cortex), bed nucleus of the stria terminalis, central nucleus of the amygdala, paraventricular, arcuate, and posterolateral areas of the hypothalamus were shown to project to the NTS and in some cases also to the dorsal motor nucleus of the vagus. The prefrontal cortical areas projecting to the NTS apparently overlap to a large degree with those cortical areas receiving mediodorsal thalamic and dopaminergic input. The retrogradely labeled cortical cells were situated in deep layers of the rat prefrontal cortex. The anterograde tracing studies revealed a prominent topography in the mediolateral termination pattern of forebrain projections to the rostral part of the NTS and to the dorsal pons. The projections to the NTS were generally bilateral, except for projections from the central nucleus of the amygdala and bed nucleus of the stria terminalis which were predominantly ipsilateral. The prefrontal cortical projections to the NTS travel through the cerebral peduncle and pyramidal tract and terminate throughout the rostrocaudal extent of the NTS. Specifically, the prefrontal cortex innervates dorsal portions of the NTS (lateral part of the dorsal division of the medial solitary nucleus, dorsal part of the lateral solitary nucleus and the caudal midline region of the commissural nucleus), areas which receive relatively sparse subcortical projections. These dorsal portions of the NTS receive major primary afferent projections from the vagal and glossopharyngeal nerves. In contrast, the subcortical projections, which travel through the midbrain and pontine tegmentum, terminate most heavily in the ventral portions of the NTS, i.e., the area immediately dorsal and lateral to the dorsal motor nucleus of the vagus. Only the paraventricular hypothalamic nucleus has substantial terminals throughout the dorsal motor nucleus of the vagus. Hypothalamic cell groups innervate the area postrema and, along with the prefrontal cortex, innervate the zone subjacent to the area postrema.(ABSTRACT TRUNCATED AT 400 WORDS)

Afferent Pathways↗

The distribution and morphological characteristics of the intracortical VIP-positive cell: an immunohistochemical analysis.

Using a sensitive immunohistochemical procedure, we have undertaken a detailed morphological characterization of the vasoactive intestinal peptide-positive (VIP-positive) neuron in the cerebral cortex of the rat. VIP-positive neurons are present in all regions of cortex, and are usually strongly bipolar, possessing long, radially directed processes with very limited branching in the tangential plane. The most extensive dendritic branching occurs in layers I and deep IV-superficial V, and the density of axonal varicosities is highest in layers II-IV. In the visual cortex, approximately 50% of the labeled cell bodies are in layer II and III and 80% of the labeled cell bodies are contained in layers I-IV (superficial 600 microns of cortex). In order to determine the density and 3-dimensional distribution pattern of these cells, we prepared serial tangential sections through the rat visual cortex, mapped the distribution of all labeled cells in each section on transparent acetate sheets, and compressed these superimposed maps. This analysis demonstrated that: (1) approximately 1% of the cortical neurons are VIP-positive, (2) their distribution is fairly uniform and statistically random, (3) there are no large areas (i.e. with a diameter greater than 100 microns) that lack a VIP-positive cell, (4) on the average, there is one VIP-positive cell per column of 30 microns diameter, and (5) the average nearest neighbor distance on the compressed display is 15 microns. Given the morphological characteristics of VIP-positive cells, these data indicate that each VIP-containing cell is identified with a unique radial volume, which is generally between 15 and 60 microns in diameter, and overlaps with the contiguous domains of neighboring VIP-positive cells. These morphological data support the notion that VIP-containing neurons play an important functional role within radially oriented columns of cerebral cortex.

Animals↗

Senescent microstructural changes in rat cerebellum.

