Are disturbances in lipid-protein interactions by phospholipase-A2 a predisposing factor in...

BIOL PSYCHIATRY 945 lY8Y;25:Y45-Y61

COMMENT

Are Disturbances in Lipid-Protein Interactions by Phospholipase-A2 a Predisposing Factor in Affective Illness?

Joseph R. Hibbeln, June W. Palmer, and John M. Davis

Current theories of affective disorders do not account for many of the biological markers replicated in patient studies. We link many biological findings in a reasonable physiological relationship, compatible with mechanisms of action of pharmacological and electroshock therapies for depression. We propose that excessive phospholipase-A2 (PL&) activity disrupts membranefluidity, composition, and therefore, the activity, of membrane- dependent proteins. Similar disruptions in these proteins are documented in depressed patients and can be accounted for by excessive PLAz activity. This paradigm accounts for disturbances in the activity of Na-K-ATPase, betaz- and alpha2-adrenergic receptors, MAO, norepinephrine and serotonin uptake, and imipramine binding. Disturbances in other membrane-dependent proteins, tyrosine and tryptophan hydroxylase, can explain the biogenic amine hypothesis. Inhibition of glucocorticoid receptor and TRH receptor binding to their respective ligands by P.&AZ may explain patient nonsuppression in the Dexamethasone Suppression Test and poor response in the TRH stimulation test. Phys- iological regulators of PLA2 activity; calcium, cortisol, estrogen, progesterone, and PGE, are documented abnormalities in some patients with aftective disorders and consistent with excessive PL& activity. Thus, postpartum depression and premenstrual tension syndrome may be described in the paradigm. The mechanisms of action of tricyclic antidepressants, lithium, electroconvulsive shock, and some novel antimanic agents can be described in terms of alterations of PL& activity. Interestingly, ethanol perturbs membrane juidity and membrane-bound enzymes in a manner similar to excessive PL& activity. A hereditary factor predisposing patients to affective disorders may be a gene defect at either PLA2 or in its regulation.

Introduction

The norepinephrine hypothesis introduced 20 years ago (Bunney and Davis 1965; Schild- kraut 1965) and the serotonin theory remain unproven. The amine hypothesis postulates a functional deficit in neurotransmitter production or uptake or degeneration or receptor

From the Departments of Psychiatry, University of Illinois at Chicago and UCLA (J.R.H.); the Department of Pharmacology, University of Illinois at Chicago (J.W.P.); and the Illinois State Psychiauic Institute, Chicago, IL (J.M.D.)

Supported in part by the John D. and Catherine T. MacArtkr Foundation. Address reprint requests to 1. R. Hibbeln, Department of Psychiatry, Education Office (116A3). Sepulveda VAMC, 161 I I

Plummer St., Sepulveda CA 91343. Received April 21, 1988; wised September 13, 1988.

8 1989 Society of Biological Psychiatry 0006-3223/89/$03.50

946 BIOL PSYCHIATRY 1989:25:945-961

J.R. Hibbeln et al.

function. There are a number of replicated biological abnormalities described in depression that provide potentially important clues. Each abnormality is regulated by membrane- bound proteins whose activity can be mediated by phospholipase-A2 (PLA2) digestion of their lipid environment. We would suggest that one of the causative factors is an abnormality in PLAl or in its regulation, such that PLA2 activity is functionally increased in depression. We will use the abbreviation PLA2 to indicate an abnormality in either PLA2 or its regulation. We do not suggest that excess PLA2 activity is necessarily the sole or principal cause of depression, but rather that PLAz could be a contributing factor that could bias each of these neurotransmitter systems in a direction that could lead to depression. It is possible that more than one system is involved in depression, and PLAl could influence several systems in the direction of depression. As PLAz is an enzyme, its regulation is under genetic controls, and an inherited excess of PLAz activity could be a predisposing factor to depression. As the location of the genes controlling PLAz and its regulation are deciphered, it would be interesting if the gene loci regulating PLA2 and its activity coincided with the gene for depression. Specifically, we hypothesize that the occurrence of PLAZ activity is increased in depression, leading to a disruption in lipid composition, in turn disrupting the activity of the membrane-bound proteins associated with each of the replicated abnormalities (see Table 1) described in depressed patients and pharmacological effects (see Table 2).

