Affective and Atopic Disorders and Cyclic AMP Helen J. Ossofsky

I

N JULY 1972 the clinical findings associated with endogenous depression in 220 infants and children were reviewed.’ Endogenous depression is defined as a group of heterogeneous syndromes having in common a pervasive mood alteration influenced by hereditary and biologic factors. Discovery that almost half of children with affective disorders suffered from clinical allergies and were atopic on testing was puzzling (Table 1). A clinical diagnosis of multiple allergies was made in 100 of 220 depressed children on the basis of history and physical signs. Referral was made most frequently because of persistent nasal obstruction, chronic rhinorrhea, serous otitis, or wheezing. Of 100 suspected allergic children, all but 1 proved to be atopic. The term atopic implies a clinical allergy that appears to be inherited. The patient shows an immediate wheal and erythematous reaction to skin testing and/or a passively transferable antibody, now known as IgE. Confirmation of the atopic state in almost all suspected allergic children also seemed puzzling, since the diagnosis of allergy in children rarely is unequivocal. Could it be possible that all depressed children possess some altered immunologic response and appear to be atopic on skin testing, even in the absence of clinically recognized allergic disease? To test the hypothesis that the affective state itself might be associated with atopic reaction, all depressed children and adults referred for psychiatric evaluation between July 1972 and July 1973 were referred for allergic evaluation irrespective of the presence of allergic signs or symptoms. Several allergists were used as consultants to remove a possible artifact caused by any particular allergist. Of 109 depressed patients evaluated during this l-year period, 93 proved to be atopic. Thirteen were not tested because of financial considerations. Of three children who were tested and found to be nonatopic, two developed positive skin reactions to testing 4 and 8 months after being placed on imipramine therapy. In all patients a family history of allergy was obtained in at least one parent; frequently both parents suffered from chronic seasonal allergic symptoms never considered severe enough to warrant investigation. Twenty-five mothers of children included in the 93 proven atopic patients have subsequently been evaluated for allergies; all have proved to be atopic. Despite absence or paucity of allergic symptoms in about half of the atopic individuals, all 93 atopic patients referred during 1972-1973 were treated by routine techniques, including environmental control and desensitization. The affective

From the Georgetown

Helen J.

Ossofsky,

University

School ofMedicine. Washington, D.C. Professor of Pediatrics, Georgetown Universit! D.C.; Consulrant in Psvchiatry. Virginia Association of Children

M.D.: Clinical Associate

School of Medicine, Washington. with Learning Disabilities. An abstract of this paper was presented at the 128th annual meeting of the American Psvchiarric Association, Anaheim, Calif.. May 5-9.1975. Reprint requesis should be addressed lo Helen J. Ossofsky. M.D., Clinical Associare Professor of Pediatrics, Georgetown University School of Medicine. Washington, D.C. 20005. Q 1976 bv Grune & Stratton, Inc. Comprehensive Psychiatry. Vol. 17. No. 2 (March/April). 1976

335

336

HELEN J. OSSOFSKY

Number

%

Irritability

220

100

Easy frustration

220

100

220

100

169

77

awakening

51

23

falling asleep

17

8

101

46

Colic

133

61

Hyperactivity

125

67

span

Short attention Sleep difficulties

both

in utero Temper

tantrums

6

3

120

55

Enuresis

99

45

Allergies

99

45

Clumsiness

79

36

46

21

19

9

Speech selectively

delayed

Encopresis Reproduced

by permission

ComprPsychiatry

15:19,

from

Ossofsky

HJ: Endogenous

depression in infancy and childhood.

1974.

disorder was treated concomitantly with imipramine HCl or, in a few adults, with desipramine HCI. As depression was relieved, several children developed allergic respiratory symptoms for the first time, despite immunotherapy. In these children, allergic symptoms were promptly relieved by increasing the strength of the vaccine and/or decreasing the time interval between injections. Development of allergic symptoms was not accompanied by exacerbation of depression. All 93 atopic patients have been followed for 28 months; most of the original 99 allergic children evaluated prior to July 1972 have been followed for periods up to 8 years. These children have shown frequent seasonal exacerbations of allergic symptoms that were independent of exacerbations of depression. In retrospect, it is a clinical impression that the children receiving successful immunization did considerably better than nonimmunized children; maintenance doses of imipramine tended to be significantly smaller and could be discontinued for longer intervals. Precise analysis of this earlier clinical material is not available; many of the original patients have since been tested and are undergoing desensitization. The intimate relationship of allergy and depression suggested an abnormality in a neurotransmitter and/or the hypothalamic-pituitary-target-organ axis might be common to both clinical conditions. Alterations in adrenocorticosteroid excretion have been observed in some depressed states.2 Adrenocorticoids are accepted treatment of many allergic conditions. Both depression and allergy have significant connections with endocrine functions; both exist in the absence of known endocrinopathy. A study of hormonal function mediated by the adenosine monophosphate system seemed appropriate. Any threat to homeostasis triggers hormonal secretion. All hormones are transported via blood, and under normal circumstances, specificity of hormonal action resides in a remarkable specificity of chemical receptors in the target organ. These unique receptors react exclusively to a specific hormone signal, i.e., thyroid-stimulating hormone is picked up exclusively by a specific receptor on a

337

CYCLIC AMP

Fig.