Senescent changes in Sprague-Dawley rat cerebellar microstructure have been quantified, focusing on the dominant element of cerebellar information processing, the Purkinje cell. In Golgi-Kopsch sections, many 26-month-old Purkinje cells appear defoliated, with small distal dendrites and spiny branchlets being most affected. The mean Purkinje cell area (soma plus dendrites) in computer-oriented sagittal sections is significantly decreased from 20,675 +/- 1,355 micron2/cell in 6-month-old rats to 17,088 +/- 1,107 micron2/cell in 26-month rats. These morphologic changes may be the hallmark of dying cells: in hematoxylin and eosin (H + E)-stained sections from the same rats we also observe a significant senescent decrease in Purkinje neuron density in every vermis lobule examined (lobules II-VII). Overall, the mean number of Purkinje cells/mm of Purkinje cell layer (measured in 10 micron thick sagittal sections) declines from 16.6 +/- 0.8 cells/mm in young rats to 12.5 +/- 0.2 cells/mm in old rats. As Purkinje cells are lost, so too are ethanolic phosphotungstic acid-stained (EPTA) synapses in the upper molecular layer of the cerebellar vermis (lobules VIII-X), and there is a highly significant within-subjects correlation between Purkinje cell density and synaptic density. Overall, synaptic density (in sagittal, 842 micron2 thin sections) decreases significantly from an average of 150,485 +/- 3,641 synapses/mm2 in 6-month rats to an average of 125,000 +/- 4,849 synapses/mm2 in 26-month rats. These changes are consistent with previous electrophysiologic and biochemical data showing age pathology of the cerebellum.

Aging↗

Dorsal noradrenergic bundle lesions fail to alter opiate withdrawal or suppression of opiate withdrawal by clonidine.

Previous work has shown that clonidine effectively suppresses many of the signs of opiate withdrawal. The present study was designed to test the hypothesis that the suppression of opiate withdrawal by clonidine is mediated by forebrain noradrenergic projections of the locus coeruleus. Two groups of 24 rats each were subjected to either a 6-hydroxydopamine lesion of the dorsal noradrenergic bundle (Lesion group) or a sham, vehicle injection (Sham group). All rats were made dependent on morphine by subcutaneous implantation of one 75 mg silastic morphine pellet for three days followed by 3 more days with two additional 75 mg pellets. Following removal of the morphine pellet, withdrawal was precipitated in all rats by subcutaneous injection of 4 mg/kg of naloxone. Pretreatment 10 min. before withdrawal with clonidine (0.1 or 0.2 mg/kg) produced a significant attenuation of withdrawal signs as compared to saline injected rats; this effect was equally significant in both sham and lesion groups. Lesions of the locus coeruleus had no effect on withdrawal, nor did they affect the ameliorating action of clonidine. These results substantiate the observation that clonidine can effectively attenuate signs of opiate withdrawal in the rat, but fail to support the hypothesis that these effects are mediated by the forebrain projections of the locus coeruleus.

Animals↗

Destruction of dopamine in the nucleus accumbens selectively attenuates cocaine but not heroin self-administration in rats.

The hypothesis that separate neural systems mediate the reinforcing properties of opioid and psychomotor stimulant drugs was tested by examining the role of mesolimbic dopamine (DA) neurons in maintaining intravenous heroin and cocaine self-administration. After local destruction of the DA terminals in the nucleus accumbens (NAcc) with 6-hydroxydopamine (6-OHDA), rats trained to self-administer cocaine and heroin on alternate days were observed for changes in their drug-seeking behaviors. Postlesion responding for cocaine showed a time-dependent decrease or extinction, whereas heroin self-administration showed a time-dependent recovery. By the fifth trial postlesion, heroin self-administration had recovered to 76% of prelesion baseline levels, but cocaine self-administration had dropped to 30% of prelesion baseline rates. Thus, selective lesions of the DA terminals in the nucleus accumbens significantly attenuate cocaine but not heroin self-administration. These data support the hypothesis that independent neural substrates are responsible for the reinforcing actions of these two drugs.

3,4-Dihydroxyphenylacetic Acid↗

Destruction of the locus coeruleus or the dorsal NE bundle does not alter the release of punished responding by ethanol and chlordiazepoxide.

