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Biomedical subjects

G A Higgins

Publications and source records attributed to G A Higgins.

At least 91 records · Page 5Linked to original sources
PubMed1991

Evidence that the unilateral activation of 5-HT1D receptors in the substantia nigra of the guinea-pig elicits contralateral rotation.

1. The effects of various 5-hydroxytryptamine (5-HT) receptor agonists were examined following unilateral infusion into the substantia nigra (SN) of the guinea-pig. 2. The 5-HT1 receptor agonists, 5-carboxamidotryptamine (5-CT) (2-25 micrograms), sumatriptan (10-25 micrograms) and RU24969 (25 micrograms) all induced a marked contralateral rotation. In contrast, the selective 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH DPAT, 10-25 micrograms) produced only a very small response, whilst the selective 5-HT1C/5-HT2 receptor agonist (+-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride ((+/-)-DOI) (25 micrograms) and the 5-HT3 receptor agonist, 2-methyl 5-HT (2-Me5-HT, 25 micrograms) were without effect. 3. The contralateral rotation induced by 5-CT (10 micrograms) was attenuated following pretreatment with the non-selective 5-HT1/5-HT2 receptor antagonists methiothepin (1 mg kg-1, s.c.) and metergoline (5-10 mg kg-1, s.c.) but not the 5-HT1C/5-HT2 antagonist ritanserin (1 mg kg-1, s.c.) or the 5-HT3 antagonist, ondansetron (0.5 mg kg-1, s.c.). An involvement of dopaminergic systems in the rotational response to 5-CT was implied by the antagonism of 5-CT-induced rotation by haloperidol (0.3 mg kg-1, s.c.). 4. At doses lower than those required to produce contralateral rotation, 5-CT (0.08-0.4 micrograms) and sumatriptan (2 micrograms) induced a small, but nonetheless consistent, ipsilateral rotation. 5. The data with agonists and antagonists taken together suggest that 5-CT-induced contralateral rotation may be mediated by 5-HTID receptor activation but definitive classification of the receptor will not be possible until selective 5-HTID-antagonists become available. This may therefore represent the first model to study this receptor subtype in vivo.

Animals↗
PubMed1991

Opportunities for treatment of psychoactive substance use disorders with serotonergic medications.

The authors review both the preclinical and the clinical evidence for a role of serotonin (5-HT) systems in the regulation of drug-taking behavior. Animal studies show that pharmacologic treatments that enhance 5-HT function, notably selective reuptake inhibitors, reduce the self-administration of a variety of substances of abuse, including ethanol and cocaine. These treatments also tend to suppress consummatory behavior in general. In contrast to the broad spectrum of suppression following 5-HT enhancement, selective antagonists at the 5-HT3 receptor subtype have been reported to reduce ethanol but not cocaine or food intake. Although essentially limited to alcohol abusers, clinical studies seem to support the preclinical findings that a number of 5-HT reuptake inhibitors decrease interest in and intake of alcohol in mild-moderate ethanol-dependent individuals. Furthermore, other serotonergic drugs may show utility in the treatment of alcohol abuse. Another way in which serotonergic medications can be used in treating substance abuse is by the treatment of comorbid psychoactive illness for which such drugs are already known to be effective, e.g., depression and anxiety disorders.

Alcoholism↗
PubMed1990

Cardiovascular effects of 5-HT1A receptor agonists injected into the dorsal raphe nucleus of conscious rats.

The aim of this study was to investigate the cardiovascular effects of the 5-HT1A receptor agonists, 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), flesinoxan and 5-carboxamidotryptamine (5-CT) following injection into the dorsal raphe nucleus of conscious rats. 8-OH-DPAT (0.5-2.5 micrograms), hypotension, bradycardia and flat body posture. In contrast, injection of 8-OH-DPAT (0.5 microgram) into the median raphe nucleus caused no cardiovascular changes or flat body posture. (-)Pindolol (0.5 microgram dorsal raphe nucleus) had little effect on cardiovascular parameters, but significantly attenuated the cardiovascular effects of 8-OH-DPAT (0.5 microgram dorsal raphe nucleus). N-Methylatropine (1 mg/kg i.v.) antagonised the cardiovascular effects of 8-OH-DPAT (0.5 microgram dorsal raphe nucleus), suggesting these were vagally mediated. Both pretreatments also appeared to reduce 8-OH-DPAT-induced flat body posture. The results suggest that 8-OH-DPAT activates 5-HT1A receptors in the dorsal raphe nucleus to cause hypotension and bradycardia.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1990

Behavioural effects of serotonin agonists and antagonists in the rat and marmoset.