1.

mation cyclic

and

Enzymatic destruction

for-

ATP

of

adenyl cyclase

cl

AMP.

thyroid ce11.3s4Whether the specific chemical receptor lies on the target-cell membrane or resides within the target cell is uncertain; however, once inside the cell the hormonal signal is biochemically picked up and carried by a “second messenger.” Sutherland, Rall, and associates were the first to discover the adenine nucleotide, adenosine 3’,5’-monophosphate (abbreviated cyclic AMP or CAMP), and to advance the second-messenger hypothesis of chemotransmission.5 According to these workers, hormones (first messengers) exert their effects by promoting formation of intracellular cyclic AMP (second messenger) from adenine triphosphate (ATP) under catalytic influence of the enzyme adenyl cyclase.6s7 Sutherland and co-workers recognized that the intracellular concentration of cyclic AMP was regulated not only by its rate of synthesis but also by its rate of degradation. Since Sutherland’s initial report, a class of enzymes (the cyclic nucleotide phosphodiesterases) has been found to control the degradation rate of cyclic AMP (Fig. 1).8 Intracellular cyclic AMP relays the hormonal signal from the cell surface to the inner cytoplasm and nucleus by controlling a wide variety of enzymatic processes that appear to be preprogrammed for specificity. Evidence indicates that cyclic AMP activity is carried out by the activation of numerous protein kinases present in inactive forms within each celLg The specificity of response of an individual cell to cyclic AMP depends upon the nature of the protein kinases within the cell. In bacteria, cyclic-AMP-dependent receptor proteins (kinases) have been shown to effect gene transcription.‘O*l’ The cyclic AMP system is known to be influenced at many reaction sites. Adenyl cyclase may be stimulated or inhibited by a group of fatty acids called prostaglandins, which are found in all tissues. I2 Most enzyme reactions occur only in the presence of specific ions, e.g., Ca++ appears necessary for the cyclicAMP-mediated activation of phosphorylase kinase in muscle (Fig. 2).13

cl ATP

Fig.

2.

Influences

on cyclic

AMP

activity;

most

reactions

require

the

presence

of specific

ions

338

HELEN

J. OSSOFSKY

Adrenal cyclic-AMP-dependent hormonal systems are the most studied of the many cyclic AMP systems related to the pathogenesis of the diverse symptoms of depression and allergy. In response to emotional or physical stress, the hypothalamus releases corticotropin-releasing hormone (CRH) at accelerated rates. CRH brings about release of adrenocorticotropic hormone (ACTH) from the anterior pituitary. Within minutes ACTH induces cortisol and corticosterone secretion in the adrenal gland. The manner in which ACTH promotes corticosteroidogenesis is under intense investigation; however, all proposed hypotheses involve cyclic AMP.14-18 The mechanism by which ACTH brings about aldosterone production is also believed to involve increased production of cyclic AMP.1g-21 Cortisol is metabolized to aldosterone only in the presence of cyclic AMP. Under the influence of dietary salt restriction, cortisol bypasses the cyclic AMP system and is rerouted to form aldosterone.22 Elaborate pathways involved in steroid synthesis from cholesterol provide varied sites for inborn errors of metabolism. Studies of steroid metabolites in depression suggest subclinical adrenocortical hyperfunction may exist in some patients, whereas a chronic hypofunctioning adrenal may be present in othersz3 A defect in cyclic AMP, its precursors, its degradation products, or its turnover rate might account for the varied patterns of steroid excretion found in depressed patients. Laboratory evidence that cyclic AMP is involved in depression has been reported. In 1970, Robison and co-workers reported that the urinary excretion of cyclic AMP was increased in affective disorders; it appeared that the increased enzyme was not of central nervous system origin .24Other investigators have suggested that depressive states are associated with a cyclic AMP deficiency and that an increase in excretion of urinary cyclic AMP is associated with improvement, or with mania. Paul and co-workers noted that the concentration of urinary cyclic AMP is increased on the day of rapid switch from depression to mania in manic-depressive patients; they have suggested that cyclic AMP may trigger the increase in catecholamines noted during the manic phase of manicdepressive illness.25 Changes in cyclic AMP activity may be produced by allosteric changes in enzyme configuration.26 Optical changes of enzymes are both rapid and rapidly reversible. The possibility that allosteric rotations might account for the remarkably rapid “switch” phenomenon characteristic of a group of depressed patients is tantalizing. Cyclic AMP appears to influence some biologic rhythms, especially those influenced by the adrenal feedback mechanism.27*28A diurnal variation in urinary cyclic AMP excretion has also been reported. 2QThere has been a recent report of a diurnal variation in the sensitivity of beta receptor to light intensity.30 The therapeutic effectiveness of compounds as dissimilar as thyroid hormone(s) and imipramine in the treatment of depression warrants examination. Stimulation of the anterior pituitary by hypothalamic thyroid-releasing hormone (TRH) favors production and release of thyroid-stimulating hormone (TSH). The action of TRH, as with all releasing hormones, is carried out through cyclic AMP.31 TSH stimulates biosynthesis, storage, and release of all three thyroid