Interactions between Phospholipase A2 and Tyrosine Hydroxylases

Tyrosine hydroxylase is the rate-limiting step for catecholamine synthesis, and PLA:! regulates its lipid environment and activity (for review see Mandell 1984). PLA2 (from V. russelli) decreases tyrosine hydroxylase (Kuszenski 1983). At low levels of activity (0.0002 U), PLA2 preferentially digests phosphatidylserine, which contains the fatty acid (22:6) (Salem et al. 1986). Tyrosine hydroxylase is especially sensitive to activation by phosphatidylserine (Lloyd and Kaufman 1979). We note that phosphatidylserine (22:6) is almost unique to brain synapses (Sun et al. 1983). Given intravenously, phosphatidylserine (22:6) from brain increases dopamine, norepinephrine, and epinephrine turnover in mouse cortex (Toffano et al. 1976). In contrast, soy bean phosphatidylserine, with few fatty acid chains (22:6), did not affect catecholamine turnover. Phospholipid liposomes containing phosphatidylserine have been shown to increase cerebrospinal fluid levels of homovanillic acid (HVA) and 5hydroxyindoleactic acid (5-HIAA) in Alz- heimer’s patients (Argentiero et al. 1980). Similar phospholipid liposomes have been shown to have an antidepressant effect in a double-blind clinical study (Roccatagliata et al. 1978).

Disturbances in Glucocorticoid Metabolism and Phospholipase-AZ

Many depressed patients have elevated cortisol, corticotropin-releasing factor (CRF) and fail to suppress to dexamethasone (Carroll 1985; Potter et al. 1987). As there is evidence that excessive PLA2 activity inhibits the binding of glucocorticoids to their receptors in the liver (Westphal et al. 1978; Leach et al. 1983), we would hypothesize that excessive PLA2 activity would inhibit negative feedback by diminishing the ability of cells to sense glucocorticoid levels at both the central and pituitary levels, thus leading to an increased release of CRF as well as excess adrenocorticotropic hormone (ACTH) release. There is evidence that PLAz stimulation by mellitin can lead to increased ACTH and beta-endor-

Lipid-Protein Interactions by Phospholip~e-A* BIOL PSYCHIATRY %7 l989;25:945-.96l

Table 1. The Relationship of Biological Findings in Depression to Phospholipase-A2 Activity

Human studies in Biochemical studies of depressed vs normal phospholipase-A2 (PLA,)

Calcium Calcium in CSF . . . . . . . . . . . . . . 7 Calcium activates PLAt . . . . . . . . . . . . . . .

a. b. C,

d.

Membrane transport Na-K ATPase activity . . . . . . . . . 1 PLA2orFFAonNa-KATPase . . . . . . . . . . . 5-HT uptake in platelets. . . . . . . . . 1 PLA2 activity on 5-HT uptake,. . . . . . . . . . . Imip~~ne binding . . . . . . . . . . . . 4 PLA2 activity on imipmmine binding . . . . . . Ca-Mg ATPase activity.. . . . . . . . j. PLAz activity on Ca-Mg ATPase . . . . . . . , .

Neurotransmitter receptors e+Adrenergic receptor

a. Receptor number (B,,,) . . . . . . b. Binding affinity (V,.)

No change c. NEPI-induced inhibition of

CAMP production . . . . . . . . . Bz-Adrenergic receptor

a. NEPI and ISOP stimulation of adenylate cyctase ., . . . . . . . .

b. Effect due to decreased coupling

a.

b.

C.

Basal Cortisol (plasma, urine and CSF) . . . . . , . . . . . . . . .

Cortical post-Dexamethasone Suppression Test _ . . . . . . . . .

TSH response to TRH . . . . . . . . .

Neurotransmitters, merabolites, related enzymes a. Homovanillic acid in CSF . . .

b. 5-HIAA in CSF (suicide) . . . . . .

a Prostaglandin-E2 in CSF . . . . . . . .

b.

c.

d.

e.

Serum free fatty acids increase with severity of symptoms . . . , .

Phosphatidylcholine decreased in some blood com~nents . . . . . . .

Alterations in RBC membrane biophysics noted by ESR

Suicide victims have relatively disrupted neuronal membranes

a. b.

Response to Con-A stimulation . . . Lymphocyte number

postbereavement . . . . . . . . . . . , .

t PLA2 activity on receptor number. . . . . . . . . PLAr activity on binding affinity

No change PLAz activity on NEPI-induced inhibition of

CAMP production . . . . . . . . . . . .

PLAr activity or FFA on ISOP stim. of adenylate cyclase . . . . . . . , . , . . . . .

Inhibition of N-protein prevents coupling

Neuroendocrine PLAz activity inhibits glucocorticoid

binding to glucocorticoid receptor; lack of negative feedback causes cortisol to increase . . . . . . . . . . . . . . .

PLAr activity inhibits TRH binding to TRH receptor; TSH response is . . . . . . . . . . . . .

c. Overall immune function in depressed patients. . . . . , . , . .

Low levels of PLAr activity can decrease tyrosine hydroxylase activity and would result in decreased HVA and NEPI , . . . .