The present study was conducted to investigate the effects of various 5-hydroxytryptamine (5-HT) agonists and antagonists on motor behaviour in rats and marmosets. Various motor-based responses were assessed after central or peripheral administration of 5-HT agents to rats and marmosets. Drugs acting as agonists at the 5-HT1A receptor (8-OHDPAT, gepirone, BMY-7378, NAN-190, PAPP (LY165163) and flesinoxan) and 5-HT2/1C receptors (DOI) were found to reverse neuroleptic-induced catalepsy in the rat whereas 5-HT2/1C antagonists (mianserin, ritanserin and ICI-170,809) and the 5-HT1 antagonist ((+/-)pindolol) increased catalepsy. Agonists acting at 5-HT3 receptors (phenylbiguanide and 2-methyl-5-HT) had no effect on catalepsy. The putative 5-HT1A antagonist, (+/-) pindolol, attenuated the reversal of catalepsy by 8-OHDPAT. Although both 8-OHDPAT and BMY-7378 were tested, only the latter was found to reduce apomorphine-induced stereotypy. Bilateral or unilateral infusions of 8-OHDPAT, BMY-7378 or pindolol into the substantia nigra of non-lesioned rats had no effect on spontaneous locomotor or rotational activity, respectively. However, 8-OHDPAT and BMY-7378 were found to increase or decrease motor activity, after injection into the median or dorsal raphe nuclei, respectively. Finally, 8-OHDPAT and BMY-7378 were found to be inactive against MPTP-induced bradykinesia in the marmoset. It is concluded that both 5-HT1A and 5-HT2/1C receptors are involved in the anti-cataleptic effects of 5-HT agents. The 5-HT1A receptors are probably situated within the raphe, whereas the location of the 5-HT2/1C receptors remains undetermined.

Animals↗
PubMed1990

The Alzheimer amyloid precursor-related transcript lacking the beta/A4 sequence is specifically increased in Alzheimer's disease brain.

The deposition of cerebrovascular and plaque amyloid in the CNS is a primary feature of Alzheimer's disease and aged Down's syndrome pathology. The localization of the Alzheimer amyloid protein precursor (APP) gene on chromosome 21, along with its overexpression in Down's syndrome brain compared with normal brain, suggests that alterations in APP gene expression may play a role in the development of the neuropathology common to the two diseases. In the present report, we demonstrate that a specific spliced form of mRNA that is transcribed from the APP gene and that lacks the beta/A4 sequence is elevated in the nucleus basalis, occipitotemporal cortex, and parahippocampal gyrus in Alzheimer's disease brain relative to controls. These results are based on combined data from RNA slot blot analysis, in situ hybridization, and polymerase chain reaction quantification of specific mRNAs taken directly from tissue sections.

Aged↗
PubMed1990

Altered levels of amyloid protein precursor transcripts in the basal forebrain of behaviorally impaired aged rats.

The beta/A4 protein is a constituent of plaque and vascular amyloid deposits in Alzheimer disease. Previous studies have shown increased levels of amyloid protein precursor (APP) mRNA in basal forebrain neurons in the disease. Morphological and neurochemical changes occur within the forebrain in Alzheimer disease and are also correlated with behavioral impairments in aged rats. Recent studies suggest that decreased nerve growth factor responsiveness of basal forebrain neurons is a feature of normal aging and of Alzheimer disease. We have used in situ hybridization to show that the abundance of specific forms of APP mRNA, which contain an inserted Kunitz-type serine protease inhibitor motif (APP-751, APP-770, and APP-related 563), are increased relative to the noninserted form (APP-695) of APP mRNA in the basal forebrain of aged rats. This increase appears to be specific to animals who exhibit spatial memory deficits but not aged rats without behavioral impairments.

Aging↗
PubMed1989

Localization of nerve growth factor receptor messenger RNA and protein in the adult rat brain.

We have used in situ hybridization and immunocytochemistry to map the cellular localization of NGF receptor (NGF-R) mRNA and protein in the adult rat brain. In addition to basal forebrain magnocellular neurons, NGF-R is widely expressed within the CNS, including neurons of the caudate/putamen, ventral premamillary nucleus, mesencephalic trigeminal nucleus, prepositus hypoglossal nucleus, raphe nucleus, nucleus ambiguous, and Purkinje cells of the cerebellum. Cells of the vestibulocochlear ganglion also contain NGF-R mRNA and protein. Ventricular subependymal cells and tanycytes are clearly stained by immunocytochemistry, yet only very weak hybridization is detectable in these cells. Also, greater amounts of NGF-R protein than of mRNA appear to be present in the glomeruli of the olfactory bulb, area postrema, and nucleus tractus solitarius. Areas that contain only NGF-R immunoreactive fibers and terminals can be distinguished from the cellular sites of NGF-R biosynthesis and include the suprachiasmatic nucleus, the principal olivary pretectal nucleus, the superior colliculus, the inferior olive, and the principal and spinal trigeminal nuclei. This study shows that NGF-R is widely expressed within individual neurons in different areas of the rat brain and identifies new potential CNS target sites of endogenous NGF.