CYCLIC

AMP

339

hormones. In this discussion thyroxine and triiodothyronine are referred to as “thyroid hormone:” calcitonin is related to calcium metabolism, and its use in depression has not been reported. Administration of cyclic AMP to thyroid tissue produces changes indistinguishable from those of TSH: cyclic AMP enhances Likewise, inhibition of cyclic both production and release of thyroid hormone. 32*33 AMP degradation has the same effect as administration of TSH. Most observations of thyroid function have been made from clinical expression of too much or too little circulating hormone. Physiologically, thyroid hormone exerts a widely diffuse action; the biochemical mechanisms by which it asserts its effects are undergoing intense study. Thyroid hormone does not appear to have any discrete target cell(s). The discovery that thyroid hormone increases the activity of adenyl cyclase, the enzyme that generates cyclic AMP, may define the primary role of thyroid hormone. 34 In man, thyroxine and triiodothyronine are unique among hormones; both have a delayed onset of action of hours or days and a duration of action of weeks, in contrast to the minute-to-minute regulation of glucocorticoids and other hormones. Ablation of the thyroid is compatible with prolonged survival even without exogenous therapy. Thyroid hormones appear to afTect the quality of life rather than life itself. Normal growth and development require precise amounts of thyroid at precise times. Excess thyroid administered to young thyroidectomized animals does not restore normal growth; the catabolic effect of thyroid may further stunt growth. In man, timing is critical around birth; delay in treating neonatal hypothyroidism leads to irreversible mental retardation. Central nervous system influence of thyroid continues beyond infancy; interestingly, the familiar ability of thyroid to increase oxygen consumption does not apply to adult brain.35 Excess thyroid is known to cause hyperirritability, restlessness, exaggerated responses to environmental stimuli, emotional instability, and overt psychosis.36 Too little thyroid is responsible for listlessness, lack of energy, memory impairment, dulling of mental abilities, slow speech and somnolence, and even overt psychosis.:” All symptoms of thyroid dysfunction are seen in depression. Alternating somnolence and hyperexcitability in bipolar depression suggest alternating or bipolar thyroid function, Thyroid accelerates glucose catabolism; its effects on lipid metabolism are more complex. 38.3gFree fatty acids (FFA) are mobilized from adipose tissue under thyroid stimulation. The rate of release of FFA in response to epinephrine is increased by thyroid hormone and substantially reduced in thyroid deficiency. FFA mobilization in response to epinephrine is dependent upon cyclic AMP. FFA release is increased in hyperthyroidism and reduced in hypothyroidism. It appears that the ability of thyroid hormone to mobilize fatty acid is related to the presence of cyclic AMP in adipose tissue.40 Contrary to popular belief, clinical hypothyroidism rarely leads to severe obesity; an isolated functional reduction of cyclic AMP at the thyroid cell level appears insufficient to account for the obesity seen in some affective disorders. The antidepressant effects attributed to TSH and TRH4L-44 may be effected by more efficient utilization of cyclic AMP in all tissues. Cholesterol synthesis is impaired in thyroid deficiency; however, serum cholesterol rises in hypothyroidism and can be restored to normal by thyroid

