Dorothy A. Kinscherf

Elevation of cyclic GMP levels in central nervous system by excitatory and inhibitory amino acids.

—Guanosine 3′,5’cyclic monophosphate (cyclic GMP) levels in incubated slices of mouse cerebellum are increased 10‐fold by glutamate and two‐to three‐fold by glycine or γ‐aminobutyric acid (GABA). Glutamate also produces a 10‐fold increase in adenosine 3′,5’cyclic monophosphate (cyclic AMP) in the same tissue. However, GABA decreases cyclic AMP levels 30‐40 per cent, and glycine produces only a transient 50 per cent accumulation of this cyclic nucleotide. Theophylline slightly augments the accumulation of cyclic GMP produced by all three amino acids but markedly attenuates the accumulation of cyclic AMP produced by glutamate. In the absence of Ca2+, none of the three amino acids has any effect on cyclic GMP levels, and glutamate produces only a 50 per cent rise in cyclic AMP levels. The decrease of cyclic AMP levels produced by GABA is not affected by theophylline or by the absence of Ca2+. These data suggest an involvement of both cyclic GMP and cyclic AMP in the neurochemical actions of glutamate, GABA and glycine.

Influence of divalent cations on regulation of cyclic GMP and cyclic AMP levels in brain tissue.

—Depolarizing concentrations of K+ elevate levels of both adenosine 3′,5′monophosphate (cyclic AMP) and guanosine 3′,5′monophosphate (cyclic GMP) in incubated slices of mouse cerebellum. Calcium is an essential requirement for the K+ ‐induced accumulation of cyclic GMP. Barium and Sr2+, but not Mn2+ or Co2+, can substitute for Ca2+ in this process. Relatively high concentrations of Mg2+ inhibit the effect of Ca2+ on K+‐induced accumulation of cyclic GMP. In contrast, depolarizing concentrations of K+ are capable of elevating cyclic AMP levels in brain slices suspended in media containing Mg2+ and no other divalent cations. High concentrations of Ca2+ (1 mm or greater) augment this Mg2+ ‐dependent, K+‐induced accumulation of cyclic AMP, however. Strontium and Mn2+, but not Ba2+ or Co2+, can substitute for Ca2+ in this process, and high concentrations of Mg2+ are not inhibitory. The divalent cation ionophore, A‐23187 (10 μm), in the presence of extracellular Ca2+ elevates the level of cyclic GMP, but not cyclic AMP, in incubated mouse cerebellum slices.

Cyclic nucleotides in epileptic brain: effects of pentylenetetrazol on regional cyclic AMP and cyclic GMP levels in vivo.

Levels of cyclic AMP and cyclic GMP were measured in cerebral cortex, cerebellum, striatum, thalamus, and hippocampus of mice prior to and during seizures induced by pentylenetetrazol (100 mg/kg). Cyclic GMP levels rose in striatum, and perhaps in cerebellum and cerebral cortex, within 30 sec following pentylenetetrazol injection and prior to the onset of clinical seizure activity. At the onset of clonic seizures, cyclic GMP levels were increased in cerebellum, cerebral cortex, and striatum; continued clonic seizure activity further elevated cyclic GMP levels in these areas and also increased its levels in thalamus and hippocampus. No changes in cyclic AMP levels were observed until the onset of seizure activity, when the level of this nucleotide rose in all regions except striatum. Despite continued seizure activity, cyclic AMP subsequently fell in cerebellum and thalamus. Tonic seizures increased cyclic GMP levels even more than clonic seizures but did not increase cyclic AMP levels. These data indicate that seizure activity affects cyclic AMP and cyclic GMP differently in various regions of the CNS and that regional changes of cyclic nucleotide levels are dependent upon the type of seizure activity. The results also suggest that not all of the changes in levels of cyclic GMP produced by pentylenetetrazol are a consequence of seizure activity, but that those of cyclic AMP are.

COMPARISON OF THE EFFECTS OF DEPOLARIZING AGENTS AND NEUROTRANSMITTERS ON REGIONAL CNS CYCLIC GMP LEVELS IN VARIOUS'ANIMALS

Abstract— The effects of 121 mm‐K+, 10 mm‐glutamate, 5 mm‐GABA, 1 mm‐glycine, 0.1 mm‐NE, and 1–10 μmACh on cyclic GMP levels in tissue slices prepared from cerebral cortex and cerebellum of mouse, rabbit, guinea‐pig, cat, and rat were studied. Basal levels of cyclic GMP in the cerebella of mice, guinea‐pigs and cats were 4–15 and 70 pmol/mg prot in rat, whereas in the cerebral cortex of the same animals, levels were only 0.6–2 pmol/mg prot. In contrast, basal levels of the cyclic nucleotide were 1–2 pmol/mg prot in both of these regions in rabbit brain. Only 121 mm‐K+ was capable of increasing cyclic GMP levels in all the tissues studied. Elevations ranged from 30% in rat cerebral cortex to 2800% in mouse cerebellum. Glutamate produced a 30–1000% rise of cyclic GMP levels in all tissues except rabbit cerebellum. NE elevated levels of cyclic nucleotide 2‐ to 3‐fold in slices of cerebellum from all species studied but had no effect in cerebral cortex. GABA and glycine had no effect in any tissue except mouse cerebellum. ACh had no consistent effect on levels of cyclic GMP in any brain region investigated. These results suggest that mechanisms regulating cyclic GMP levels in mammalian CNS vary among brain regions and among animal species.

