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C R Snell

Publications and source records attributed to C R Snell.

At least 37 records · Page 2Linked to original sources
PubMed1986

Histidyl-proline, a rapidly degraded metabolite of thyrotropin releasing hormone, has behavioural activity.

The effects of intracerebroventricular (ICV) administration of histidyl-proline (His-Pro; 0, 1, 10 and 100 micrograms/rat), a rapidly degraded metabolite of thyrotropin releasing hormone (TRH), were assessed using three behavioural paradigms. Locomotor activity was significantly increased over 30, but not 90, min following administration of the highest dose. This stimulatory effect was more apparent when naive rats were tested in an open field without any prior exposure to the apparatus; the effect was attenuated on a second exposure. His-Pro treated subjects also tended to prefer the area near the walls of the apparatus. The effects of the dipeptide on visual perception were studied, using a two-choice task. A low but not high (10, versus 100 micrograms/rat) dose of His-Pro increased response switching, but did not affect response repetition, latencies or percent correct performance. The results indicate that His-Pro can alter behaviour by affecting motor output, as well as emotional processes.

Animals↗
PubMed1985

Stereospecific binding sites for [3H]nicotinamide adenine dinucleotide in the rat brain.

NAD is a potent inhibitor of electrical activity in the dentate gyrus of the guinea pig hippocampus. NAD is rapidly degraded by an NADase enzyme present on synaptosomal membranes that we have recently found to be inhibited by nicotinamide mononucleotide. In this report we have characterised the binding sites present on brain membranes for [3H]NAD in the presence of this inhibitor. We have demonstrated two binding sites of KdS 49 nM and 4.26 microM that are modulated by GTP. From structure-activity studies we have shown the binding to be stereospecific for the beta-isomer of NAD requiring the whole of the molecule for full receptor affinity. The binding sites are distinct from those reported for adenosine and their presence has significance for the physiological role of NAD in the mammalian brain.

Animals↗
PubMed1985

Human cerebellar cortex possesses high affinity binding sites for [3H]somatostatin.

Somatostatin binding sites have been identified in the human brain using [4-3H-(Phe6)]-somatostatin-14. In contrast to that of the rat, the human cerebellar cortex possesses a high density of somatostatin binding sites, comparable to that found in either the rat or human cerebral cortex. Autoradiographic localisation of somatostatin binding sites in the human cerebellum reveals that the highest density is associated with the granule cell layer.

Aged↗
PubMed1985

Rat brain membranes possess two high-affinity binding sites for [3H]somatostatin.

This report described the first use of [4-3H-Phe6]somatostatin-14 to characterize binding sites on rat brain membranes for somatostatin-14. This ligand is superior to previously used iodinated analogues and is chemically and biologically identical to the natural ligand. Two high-affinity binding sites were found, from Scatchard analysis of competitive displacement experiments, with Kd SS1 = 0.41 and Kd SS2 = 22.9 nM. Specific binding was reversible, and kinetic analysis of the dissociation and association time-course gave an apparent Kd of 0.44 nM, in good agreement with the Kd of the higher-affinity site. Specific binding of the ligand was enriched in cerebral cortex and hippocampus, with intermediate levels in the striatum, hypothalamus and midbrain, and low levels in the pons/medulla and cerebellum. This ligand should prove to be valuable for elucidating the physiological and pharmacological significance of the two subtypes of somatostatin binding sites we have demonstrated.

Animals↗
PubMed1984

A classification of peptide ligands based on their predicted receptor conformation.

Peptides containing fewer than 50 amino acids show little ordered structure under physiological conditions. In this paper it is shown that in the receptor environment, secondary structure could be induced in small peptides that involves 87% of all the amino acid residues. The statistical methods of Chou and Fasman are used to predict the conformation of 41 peptide hormones or neuromodulators in the proteinaceous environment of the receptor, and four distinct conformational groupings are elucidated. beta-bend, beta-structure and alpha-helical conformation are possible for distinct groups of linear peptides, and disulfide bridge containing peptides show a common beta-bend beta-structure conformation at the receptor. In the predicted receptor conformation, the peptides show hydrophobic and hydrophilic domains that must reflect the distribution of corresponding regions in the ligand-binding site of the receptor. The predicted ligand conformation should allow a more rational approach to interpreting existing structure activity studies and the design of new analogs of pharmacological interest.

Animals↗
PubMed1984

Degradation of NAD by synaptosomes and its inhibition by nicotinamide mononucleotide: implications for the role of NAD as a synaptic modulator.

We have found NAD to be rapidly degraded by extracellular enzymes present on intact rat brain synaptosomes. The enzyme involved had the specificity of an NADase cleaving the molecule at the nicotinamide-glycoside linkage and was inhibited by nicotinamide mononucleotide (NMN). This inhibitor did not displace specific binding of NAD to rat brain membranes or affect electrical activity in the guinea pig hippocampus. Therefore, inclusion of NMN in binding assays allowed unambiguous demonstration of two specific NAD binding sites on rat brain synaptosomal membranes (KD1, 82 nM, KD2, 1.98 microM). The depressant action of NAD on the evoked synaptic activity of the guinea pig hippocampus was not blocked after inhibition of NAD degradation with NMN. The physiological implications of these results for the function of NAD as a neurotransmitter or neuromodulator in the CNS are discussed.