340

HELEN J. OSSOFSKY

administration. The ability of thyroid hormone to promote biliary excretion of cholesterol outweighs its role in increasing synthesis; the net result of thyroid administration is a reduction in plasma cholesterol levels to norma1.45*46Surprisingly, a profoundly depressed 15year-old girl included in the current series of depressed atopic patients presented with a significantly elevated cholesterol and normal thyroid and TSH plasma levels. Cholesterol values returned to normal following administration of 450 mg imipramine and no thyroid, daily. Evasiveness of the mechanism of action of imipramine, and consideration of events leading up to its discovery, are interesting in view of a cyclic-AMP-related etiology of depression. Around 1950, Dr. Roland Kuhn was requested by the Geigy Company in Switzerland to study a new antihistaminic to see whether it might be useful as a hypnotic. No hypnotic action was noted, but Kuhn made a remarkable observation that the drug had antipsychotic effects. Not until 1956 when Kuhn tested a similar antihistaminic (G-22355, later known as imipramine) was the true antidepressant action appreciated.47 The antidepressant effects of imipramine are so striking that its antihistaminic properties have virtually been forgotten. The ability of imipramine to stop enuresis and reverse many of the somatic abnormalities present in depressed patients suggests that the therapeutic properties of the drug may be related to a unique regulatory effect on cyclic AMP function. Tricyclics have been shown to inhibit cyclic AMP degradation.48 Tricyclic antidepressants inhibit phosphodiesterase activity; this inhibition is reported to be dose-dependent. Tricyclics have been reported to have some inhibitory effect on ATPase4g and, by making more ATP available, increase cyclic AMP concentration without influencing degradation. Demonstration that tricyclics act at varied sites within the cyclic AMP system provides a rational basis for the individualization of dosage schedules required for successful treatment of depression. Similarities between hormone- and immune-mediated responses are striking. Evidence is accumulating that cyclic AMP is related to atopic states in at least four major areas: through its participation in adenyl cyclase blockade, through its role in antibody formation, through its ability to increase the number of immunocompetent cells, and by virtue of its participation in histamine inhibition. The sympathetic division of the efferent peripheral autonomic nervous system is considered to have two receptors, alpha and beta.50 Beta receptors are further classified into two groups according to end-organ response.5’ Stimulation of one group of beta receptors results in bronchial muscle relaxation.52 In the bronchial muscle cell, adenyl cyclase is believed to be the beta receptor responsible for enzymatic conversion of adenosine triphosphate (ATP) to cyclic AMP. In 1962, Szentivanyi proposed the beta-adrenergic blockade theory of allergic disease.53 According to Szentivanyi, adenyl cyclase does not respond with normal bronchodilator activity. Epinephrine, ephedrine, isoproterenol, steroids, and methylxanthines are used successfully in the treatment of asthma; all are known to increase levels of cyclic AMP. Endogenous or exogenous catecholamines increase cyclic AMP levels by stimulating adenyl cyclase activity;54 methylxanthines (aminophylline and tbeophylline) increase cyclic AMP by blocking phosphodiesterase activity. 55 The clinical observation that aminophylline may be effective in epinephrine-resistant asthma suggests that abnormalities in at least

341

CYCLIC AMP

two loci of the cyclic AMP system may result in clinical asthma. Paradoxical asthma following isoproterenol aerosols is believed to result from the blocking of cyclic AMP formation by a metabolite of isoproterenol;56 thus asthma appears to have multiple etiologies involving the cyclic AMP system (Fig. 3). Ishizuka has demonstrated that cyclic AMP enhances antibody formation, both in vitro and in vivo.57 Antibody response is believed to rely upon the recognition of antigen by a specific receptor site. It is hypothesized that atopic states arise from genetically poor or insufficient numbers of receptors to a given antigen; antibody formation is stimulated by both cyclic AMP and stabilizers of cyclic AMP.“X In vitro cyclic AMP is capable of increasing the number of antibody-forming cells.“g The formation of lymphocytes and thymocytes is increased by cyclic AMP stimulation.6” Cyclic AMP is known to inhibit antigenically induced histamine release; several compounds (methylxanthines and catecholamines) known to increase cyclic AMP concentration also bring about histamine inhibition.“‘*62 Failure of the cyclic AMP system to inhibit histamine might play an important role in the pathogenesis of allergic symptoms. Cyclic AMP dysfunction reconciles the association of depression and atopic states without implying that allergies cause depression or that all depressed individuals suffer from clinical allergy. Since enzyme synthesis occurs either at the level of the gene or the ribosome, abnormalities of the cyclic AMP system are in keeping with the known hereditary nature of both depression and allergy. The cyclic AMP system provides a unifying hypothesis for the protean manifestations of affective disorders. Cyclic AMP is as ubiquitous as water, yet it participates only in specialized functions. Specificity is provided by the fact that cyclic AMP activity is evoked by one specific stimulus arriving at one precise location; the responses cyclic AMP promotes are unique functions of highly specialized innate intracellular enzyme systems. Symptoms of depression are also ubiquitous, yet they are also highly specific. The irritability and hyperactivity of the depressed child may be related to calcium and/or thyroid-provoked cyclic AMP activity; enuresis and premenstrual Auid retention noted in some depressed children and adults may be brought about by actions of calcium, aldosterone, angiotonin II, and sodium and potassium Catecholamines epinephrine ephedrine isoproterenol steroids

