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J F O'Callaghan

Publications and source records attributed to J F O'Callaghan.

5 recordsLinked to original sources
PubMed1995

Inhibition of the ATP-sensitive potassium channel in the guinea pig substantia nigra by BMS 181100 is not mediated by a sigma-binding site.

Quantitative autoradiography of brain tissue has revealed a high density of binding sites for the K-ATP channel antagonists, the sulphonylureas, and for sigma-ligands in the substantia nigra (SN). In view of the high density of the two binding sites in the SN the possibility has been investigated that the K-ATP channel and the sigma-binding site are functionally linked. The K-ATP channel-mediated membrane hyperpolarisation and decrease in input resistance produced by hypoxia and by the metabolic inhibitor, cyanide, in rostral substantia nigra pars compacta neurons are antagonised by the sigma-ligand BMS 181100. In addition, BMS 181100 antagonises activation of the K-ATP channel by diazoxide; cromakalim is found to be without effect in these neurons. Antagonism of the cyanide-induced hyperpolarisation is dose dependent and is observed at concentrations of the drug which have no observable effect on the resting membrane properties of the neurons. By contrast, the nonselective sigma ligands 1,3-di-O-tolylguanidine (10 microM) and (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine (100 microM), and the selective sigma 1-ligand (+)-pentazocine (5-10 microM) have no effect on the cyanide-induced hyperpolarisation. 5-HT (50-100 microM) and the selective 5-HT1A receptor agonist 8-OH-DPAT (50 microM) also fail to antagonise the cyanide-induced hyperpolarisation. The antagonism of the cyanide-induced hyperpolarisation by BMS 181100 persists in the presence of tetrodotoxin (1 microM) and in the presence of high concentrations of (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine, but not under conditions of reduced calcium (0.1-0.2 mM) and raised magnesium (6 mM) concentrations, which block synaptic transmission. It is concluded that in substantia nigra phasic neurons the sigma-binding site does not regulate activation of the ATP-sensitive channel. However, BMS 181100 antagonises K-ATP channel activation in these neurons independently of sigma-binding sites and 5-HT receptors. This action of BMS 181100 is TTX insensitive and Ca2+ dependent.

Adenosine Triphosphate↗
PubMed1995

Possible intermixing of neurons from the subthalamic nucleus and substantia nigra pars compacta in the guinea-pig.

A population of cells in the anterior substantia nigra pars compacta (SNPc) of the guinea-pig have been reported previously that differ from classical dopaminergic neurons in terms of their active and passive membrane properties. To investigate this population further, anterior nigral neurons (n = 17) were compared with neurons in the adjacent subthalamic nucleus (STN: n = 26). The anterior nigral neurons were found to be indistinguishable from STN neurons in their action potential characteristics, firing rate, resting membrane potential and input resistance. A low-threshold calcium conductance and anomalous rectification could be demonstrated in cells from both groups. Furthermore, the gross morphological characteristics of anterior nigral neurons and STN neurons were very similar, as assessed following the intracellular injection of biocytin. A further similarity was seen in the response of the two cell groups to cyanide (200 microM) and apomorphine (500 microM). Cyanide hyperpolarised the membrane potential of all STN neurons and the majority (77.8%) of anterior nigral neurons, in both cases producing a concomitant reduction in firing rate. These changes were accompanied by an increase in membrane conductance for potassium ions. Apomorphine depolarised the membrane potential of all STN neurons and anterior nigral neurons, in most cases increasing the input resistance (83.3% of STN neurons and 100% of anterior nigral neurons). In both groups of cells, when firing rate was affected, an increase was usually seen. Given the physiological, morphological and pharmacological similarities of STN and anterior nigral neurons, the most parsimonious interpretation is that the anterior nigral neurons belong to the STN. However, the anterior nigral neurons were found in slices that, when resectioned, contained tyrosine hydroxylase (TH)-immunoreactive cell bodies in every section, in a location corresponding to the SNPc. The implication is that in the guinea pig the SNPc and STN (usually considered to be anatomically distinct nuclei) intermix at this level for several hundred microns. This close association of the STN and the compacta was further demonstrated by the presence of TH-positive varicose and non-varicose neuronal processes within the STN.

Animals↗
PubMed1994

Selegiline enhances survival and neurite outgrowth of MPP(+)-treated dopaminergic neurons.

Selegiline was added to co-cultures of mesencephalon and neostriatum of C57BL/6 mouse embryos according to three schemes: (i) before and (ii) after cells were exposed to the toxin 1-methyl-4-phenylpyridinium (MPP+), (iii) in control cultures. In all schemes, selegiline enhanced the morphological differentiation of dopaminergic neurons and with delayed treatment, significantly increased their survival. These results indicate that selegiline exhibits trophic-like actions and can rescue MPP(+)-injured dopaminergic neurons in cultures.

1-Methyl-4-phenylpyridinium↗
PubMedDate not supplied

(-)-Baclofen-induced and constitutively active inwardly rectifying potassium conductances in cultured rat midbrain neurons.

Biophysical and pharmacological properties, and development of the (-)-baclofen-induced potassium (KBac) conductance and the constitutively active inwardly rectifying potassium (KIR) conductance were characterised using the patch-clamp technique in cultured embryonic rat midbrain neurons. KBac conductance was induced by (-)-baclofen acting on gamma-aminobutyric acid B (GABAB) receptors, and displayed a high degree of selectivity for potassium ions, an approximate square-root dependence of conductance on extracellular potassium concentration and strongly voltage-dependent activation. Ba2+ blocked the conductance in a voltage-independent manner, whereas Cs+ produced a voltage-dependent block. In the same preparation, the KIR conductance displayed biophysical properties indistinguishable from those of the KBac conductance. Block of KIR currents by Ba2+ was voltage independent (KI, 4 microM), whereas Cs+ produced a voltage-dependent block (KI, 370 microM at -100 mV, equivalent valence, z', 1.67). The KBac and KIR conductances additionally displayed a strikingly similar pattern of development in culture; the specific conductance (nS/pF) of both conductances increased two- to three-fold between the first and second week in vitro, and remained constant thereafter.

Animals↗