The hypothetical involvement of central noradrenergic projections in the manifestation of "anxiety" and the "anti-anxiety" effects of alcohol and benzodiazepines was tested in an operant conflict situation by examining the effects of destruction of this noradrenergic system on response rates. Rats were trained on a Geller-Seifter conflict test [9] modified for incremental shock [21], in which two food-reinforced lever press components were separated by a time-out. Responses during the "food-alone" component (RI) were reinforced on a random interval schedule-30 sec; responses during the "time-out" component were never reinforced; and responses during the conflict component (CONFLICT) were continuously reinforced with both food and shock. This shock strength increased incrementally with each successive shock during the conflict period. Each session consisted of two cycles of a 5 min RI period, a two min time out, and a two min CONFLICT period presented in succession. Both ethanol (0.5 to 1.0 g/kg) and chlordiazepoxide (5 and 10 mg/kg) produced a significant increase in punished responding during the CONFLICT component. Ethanol, but not chlordiazepoxide (CDP) also significantly decreased responding during the RI component. Virtual total destruction of the dorsal noradrenergic projection with 6-hydroxydopamine (6-OHDA), or destruction of the locus coeruleus itself, failed to significantly alter baseline responding or the release of punished responding to ethanol or CDP. These results do not support the hypothesis that the locus coeruleus projections have an essential role in "anxiety" or in the "anxiety-reducing" properties of ethanol or the benzodiazepines.

Animals↗

Detection of the messenger RNA coding for preproenkephalin A in bovine adrenal by in situ hybridization.

The messenger RNA (mRNA) coding for the adrenal precursor of enkephalins (preproenkephalin-A) has been detected in bovine adrenal medulla cells using in situ hybridization with 32P-labelled preproenkephalin A (PPA) complementary DNA. In formaldehyde- and Carnoy-fixed tissue sections, an intense elective labelling restricted to the cells located at the periphery of the adrenal medulla can be detected after hybridization procedure, using X-ray film and classical autoradiographic procedure. Adequate controls show that this labelling is obtained only using PPA complementary DNA, inserted or not in its vector. Distribution of PPA mRNA appears identical to that of its immunoreactive end products, namely Met-enkephalin and BAM22 peptide, detected by immunohistochemistry. Norepinephrine, detectable using monoamine histofluorescence, appears restricted to the cells of the center of the gland unlabelled for PPA mRNA and its end-products. Cultured bovine adrenomedullary cells that exhibited enkephalin immunoreactivity also contain PPA mRNA located in their cytoplasm.

Adrenal Glands↗

Brain-specific genes have identifier sequences in their introns.

The 82-nucleotide identifier (ID) sequence is present in the rat genome in 1-1.5 X 10(5) copies and in cDNA clones of precursors of brain-specific mRNAs. One brain-specific gene contains more than one ID sequence in its introns. There is an excess of ID sequences to brain genes, and some ID sequences appear to have been inserted as mobile elements into other genetic locations. Therefore, brain genes contain ID sequences in their introns, but not all ID sequences are located in brain gene introns. A brain ID consensus sequence has been obtained by comparing 8 ID nucleotide sequences.

Amino Acid Sequence↗

Anesthesia does not increase opioid peptides in cerebrospinal fluid of humans.

One theory of narcosis postulates that inhaled anesthetics produce general anesthesia by causing the release of endogenous opioid peptides. In the present study, however, the concentration of immunoreactive beta-endorphin-like material (eight patients) or leu-enkephalin (four patients) did not increase in cerebrospinal fluid of patients 5 min after induction of anesthesia with thiopental, 2-5 mg/kg and N2O 70%; after an additional 10 min, during which halothane was added; at 5, 15, and 60 min after surgical incision; or after 30 min in the recovery room. Therefore, any contribution of the endorphin system to the production of general anesthesia does not appear to require the release of beta-endorphin.

Analgesia↗

The functional significance of neurotransmitter diversity.