Animals↗
PubMed1989

NGF receptor gene expression is decreased in the nucleus basalis in Alzheimer's disease.

Basal forebrain neuronal atrophy in Alzheimer's disease (AD) may be caused by a deficit in the NGF responsiveness of magnocellular cholinergic neurons which project to the cerebral cortex and hippocampal formation. We have used in situ hybridization to show that NGF-receptor (NGF-R) mRNA-positive neurons are lost within all divisions of the nucleus basalis of Meynert (Ch4 cell group) in AD patients as compared to normal aged controls. The posterior division of the nucleus basalis showed the largest decrease in NGF-R mRNA hybridization in the disease, with no overlap in neuronal number between AD cases and normal controls. Northern (RNA) blotting showed decreased levels of NGF-R mRNA in the nucleus basalis in the disease. No differences in the number of NGF-R mRNA-positive neurons between normal aged and AD patients were detected within the NGF-responsive cell groups of the medial septum (Ch1) and nucleus of the vertical limb of the diagonal band (Ch2). These results show that NGF-R gene expression is selectively reduced within basal forebrain neuronal populations which exhibit degenerative changes in AD.

Aged↗
PubMed1989

NGF induction of NGF receptor gene expression and cholinergic neuronal hypertrophy within the basal forebrain of the adult rat.

Chronic infusion of nerve growth factor (NGF) into the forebrain of the adult rat produced increases in NGF receptor (NGF-R) mRNA hybridization, NGF-R immunoreactivity, choline acetyltransferase (ChAT) mRNA hybridization, and neuronal hypertrophy, when compared with vehicle infusion or noninfused rat brain. In situ hybridization showed NGF induction of NGF-R gene expression, documented by increases in the number of NGF-R mRNA-positive cells within the medial septum, diagonal band, and nucleus basalis magnocellularis. NGF also produced hypertrophy of ChAT mRNA-positive neurons. These results suggest that NGF produces cholinergic neuronal hypertrophy through induction of NGF-R gene expression within the basal forebrain.

Animals↗
PubMed1989

NGF receptor reexpression and NGF-mediated cholinergic neuronal hypertrophy in the damaged adult neostriatum.

Adult cholinergic interneurons of the neostriatum are not immunoreactive for monoclonal antibody to NGF receptor, whereas the developing neostriatum is immunoreactive for this same antibody. Chronic NGF infusion into the adult neostriatum resulted in reexpression of the NGF receptor such that many cholinergic interneurons became immunoreactive for NGF receptor. NGF infusion dramatically increased the size and choline acetyltransferase immunoreactivity of these same cholinergic neurons. Additionally, in situ hybridization demonstrated an increase in the number of cells expressing NGF receptor mRNA in the NGF-infused striatum. These findings indicate that central cholinergic neurons which lose their NGF receptors during postnatal development will resume their NGF responsiveness when the tissue is damaged. Such a damage-induced mechanism may act to enhance the action of trophic factors, including NGF, released at the site of injury and enhance the responsiveness of damaged CNS neurons to exogenously administered trophic factors.

Aging↗
PubMed1989

Cellular localization of 1B236/myelin-associated glycoprotein mRNA during rat brain development.

The protein encoded by the rat brain cDNA 1B236 has been shown to be identical to myelin-associated glycoprotein (MAG). In this report we describe the cellular distribution of 1B236/MAG mRNA transcripts in rat brain by using in situ hybridization. At postnatal day 20, large numbers of 1B236/MAG mRNA-containing oligodendrocytes are concentrated in myelinated fiber tracts and throughout gray matter regions. The presence of high levels of 1B236/MAG mRNA within oligodendrocytes at postnatal day 20 is consistent with the proposed role of MAG in formation of the myelin sheath during development. In the adult brain, our results suggest that not only is 1B236/MAG mRNA expressed at reduced levels within oligodendrocytes but also 1B236/MAG or a 1B236/MAG-like mRNA is present within neurons. This localization is consistent with the results of previous immunocytochemical studies using antibodies against the 1B236/MAG mRNA with different cell-type-specific patterns of expression suggests that oligodendrocytes and neurons employ different mechanisms for regulating the same gene. Thus, different cell types may use a similar cell adhesion molecule both during myelinogenesis and in the mature nervous system.