Adenosine-mediated regulation of cyclic AMP levels in isolated incubated retinas

The effect of adenosine on the modulation of retinal cAMP levels was assessed in several mammalian species including mouse, rat, guinea pig and rabbit. Adenosine had no effect when added to incubated rat, mouse and guinea pig retinas. However, levels of cAMP were elevated in dose-dependent manner by adenosine in both light- and dark-adapted incubated rabbit retinas. Isobutylmethylxanthine (IBMX) blocked the elevation elicited by adenosine. Norepinephrine and dopamine also elevated cAMP in incubated rabbit retinas and these effects were not blocked by IBMX. The elevations of cyclic AMP levels produced by adenosine were additive with the effects of dopamine or norepinephrine. These results indicate that an adenosine-sensitive cAMP system exists in rabbit retina, and it is probably distinct from the dopamine and norepinephrine regulated cyclic AMP systems.

Phenytoin: Effects on Calcium Flux and Cyclic Nucleotides

Previous studies have demonstrated that phenytoin alters calcium conductance in isolated presynaptic nerve endings (synaptosomes) from rat or rabbit brain. Drug concentrations of 0.08 ITIM (20 μg/ml) or higher inhibit stimulated calcium influx into synaptosomes depolarized by high concentrations of potassium (69 min) by 7–58%. Calcium transport into undepolarized synaptosomes is only inhibited by 0.4 min or greater concentrations of phenytoin. Recent investigations show that in mouse brain slices, phenytoin inhibited elevations of cyclic GMP and cyclic AMP produced by ouabain or verat‐ridine. In contrast, elevations of the two cyclic nucleotides produced by high concentrations of potassium were not inhibited by phenytoin, suggesting that the anticonvulsant suppresses depolarization‐induced elevation of cyclic nucleotide levels in brain slices by inhibiting influx of sodium into cells. These data indicate that phenytoin inhibits both sodium and calcium influx into cells during cellular depolarization and alters regulation of brain cyclic nucleotide levels. Both of these actions may be important for the antiepileptic effect of phenytoin.

The Nature and Time Course of Cognitive Side Effects During Electroconvulsive Therapy in the Elderly

Cognitive and clinical changes during hospitalization were examined in 48 elderly patients with major depression treated with electroconvulsive therapy (ECT) and 55 elderly depressed patients not treated with ECT. Cognitive changes with ECT involved orientation, attention and calculation, and recall. The maximal decrement during ECT averaged 3 points on the Mini-Mental State Examination and occurred after two thirds of the treatments were administered. Baseline cognitive values returned by time of discharge. The affective symptoms improved throughout the course of treatment and remained improved while cognition returned to normal. Patients not receiving ECT showed slightly improved cognitive performance during hospitalization and small, gradual, clinical improvement.

Measurement of cyclic nucleotides in histologically defined samples of brain and retina

Abstract A method is described which allows measurement of cyclic AMP and cyclic GMP in histologically defined tissue samples containing as little as 0.6 fmol of either compound. This permits, for example, assays of freeze-dried samples as small as 0.03 μg dry weight from individual retina layers or 4-μg samples from individual layers of cerebellum. The procedure involves a modified radioimmunoassay at reduced volume for acetylated cyclic nucleotides in combination with some of the techniques previously developed for quantitative histochemical assays.

Response to Treatment of Depression in the Old and Very Old

Treatment responses were monitored in 101 depressed patients, ranging in age from 64 to 92 years, hospitalized on a geropsychiatry unit. Forty-six percent of the patients received ECT. Medications were used in the majority of patients. Responses were assessed with both depression inventories (Beck Depression Inventory and Geriatric Depression Scale) and physician-rated global improvement scores. Advanced age was not associated with poor outcome. ECT was the most important variable associated with a good response, regardless of age. (J Geriatr Psychiatry Neurol 1991;4:65-70).

Assessments on a geropsychiatry unit.

Mood, cognition, behavior, and function are each assessed at least weekly on an inpatient geropsychiatry unit. The performance in each of these four spheres near discharge is examined in relationship to initial performances. Mood is relatively independent of the other spheres with the final mood assessment correlating only with mood near the time of admission. Final cognitive, behavioral, and functional performances are related to initial performances in these three spheres but are not significantly correlated with the initial performance in the mood sphere. (J Geriatr Psychiatry Neurol 1990;3:17-20).