A major continuing theoretical issue in neurobiology is the nature of the information encoded into chemical neurotransmitters. This problem has been intensified by major recent advances in cellular neurobiology in three specific areas of work: neuronal connectivity, synaptic mechanisms, and neuronal transmitters. Countless new interneuronal connections have been revealed through the use of sensitive new cellular tracing methods, revealing a far more detailed picture of the complexities and principles of brain organization. A whole range of ionic conductance mechanisms has been detailed by the application of new methods of electrophysiological analysis, particularly useful with the in vitro preparations. Many of these mechanisms were not previously recognized, and together they provide a much richer repertoire of receptor response mechanisms upon which neurotransmitters can operate. Last, the modern methods of chemical analysis have provided an ever-increasing list of new neurotransmitter molecules, which fall conveniently into three chemical categories: amino acids, monoamines, and neuropeptides. This review considers some possible underlying principles by which the rich signaling capacity of the central nervous system may be approached conceptually and experimentally.

Biomechanical Phenomena↗

Evidence for selective release of somatostatin-14 and somatostatin-28(1-12) from rat hypothalamus.

Cysteamine administration to rats results in a marked depletion of hypothalamic somatostatin-14 (SS14) and a decrease of the potassium-evoked in vitro release of SS14 without a significant change in the content or release of somatostatin-28(1-12)-like immunoreactivity (SS28(1-12)-L1). Furthermore, cysteamine enhances the spontaneous release and markedly potentiates the potassium-evoked release of SS14 in the in vitro slice preparation. However, in vitro-administered cysteamine does not alter the spontaneous or potassium-evoked release of SS28(1-12)-LI. Immunohistochemical visualization of hypothalamic neuronal cell bodies and fibers following cysteamine administration shows a disappearance of the SS14 immunoreactive fibers and cell bodies with no apparent change in the SS28(1-12) immunoreactive fibers and cell bodies. These data suggest that, in rat hypothalamus, selective release of SS14 and SS28(1-12) can occur. The results are discussed in relation to possible sites of storage and release of the somatostatin-related peptides from synaptic nerve terminals.

Animals↗

The distribution and morphology of opioid peptide immunoreactive neurons in the cerebral cortex of rats.

Pharmacological and biochemical evidence has implied that a widespread opioid peptide system exists within the cerebral cortex to mediate a variety of opiate effects. However, immunocytochemical detection of opioid peptides in the cortex has been limited. Using antisera to enkephalin and bovine adrenal medullary peptide, both fragments of proenkephalin, and an antiserum to dynorphin A, a fragment of prodynorphin, we now describe the regional and laminar distribution of a widespread population of olfactory cortical and neocortical cell bodies and fibers with opioid immunoreactivity in rats. Neurons stained with each antiserum are distributed bimodally in layers II and III and V and VI of neocortex as well as in layers II and III of olfactory cortex. The widespread distribution and heterogeneous morphology of cortical cells containing proenkephalin and dynorphin-A immunoreactivity suggest that opioid peptide-containing neurons may influence the functioning of local, commissural, and projection neurons in rat cerebral cortex.

Animals↗

Endorphins and psychiatry: pre-clinical perspectives.

The chemical relationships among the 3 major families of endorphins are summarized, and the CNS distribution and possible circuit functions are discussed. The overlapping distributions of enkephalin and dynorphin pathways is intriguing, and their existence in classical hippocampal pathways has implications for limbic function which are not understood. Functionally the predominant effect of these systems is 'disenabling', in contrast with the 'enabling' effects of monoamines, although specific and reversible excitatory responses in hippocampal pyramidal neurons may have important behavioral implications. The complex theoretical and methodological issues that arise in attempting to establish transmitter correlates of psychiatric disorders defy simplistic hypotheses. Endorphin research, where well established agonists and antagonists are available, illustrates the problems facing other areas of peptide research in conceptualizing a peptide related pathophysiology of the major psychoses. The structural, functional and chemical indices of hypothetical forms of endorphin pathology, and the reliability of various radio-immunoassays used now to quantify known endorphins are discussed. The complex range of behaviors produced in animals by endorphin antagonists continue to make research in this area important to psychiatry.

Animals↗

Effects of opiate antagonists and their quaternary derivatives on heroin self-administration in the rat.