Methylxanthines

ATP cl

adenyl cyclase relaxes bronchial muscle

Fig. 3.

lnfluances

inhibits histamine release

on the cyclic AMP system as related to allergic phenomena

342

HELEN J. OSSOFSKY

influences on the cyclic AMP system. Cyclic-AMP-mediated combined actions of thyroid, adrenal corticosteroids, glucagon, and insulin could theoretically contribute to obesity fsllnd in certain depressed adults. Demonstration of tissue resistance to insulin in obesity supports the concept of malfunction at, at least, one receptor level. e3 Abnormal luteinizing hormone and/or estrogen expression through cyclic AMP dysfunction provide causes for menstrual and reproductive abnormalities of some depressed women. Alterations in circadian phenomena frequently encountered in depressed individuals might be explained eventually by abnormalities in beta receptors, qualitative or quantitative changes in cyclic AMP concentration, or both. Mood changes appear to be associated with disturbances throughout the central and peripheral nervous system; changes in somatic functions are not necessarily secondary to changes within the brain. It would appear that endogenous depression may involve a number of clinical syndromes caused by one or more abnormalities of the cyclic AMP system. The expression “abnormalities of the cyclic AMP system” is used here in a manner analogous to the term “diseases of infectious origin.” Cyclic AMP is a locus for biochemical malfunctions and not necessarily a pathogen in itself. In addition to the obvious possibilities of qualitative, quantitative, and turnover rate changes within the cyclic AMP system itself, pathogenesis of affective signs and symptoms might be found in biochemical factors that influence the cyclic AMP system. Alterations extracellular factors-may of prostaglandins, hormones, ions, enzymes-all influence the cyclic AMP system adversely. Anatomic lesions may also affect the cyclic AMP system and influence symptomatology. The concept of chemical transmission across synaptic spaces has been accepted. The advent of the electron microscope has permitted measurement of synaptic spaces; autonomic synaptic spaces are approximately one-third the size of somatic neuromuscular junctions. One can only speculate on the effect(s), either narrowing or widening, the synaptic cleft might have on chemotransmission. Electron microscopy of autonomic synaptic clefts of depressed individuals seems worthy of study. Simple depression need not involve brain tissue; however, schizo-affective and schizophrenic syndromes appear to involve precise locations within the brain. Involvement of the septal area may produce serious psychoses; cyclic AMP lesions along visual and auditory pathways provide biologic credence for visual and auditory hallucinations. “Somatic” symptoms associated with mood disorders may be dependent upon the anatomic location of the cyclic AMP lesion. The largest amounts of adenyl cyclase and cyclic AMP and its diesterases are found in brain tissue. Although brain tissue has the greatest capacity of all mammalian tissues to produce cyclic AMP, E4laboratory preparations of brain have produced limited information concerning the cyclic AMP system. The heterogeneity of brain tissue and the difficulty in preparing intact neurons not contaminated with glial cells limit interpretations of in vitro studies. It has been demonstrated that histamine65 and catecholamineF’ increase the accumulation of cyclic AMP in brain tissue. It has been suggested that ATP may exist in a storage complex with biogenic amines and may be released with the amines at synaptic sites. The “neurotransmitter” at some central synapses may, in fact, be

CYCLIC

343

AMP

several substances. A cyclic-AMP-related etiology of depression is not incompatible with abnormalities of biogenic amines observed in depression. At the superior cervical ganglion, synaptic transmission is enhanced by dopamine, acting on adenyl cyclase, which promotes formation of cyclic AMP.“7 By mediating hypothalamic-controlled endocrine functions, cyclic AMP is, at least indirectly, related to areas of the central nervous system possessing hypothalamic connections. An additional second messenger, cyclic guanosine 3’,5’-monophosphate (cyclic GMP), has been isolated,‘jx and the search is continuing for additional second messengers. Initial research suggests cyclic GMP may activate biologic events that oppose the action of cyclic AMP.6g Should these two nucleotides prove to function as intracellular second messengers for norepinephrine and acetylcholine, respectively, the concept “disorders of the cyclic AMP system” would have to be enlarged to include alterations in the cyclic GMP transport system. Two reports relating incidence of malignancy to allergy and affective disorders warrant consideration. A report in 1972 showed a decreased mortality rate from cancer in individuals over the age of 40 who suffered from affective psychoses.7u A controlled study in England demonstrated that individuals suffering from malignancies have a reduced incidence of allergic disorders.71 Pathogenesis of symptoms of depression is infinitely complex. Alterations of cell membrane permeability provide for additional variations of expression of cyclic AMP action. Continued probing into normal and abnormal cyclic AMP activity may clarify the relationship between affective disorders and so-called medical illnesses such as ulcerative colitis, gastric and duodenal ulcers, rheumatoid arthritis, myasthenia gravis, and migraine. Endogenous depresion appears to be a systemic disease. Cyclic AMP abnormality defines an intracellular etiology for depression; changes in extracellular hormonal secretion and excretion appear to be secondary phenomena necessary for maintenance of homeostasis. Any truly significant breakthrough in the understanding and treatment of endogenous affective disorders appears to be dependent upon vigorous basic research into normal as well as abnormal intracellular phenomena. The need to integrate basic research and clinical medicine is imperative. Future treatment of depression and allergy may depend upon refinement of pharmacologic agents developed to overcome specific malfunctions within the cyclic AMP system. REFERENCES I, Ossofsky

