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S Frith

Publications and source records attributed to S Frith.

8 recordsLinked to original sources
PubMed1999

Behavioral effects of family-selective inhibitors of cyclic nucleotide phosphodiesterases.

The effects of family selective inhibitors of phosphodiesterase (PDEI, PDE2, PDE3, PDE4, and PDE5) on the behavior of rats under either a differential-reinforcement-of-low-rate (DRL) 72-s schedule or a variable-interval (VI) 30-s schedule were determined; previous work has shown that antidepressant drugs increase reinforcement rate under long DRL schedules. The PDE4-selective inhibitor rolipram (0.03-0.1 mg/kg) reduced response rate and increased reinforcement rate under the DRL schedule in a dose-dependent manner; similar effects were observed with the tricyclic antidepressant drug desipramine (3-10 mg/kg). Both of these drugs produced biphasic effects on behavior maintained under the VI schedule, increasing response rate at the lower doses tested (rolipram: 0.003 mg/kg; desipramine: 0.03 mg/kg) and decreasing response rate at higher doses (rolipram: 0.1 mg/kg; desipramine: 0.3-18 mg/kg). Of the other PDE inhibitors tested, only the PDE5-selective inhibitor zaprinast (10 mg/kg) produced an antidepressant-like effect on DRL behavior. However, in contrast to the biphasic effects of rolipram and desipramine on VI behavior, zaprinast produced monotonic decreases in response rate (10-30 mg/kg). The PDE2-selective inhibitor trequinsin produced biphasic effects on response rate under the VI schedule, increasing rates at low doses (3-5.6 mg/kg) and decreasing rates at higher doses (18-30 mg/kg). Trequinsin also reduced response rate under the DRL schedule (30 mg/kg); however, the reduction in response rate was not accompanied by increased reinforcement rate. The PDE3-selective inhibitor milrinone (1-10 mg/kg) tended to increase response rates under both schedules while the PDE1-selective inhibitor vinpocetine did not affect behavior at the dose range tested (1-30 mg/kg). These findings suggest that inhibition of PDE4 results in a rather unique pattern of behavioral effects, most notably an antidepressant-like effect on DRL behavior. It remains to be determined if a similar effect produced by zaprinast also implicates PDE5 in the mediation of antidepressant activity or represents an effect of this drug on PDE4 activity at high doses.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1994

Involvement of beta-1 and beta-2 adrenergic receptors in the antidepressant-like effects of centrally administered isoproterenol.

Central (i.c.v.) but not peripheral (i.p.) administration of isoproterenol reduced response rates and increased reinforcement rates of rats under a differential-reinforcement-of-low-response-rate 72-sec schedule in a dose-dependent manner. This effect of centrally administered isoproterenol was similar to effects produced by administration of proven antidepressant drugs. Propranolol antagonized the effect of centrally administered isoproterenol, suggesting that the antidepressant-like effect of this agonist was mediated by beta adrenergic receptors. In addition, both the beta-1 selective antagonist betaxolol and the beta-2 selective antagonist ICI 118,551 antagonized the effect of centrally administered isoproterenol in a dose-dependent manner. These antagonists exhibited similar potency, suggesting that both beta-1 and beta-2 adrenergic receptors were involved in the mediation of the antidepressant-like effect of centrally administered isoproterenol. In rats with down-regulated beta-2 adrenergic receptors, produced by repeated treatment with clenbuterol, isoproterenol still reduced response rates and increased reinforcement rates of rats under the differential-reinforcement-of-low-response-rate schedule. By contrast, the antidepressant-like effect of the beta-2 adrenergic agonist clenbuterol was attenuated by down-regulation of beta-2 adrenergic receptors. The present results indicate that stimulation of central beta adrenergic receptors by intraventricular administration of isoproterenol produces behavioral changes similar to those observed after administration of proven antidepressant drugs. Both beta-1 and beta-2 adrenergic receptors appear to mediate the antidepressant-like effect of isoproterenol.

Animals↗
PubMed1991

Imaging Ca2+ changes in individual oligodendrocytes attacked by T-cell perforin.

Cytosolic-free calcium changes in cultured rat oligodendrocytes attacked with murine T-cell perforin were measured using digital image processing of fura-2-loaded cells. Permeability to the membrane impermeant dye, propidium iodide, and the ability to retain fura-2 were also assessed. Oligodendrocyte response to perforin attack was heterogeneous, ranging from small, transient increases in cytosolic calcium to rapid cell death. Changes in cytosolic calcium occurred in all cells and about half of the cells also became permeable to propidium iodide. Only a minority of these cells proceeded to lysis, as evidenced by loss of fura-2. The cytosolic-free calcium rises visualized here in single cells could initiate non-lethal effects, thereby disturbing oligodendrocyte function and synthesis and maintenance of myelin.

Animals↗
PubMed1989

Myelin-oligodendrocyte glycoprotein (MOG) is a surface marker of oligodendrocyte maturation.

The myelin-oligodendrocyte glycoprotein (MOG) is a minor component of central nervous system myelin. Using neonatal rat optic nerve oligodendrocyte cultures we have compared the development in vitro of MOG with galactocerebroside, myelin basic protein and 2' ,3'-cyclic-nucleotide 3'-phosphodiesterase. MOG appears on the surface of oligodendrocytes 1-2 days later than these other oligodendrocyte markers, suggesting that MOG may be a useful indicator of oligodendrocyte maturation. The relevance of these findings for investigating mechanisms of myelin injury in vitro and the role of oligodendrocyte damage in demyelinating disease is discussed.

Animals↗