Quaternary derivatives of naloxone and naltrexone, methyl naloxonium chloride(ORG 10908) and naltrexone methobromide ( MRZ 2663BR ), respectively, were compared with the parent compounds for their ability to antagonize the reinforcing properties of heroin as measured in an operant, i.v., self-administration paradigm. As expected, lower doses (up to 0.2 mg/kg) of naloxone and naltrexone produced dose-dependent increases in heroin self-administration, but at higher doses (10-30 mg/kg) these drugs produced transient decreases (20-100 min) in self-administration followed by recovery. Naltrexone was approximately 1.5 times more potent than naloxone in increasing heroin self-administration at the lower doses (up to 0.2 mg/kg) and had a slightly longer duration of action. The quaternary derivatives were ineffective as antagonists of heroin self-administration in doses 200 times greater than the effective antagonist dose of naloxone or naltrexone. These results support the hypothesis that the acute reinforcing properties of i.v. opiates associated with the sensation of the "rush" involve opiate receptors located within the central nervous system and do not involve peripheral opiate receptors.

Animals↗

Distribution of catecholamine-containing cell bodies and blood vessels in the rat nucleus tractus solitarius.

Glyoxylic acid-induced monoamine fluorescence (GIF) was used to map the distribution of catecholamine-containing cell bodies and terminals in the rat nucleus tractus solitarius (NTS) and dorsal medulla. In addition, the relative vascularity of the NTS was quantified by examination of tissue perfused with Pontamine sky blue. The GIF-reactive cell bodies within the NTS complex were caudal to the rostral pole of the area postrema and are therefore considered to be the A2 cell body group as defined by Dahlström and Fuxe. The A2 cell body group was composed of 900 (890 +/- 43, n = 3) small to medium sized neurons (15-25 micron diameter) located on the dorsal and lateral edges of the dorsal motor nucleus of the vagus. GIF terminal density was found to be most dense in the medial portion of the NTS as compared to the lateral or midline portions of the NTS, dorsal motor nucleus of the vagus, or hypoglossal nucleus. Quantitative blood vessel analysis revealed that the NTS is significantly less vascularized than the surrounding nucleus gracilius, central gray, or dorsal motor nucleus of the vagus. A full serial section analysis of NTS, stained either for GIF cell bodies, terminals or blood vessels, has been obtained; this detailed presentation of catecholamine-containing profiles and blood vessels in the dorsal medulla may facilitate future studies aimed at examining central control of autonomic function.

Afferent Pathways↗

Thalamic nucleus ventro-postero-lateralis inhibits nucleus parafascicularis response to noxious stimuli through a non-opioid pathway.

These experiments investigated the role of a specific thalamic nucleus in the cellular response to noxious and non-noxious inputs. Single-unit extracellular responses to peripheral noxious stimuli were recorded with glass micropipettes in the nucleus parafascicularis (Pf) of the rat under chloral hydrate anesthesia. Bipolar stimulating/recording electrodes were inserted in the nucleus ventro-postero-lateralis (VPL) of the thalamus, in areas responsive to the peripheral noxious stimulation. Single-unit records in Pf and multi-unit records in VPL demonstrated that both these nuclei are differentially sensitive to noxious and non-noxious inputs: Pf was more sensitive to late (200-600 ms latency) high threshold noxious inputs, while VPL was more responsive to early (10-40 ms) low threshold non-noxious inputs. Late, high threshold inputs to VPL were selectively suppressed by systemic morphine and restored by naloxone. Trains of stimuli applied to VPL suppressed the response of 76% of Pf units, to peripheral noxious stimuli but did not inhibit the response of spinal cord dorsal horn units to the same stimuli. This inhibitory effect of VPL on Pf cells was not reversed by systemically administered naloxone. The neural pathways responsible for the VPL suppression of Pf nociception appear to be neither monosynaptic nor mediated through the spinal cord dorsal horn, nor through any single, naloxone-reversible, central opioid process. Nevertheless, this inhibitory effect of VPL stimulation on Pf nociception provides a physiological basis for the analgesic effects of thalamic stimulation on clinically observed deafferentation pain. It also supports the existence of a pain modulating system at the thalamic level comparable, at least in part, with the spinal Gate Control concept.

Afferent Pathways↗