Animals↗
PubMed1989

The identification of a novel synaptosomal-associated protein, SNAP-25, differentially expressed by neuronal subpopulations.

cDNA clones of a neuronal-specific mRNA encoding a novel 25-kD synaptosomal protein, SNAP-25, that is widely, but differentially expressed by diverse neuronal subpopulations of the mammalian nervous system have been isolated and characterized. The sequence of the SNAP-25 cDNA revealed a single open reading frame that encodes a primary translation product of 206 amino acids. Antisera elicited against a 12-amino acid peptide, corresponding to the carboxy-terminal residues of the predicted polypeptide sequence, recognized a single 25-kD protein that is associated with synaptosomal fractions of hippocampal preparations. The SNAP-25 polypeptide remains associated with synaptosomal membrane components after hypoosmotic lysis and is released by nonionic detergent but not high salt extraction. Although the SNAP-25 polypeptide lacks a hydrophobic stretch of residues compatible with a transmembrane region, the amino terminus may form an amphiphilic helix that may facilitate alignment with membranes. The predicted amino acid sequence also includes a cluster of four closely spaced cysteine residues, similar to the metal binding domains of some metalloproteins, suggesting that the SNAP-25 polypeptide may have the potential to coordinately bind metal ions. Consistent with the protein fractionation, light and electron microscopic immunocytochemistry indicated that SNAP-25 is located within the presynaptic terminals of hippocampal mossy fibers and the inner molecular layer of the dentate gyrus. The mRNA was found to be enriched within neurons of the neocortex, hippocampus, piriform cortex, anterior thalamic nuclei, pontine nuclei, and granule cells of the cerebellum. The distribution of the SNAP-25 mRNA and the association of the protein with presynaptic elements suggest that SNAP-25 may play an important role in the synaptic function of specific neuronal systems.

Amino Acid Sequence↗
PubMed1989

5-HT3 receptor antagonists injected into the area postrema inhibit cisplatin-induced emesis in the ferret.

1. The purpose of the present study was to identify and investigate the role of 5-hydroxytryptamine3 (5-HT3) receptors in the area postrema in the control of cisplatin-induced emesis in the ferret. 2. Homogenate binding and autoradiography experiments using the high affinity 5-HT3 receptor ligand, [3H]-GR65630, identified the presence of a high concentration of 5-HT3 receptors in the area postrema of the ferret. 3. Intraperitoneal injection of the 5-HT3 receptor antagonists, GR38032F, GR65630A and MDL72222, at doses of 1, 0.1 and 1 mg kg-1 respectively, inhibited emesis induced by cisplatin, 9 mg kg-1 i.p. 4. Discrete injection of low doses of the 5-HT3 receptor antagonists directly into the area postrema region also inhibited cisplatin-induced (9 mg kg-1 i.p.) emesis. The dose ranges used were: GR38032F, 0.01-1 microgram; GR65630A, 0.001-0.1 microgram; MDL72222, 0.1-10 micrograms. 5. Cisplatin-induced emesis was not inhibited by discrete injection of ketanserin (30 micrograms) or methiothepin (30 micrograms) into the area postrema. Injection of the 5-HT3 receptor agonist, 2-methyl-5-HT, directly into the area postrema produced an incomplete emetic response. 6. These results confirm a role of 5-HT, and in particular 5-HT3 receptors, in the control of cisplatin-induced emesis, and show that at least one functional site for these receptors in modulating the emetic response is the area postrema, the locus of the chemoreceptor trigger zone.

Animals↗
PubMed1988

Behavioural and biochemical consequences following activation of 5HT1-like and GABA receptors in the dorsal raphé nucleus of the rat.

The behavioural and biochemical response to the 5-HT1-like receptor compounds, 5-carboxamidotryptamine (5-CT), 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), buspirone and ipsapirone and the GABA agonist, muscimol, injected into the dorsal raphé nucleus (DRN) are reported. All compounds increased social interaction under high light, unfamiliar conditions and increased punished responding in a Vogel conflict test. At doses ranging from 5-25 times greater than those which were effective in these anxiety models, muscimol, 5-CT and 8-OH-DPAT induced a marked hypothermia and a flattening of body posture. Buspirone, on the other hand, failed to induce a significant reduction in core temperature or produce a marked flattening of posture in all animals, even at doses 100 times those effective in anxiety models. Following injection of muscimol, 5-CT, 8-OH-DPAT and buspirone into the dorsal raphé nucleus, all tended to reduce the 5-HIAA:5-HT ratios in the frontal cortex, hippocampus and hypothalamus. These findings, together with available electrophysiological data suggest that these behavioural responses are a consequence of a depression of the firing of cells in the dorsal raphé nucleus, with a corresponding decrease in functional activity of 5-HT in the forebrain.

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