HJ: Endogenous depression in in-

fancy and childhood.

Compr

Psychiatry

15:19-

25, 1974 changes

with particular cholamines

H,

Strom-Olson

in manic-depressive

R:

Hu-

psychosis

reference to the excretion of cate-

in urine.

J Ment

Sci 104:696

3. Harris Differential trasynaptic membrane

MW,

26:40%461,

Kuffler

SW,

chemosensitivity areas

on

the

in parasympathetic

Dennis

Sutherland

of epinephrine

MJ:

Chem 224:463-475,

of synaptic and exneuronal neurons

surface of the

RE:

Cellular

Prog Biophys Mol Biol

1973

5. Rail TW,

6. Rail TW,

EW, Berthet I: Effect

and glucagon on the reactivation

of phosphorylase AJ,

Gorman

responses to cyclic AMP.

704,

1958

of acetylcholine.

Proc R Sot Lond [Biol] 177:541&553,1971 4. Bitensky

2. Weil-Malherbe moral

frog, tested by microapplication

in liver homogenates.

J Biol

1957

Sutherland

cyclic adenine ribonucleotide J Biol Chem 232:106551076,

EW: Formation

of a

by tissue particles. 1958

344

7. Sutherland EW, Rall TR: Fractionization and characterization of a cyclic adenine ribonucleotide formed by tissue particles. J Biol Chem 232:1077-1091, 1958 8. Appleman MM, Thompson WJ, Russell TR: Cyclic nucleotide phosphodiesterases, in Greengard P, Robison GA (eds): Advances in Cyclic Nucleotide Research, vol 3. New York, Raven Press, 1973, p 65 9. Kuo JF, Greengard P: Cyclic nucleotide-dependent protein kinases. IV. Widespread occurrence of adenosine 3’,5’-monophosphate-dependent protein kinase in various tissues and phyla of the animal kingdom. Proc Nat1 Acad Sci USA 64:1349-1355, 1969 IO. Langan TA: Protein kinases and protein kinase substrates, in Greengard P, Robison GA (eds): Advances in Cyclic Nucleotide Research, ~013. New York, Raven Press, 1973, p99 1I. Kish VM, Kleinsmith LJ: Nuclear protein kinases. Evidence for their heterogeneity, tissue specificity, substrate specificities, and differential responses to cyclic adenosine 3’:5’-monophosphate. J Biol Chem 249:750-760, 1974 12. Horton EW: Hypotheses on physiological roles of prostaglandins. Physiol Rev 49:122Z161, 1967 13. Brostrom CO, Hunkeler FL, Krebs EG: The regulation of skeletal muscle phosphorylase kinase by Ca’+. J Biol Chem 246:1961~1967, 1971 14. Haynes RC Jr, Berthet L: Studies on the mechanism of action of the adrenocorticotropic hormone. J Biol Chem 225:115-124, 1957

15. Koritz SB, Hall PF: End-product inhibition of the conversion of cholesterol to pregnenolone in an adrenal extract. Biochemistry 3:1298-1304, 1964 16. Urquhart J, Krall RL, Li CC: Analysis of the Koritz-Hall hypothesis for the regulation of steroidogenesis by ACTH. Endocrinology 83:390-394,1968 17. Garren LD, Ney RL, Davis WW: Studies on the role of protein synthesis in the regulation of corticosterone production by adrenocorticotropin hormone in vivo. Proc Nat1 Acad Sci USA 53:1443-1450, 1965 18. Garren LD, Davis WW, Crocco RM, et al: Puromycin analogs: Action of adrenocorticotropic hormone and the role of glycogen. Science 152:1386-1388, 1966 19. Sutherland EW, Rail TW: The relation of adenosine 3’S’-phosphate and phosphorylase to the actions of catecholamines and other hormones. Pharmacol Rev 12:265-299, 1960 20. Roos BA: ACTH and CAMP stimulation