Adenosine↗
PubMed1984

The regulation of delta-opiate receptor density on 108CC15 neuroblastoma X glioma hybrid cells.

The effect of exogenous substances on the expression of opiate receptors on 108CC15 neuroblastoma X glioma hybrid cells has been studied. Cell differentiation by culture in the presence of N6-O2-dibutyryl adenosine 3',5'-cyclic monophosphate induced a three fold increase in opiate receptor density. When the cells were grown in the presence of 10(-5) M morphine hydrochloride for up to 23 days, opiate receptor densities were reduced by only 30% when compared with matched controls. Culture in the presence of 10(-7) M D-Ala2-D-Leu5-enkephalin produced opiate receptor down regulation of 73% compared to controls after only 4 h of treatment. The down regulation process could be inhibited by continued exposure to D-Ala2 D-Leu5-enkephalin at concentrations greater than 4 nM; below this concentration down regulation was rapid and irreversible. A model to explain these observations is described.

Animals↗
PubMed1984

Benzodiazepines modulate the A2 adenosine binding sites on 108CC15 neuroblastoma X glioma hybrid cells.

We have demonstrated high affinity diazepam binding sites of the Ro5-4864 benzodiazepine receptor subtype on 108CC15 neuroblastoma X glioma hybrid cells. These cells were previously shown to have purinoceptors of the A2 adenosine subtype and we have now found that [3H]-adenosine can be displaced from this binding site by the benzodiazepines and related compounds that can also bind to the Ro5-4864 site. Diazepam was found to have no intrinsic activity at the A2-receptor as measured by the stimulation of adenosine 3':5'-cyclic monophosphate (cyclic AMP) production in this cell line. At concentrations sufficient to compete for the A2-receptor, diazepam was shown to facilitate, by approximately 2 fold, the stimulation of cyclic AMP by adenosine. These effects are not due to inhibition of adenosine uptake or phosphodiesterase activity, but are probably a consequence of modulation of the coupling of the A2-receptor to cyclic AMP production in this hybrid cell line.

Animals↗
PubMed1983

Down regulation of opiate receptors on 108CC15 hybrid cells is inhibited by receptor occupancy.

This study reports on the molecular mechanism of delta-opiate receptor down regulation on 108CC15 neuroblastoma X glioma hybrid cells. The down regulation induced by culture in the presence of 10(-5) M 2-D-Ala, 5-D-Leu-enkephalin (DADLE) can be prevented by continued exposure to ligand concentrations greater than 4 nM, the Kd of the binding site. Below this concentration, down regulation is a rapid and irreversible process. It is deduced that the internalization process in this cell line is initiated when unoccupied receptor dimers are present. These results have important implications for down regulation studies using cultured cell lines and studies of receptor regulation in vivo after chronic treatment with neuroactive drugs.

Animals↗
PubMed1983

Nicotinamide adenine dinucleotide depresses synaptic transmission in the hippocampus and has specific binding sites on the synaptic membranes.

The electrical activity of transverse slices of hippocampus was used as a bioassay in which extracts of fresh brain tissue were screened for biological activity. A factor that depressed synaptic transmission was identified as nicotinamide adenine dinucleotide (NAD). This depressant action of NAD could be observed at concentrations in the range 1-10 microM and the degree of depression was monotonically related to the concentration of NAD in the bathing medium. NAD did not affect the antidromic invasion of the granule cells nor did it alter the relationship between the electrically evoked excitatory postsynaptic field potential (e.p.s.p.) and the population discharge of the granule cells (population spike). These results suggest that NAD did not affect the electrical excitability of the neuronal membranes. NAD had little effect on the sensitivity of granule cells to iontophoretically applied L-glutamate, the putative excitatory transmitter for the perforant path-granule cell pathway. Pure synaptosomal membranes, free of mitochondria, had two binding sites for NAD: a high affinity site with a Kd of 1 microM and a low affinity site with a Kd of 17 microM. These sites were similar in affinity to those of mitochondria, although the density of the high affinity sites was 5 X greater in the synaptosomal membranes. Adenosine had a relatively weak affinity for the NAD binding sites. It was concluded that NAD probably depressed synaptic transmission in the dentate gyrus by binding to sites on the presynaptic nerve terminal and reducing the amount of transmitter released by a nerve impulse. The physiological significance of this view is discussed.

Animals↗
PubMed1978

Isolation of the C-fragment and C'-fragment of lipotropin from pig pituitary and C-fragment from brain.

Three novel peptides derived from lipotropin, the C-Fragment (residues 61-91), C'-Fragment (61-87) and N-Fragment (1-38), were isolated from pig pituitary, and the C-Fragment was shown to be present in brain. The experimental procedures developed for their isolation are described. The formation of each of the fragments involves enzymic cleavage of lipotropin at consecutive basic residues, with specificity identical with that involved in the activation of known prohormones. In brain assays C-Fragment exhibits a range of biological activities related to its ability to act as an inhibitory neurotransmitter.

Amino Acids↗