HELEN J. OSSOFSKY

of adrenal ribosomal protein phosphorylation. Endocrinology 93: 1287- 1293,1973 21. Sutherland EW, Robison GA: The role of cyclic 3’,5’-AMP in responses to catecholamines and other hormones. Pharmacol Rev 18:145161, 1966 22. Marusic ET, Mulrow PJ: Stimulation of aldosterone biosynthesis in adrenal mitochondria by sodium depletion. J Clin Invest 46:2101~2108, 1967 23. Carpenter WT Jr, Bunney WE Jr: Adrenal cortical activity in depressive illness. Am J Psychiatry 128:31-40, 1971 24. Robison GA, Cooper AJ, Whyebrow PC, et al: Cyclic AMP in affective disorders. Lancet 2:1028%1029.1970 25. Paul MI, Cramer H, Bunney WE Jr: Urinary adenosine 3’,5’-monophosphate in the switch process from depression to mania. Science 171:300-303,197l 26. Tarui SK, Nonaka K, Ikura Y, et al: Stereospecific sugar transport caused by the thyroid stimulating hormone and adenosine 3’,5’monophosphate in the thyroid gland and other tissues. Biochem Biophys Res Commun 13:329333, 1963 27. Orth DN, Island DP: Light synchronization of the circadian rhythm in plasma cortisol (I7-OHCS) concentration in man. J Clin Endocrinol Metab 29:479-486,1969 28. Krieger DT, Kreuzer J, Rizzo F: Constant light: Effect on circadian pattern and phase reversal of steroid and electrolyte levels in man. J Clin Endocrinol Metab 29: 1634- 1638,1969 29. Murad F, Pak CY: Urinary excretion of adenosine 3’,5’-monophosphate and guanosine 3’,5’-monophosphate. N Engl J Med 286:13821387, 1972 30. Romero JA, Axelrod J: Pineal @-adrenergic receptor: Diurnal variation in sensitivity. Science 184:1091-1092, 1974 3 1. Poirier G, Burden N, Labrie F, et al: Partial purification and some properties of adenyl cyclase and receptor for TRH from anterior pituitary gland. Excerpta Medica International Congress Series 256:85, 1972 32. Pastan I, Katzen R: Activation of adenyl cyclase in thyroid homogenates by thyroidstimulating hormone. Biochem Biophys Res Commun 29:722-798, 1967 33. Gilman GA, Rall TW: Studies on the relation of cyclic 3’,5’-AMP (CA) to TSH action in beef thyroid slices. Fed Proc 25:617, 1966 34. Levey GS, Skelton L, Epstein SE: Decreased myocardial adenyl cyclase activity in hypothyroidism. J Clin Invest 48:2244-2250, I969

CYCLIC

345

AMP

35. Barker SB, Klitgaard HM: Metabolism of tissues excised from thyroxine-injected rats. Am J Physiol 1708-86, 1952 36. Lidz T: Emotions and mentation, in Werner SC, Ingbar SH (eds): The Thyroid: A Fundamental and Clinical Text (ed 3). New York, Harper & Row, 197 I, pp 627-629 37. Asher R: Myxoedematous madness. Br Med J 2:555-562, 1949 38. Bray GA, Goodman HM: Role of thyroid hormones in lipolysis. Am J Physiol 210:10531058, 1966 39. Bray GA, Goodman HM: Metabolism of adipose tissue from normal and hypothyroid rats. Endocrinology 82:860-864, 1968 40. Goodman HM: Permissive effects of hormones on lipolysis. Endocrinology 86: 1064 1074. 1970 41. Kastin AJ, Ehrensing RH, Schalch DS, et al: Improvement in mental depression with decreased thyrotropin response after administration of thyrotropin-releasing hormone. Lancet 2:740-742, 1972 42. Prange AJ Jr, Lara PP, Wilson IC, et al: Effects of thyrotropin-releasing hormone in depression. Lancet 2:999- 1002, 1972 43. Plotnikoff NP, Prange AJ Jr, Breese GR, et al: Thyrotropin-releasing hormone: Enhancement of dopa activity by a hypothalamic hormone. Science 178:417-418, 1972 44. Prange AJ Jr, Wilson IC, Knox AE, et al: Thyroid-imipramine clinical and chemical interaction. Evidence for a receptor deficit in depression. J Psychiatr Res 9:187-205, 1972 45. Peters JP, Man EB: The significance of serum cholesterol in thyroid disease. J Clin Invest 29:1.- II, 1950 46. Friedman M, Byers SO, Rosenman RH: Changes in excretion of intestinal cholesterol and sterol digitonides in hyper- and hypothyroidism. Circulation 5:657-660, 1952 47. Kuhn R: The imipramine story, in Ayd FJ, Blackwell B (eds): Discoveries in Biological Psychiatry. Philadelphia, JB Lippincott, 1970, p 205 48. Abdulla YH, Hamadah KH: 3’,5’-cyclic adenosine monophosphate in depression and mania. Lancet I:378838I, 1970 49. Farska I, Sikora J. Krulik R: The effect of psychotropic drugs on phosphodiesterase CAMP, ATPase and on 5’nucleotidase. Act Nerv Super (Praha) 15:124~125,1973 50. Ahlquist RP: A study of the adrenotropic receptors. Am J Physiol 153:586~600,1948 51. Lands AM, Arnold A, McAuliff JP, et al: Differentiation of receptor systems activated by sympathomimetic amines. Nature 214:597-598, 1967

52. Widdicombe JG, Sterling GM: The autonomic nervous system and breathing. Arch Intern Med 126:31 l-329, 1970 53. Szentivanyi A: The beta adrenergic theory of the atopic abnormality in bronchial asthma. J Allergy 42:203-232, 1968 54. Logsdon PJ, Middleton E Jr, Coffey RG: Stimulation of leukocyte adenyl cyclase by hydrocortisone and isoproterenol in asthmatic and nonasthmatic subjects. J Allergy 50:45 56, 1972 55. Robison GA, Butcher RW, Sutherland EW: Cyclic AMP. New York. Academic Press. 197 I, pp 84-88 56. Reisman RE: Asthma induced by adrenergic aerosols. J Allergy 46:162- 177, 1970 57. Ishizuka M. Gafni M, Braun W: Cyclic AMP effects on antibody formation and their similarities to hormone-mediated events. Proc Sot Exp Biol Med 134:963-967, 1970 58. Braun W. lshizuka M, Winchurch R. et al: Cells and signals in immunological nonresponsiveness. Ann NY Acad Sci 181:289 298, 1971 59. lshizuka M, Braun W, Matsumoto T: Cyclic AMP and immune responses. I. Influence of poly A:U and CAMP on antibody formation in vitro. J lmmunol 107:1027-1035, 1971 60. Winchurch R, lshizuka M. Webb D. et al: Adenyl cyclase activity of spleen cells exposed to immunoenhancing synthetic oligo- and polynucleotides. J lmmunol 106:1399-1400, 1971 61. Lichtenstein ML, Margolis S: Histamine release in vitro: Inhibition by catecholamines and methylxanthines. Science 16 I :902 903, 1968 62. Lichtenstein ML, DeBernardo R: The immediate allergic response: In vitro action of cyclic AMP-active and other drugs on the two stages of histamine release. J Immunol 107:1131~ 1136, 1971 63. Amatruda JM, Livingston JN, Lockwood DH: Insulin receptor: Role in the resistance of human obesity to insulin. Science 188:264 266. 1975 64. Kaliuchi S. Rail TW, Mcllwain H: The effect of electrical stimulation upon the accumulation of adenosine 3’,5’-phosphate in isolated cerebral tissue. J Neurochem 16:485-491. 1969 65. Kakiuchi S, Rail TW: Studies on adenosine 3’.5’-phosphate in rabbit cerebral cortex. Mol Pharmacol4:379-388, 1968 66. Kakiuchi S, Rail TW: The influence of chemical agents on the accumulation of adenosine 3’,5’-phosphate in slices of rabbit cerebellum. Mol Pharmacol4:3677378, 1968 67. Kebabian

JW.

Greengard

P: Dopamine-

346

sensitive adenyl cyclase: Possible role in synaptic transmission. Science 174:134661349, 1971 68. Asbman DF, Lipton R, Melicow MM, et al: Isolation of adenosine 3’,5’-monophosphate and guanosine 3’,5’-monophosphate from rat urine. Biochem Biophys Res Commun 11:330334, 1963 69. Stone TW, Taylor DA, Bloom FE: Cyclic AMP and cyclic GMP may mediate opposite

HELEN J. OSSOFSKY

neuronal responses in the rat cerebral cortex. Science 187:845-847, 1975 70. Ebumehko, Bn: An analysis of various data concerning patients with affective psychosis who died after 40 years of age. Zh Neuropatol Psikiatr 72:5688573, 1972 71. Alderson M: Mortality from malignant disease in patients with asthma. Lancet 2:14751477, 1974

Affective and atopic disorders and cyclic AMP.

Affective and Atopic Disorders and Cyclic AMP Helen J. Ossofsky I N JULY 1972 the clinical findings associated with endogenous depression in 220 inf...
969KB Sizes 0 Downloads 0 Views