Other fiitdings

t PLAs is the rate-limiting step in prostaglandin synthesis. , . . . . . . . . . . ,

PLAr releases free fatty acids in proportion

t to activity . . . . . . . . . . . . . . . . . . . . . . ...* PLA2 digests phosphatidylcholine . . . . . . . . .

PLAz activity perturbs membrane fluidity in similiar manners

PLAr perturbs neuronal membranes

Immune function

4 PLAr activity on response to Con-A. . . . . . .

i PLAz activity on lymphocyte mitogenesis . ,

1 PLA2 intimately involved in macrophage

function, neutrophil cytotoxicity, and prostaglandin release . . . . . . . . . . . . . . . . .

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948 BIOL PSYCHIATRY 1989;25:945-961

J.R. Hibbeln et al.

Table 2. The Relationship of Pharmacological Therapeutics to Phospholipase-A2 in Affective Disorders

Patient studies: Biochemical studies:

Findings in depressed vs normal Relationship to phospholipase-Al (PLA2)

I.

2.

3.

4.

5.

6.

I.

8.

Tricyclic antidepressants blockade of

NEPIIS-HT is immediate, but therapeutic

onset is delayed

Lithium is effective in mania and

depression

Carbamazepine. effective in mania and

depression

Electroconvulsive shock treatment

effective only when seizures are induced;

may have an anticonvulsant effect

Glucocorticoids initially induce euphoria

S-adenosyl methionine (SAMe) is a novel

antidepressant

Valproate is a novel antimanic agent

Reserpine induces depressed-like state via

catecholamine depletion

I.

2.

3.

4.

5 _

6.

1.

8.

TCAs and other antidepressants inhibit PLAz activity; accumulation on phospholipids (and effects

on membrane bound proteins?) is delayed

Lithium reduces calcium availability by reducing

PIP2 recycling; neurotransmitter-stimulated Ca

release is regulated by PLAz

Carbamazepine inhibits PIP* recycling

PLAz is involved in seizures; prolonged release of

PCE2 post-ECS may inhibit PLAz

Glucocorticoids induce lipomodulin, which inhibits

PLAz

SAMe (via methylation) may restore membrane

phospholipids digested by PLA2

Valproate inhibits methylation and production of

phosphatidylcholine; endogenous SAMe accumulates

PLAz links Ca to fusogenic process in synaptosomes;

alpha-bungerotoxin, which has PLAz as active

component, depletes neurotransmitters

phin-IR release from the pituitary (Heisler et al. 1982; Knepel and Meyen 1986). Fur-

thermore, dexamethasone inhibition of ACTH release is dependent on PLA2 (Hirata et al. 1980; Davidson et al. 1987). Circulating cortisol or dexamethasone binds to glucocorticoid receptors in the pituitary, including lipomodulin, which in turn inhibits PLAz,

which inhibits ACTH release (Axelrod and Reisine 1984). If excessive PLA2 inactivated the glucocorticoid receptor at the pituitary level, then the pituitary would not be able to sense high levels of circulating cortisol (or dexamethasone), and hence, lipomodulin

would not be induced. Without lipomodulin inhibition of PLA*, excessive ACTH release would continue, thus evoking a failure in the negative feedback system.

TRH Response Test

Some depressed patients have a blunted response of thyroid-stimulating hormone (TSH) to thyrotropin-releasing hormone (TRH) infusion or to TRH stimulation of prolactin release (Sachar et al. 1980; Extein et al. 1982; Judd et al. 1982; Allen et al. 1987). The binding of pituitary TRH to the TRH receptor is inhibited by phospholipase-AZ hydrolysis of the membrane, but not by phospholipase-C or D (Loh and Law 1980; Ogawa et al. 1982).

Estrogen and Progesterone

Depression is more common in women, and they suffer related phenomena, such as

postpartum depression and premenstrual tension syndrome. We note that estrogen and progesterone regulate PLAz in the uterus (Liggins 1979; Thombum and Challis 1979;

Lipid-Protein Interactions by ~ospbolipa~-A* BKX. PSYCHIATRY 949 1989;25:945-%I

Dey et al. 1982; Danfortb and Scott 1986; Levin et al. 1986; Bonney and Franks 1987). These hormones cross the blood-brain barrier (McEwen et al. 1979). Bonney (1985) showed that PLAz activity is highest in human endometrium in a late luteal phase at approximately the same time that symptoms of p~rnens~~ tension syndrome occur. The role of estrogen and progesterone in depression and their effect on brain PLA2 is uncertain.

Interactions between Beta*-Adrenergic Receptors and Phospholipase-A2

Depressed patients have a decreased number of beta,-adrenergic receptors, as described by Pandey et al. (1979) and replicated by others (Extein et al. 1979; Mann et al. 1985). Phospholipase-AZ release of free fatty acids and lysophospholipids has been shown to have tbe same effect of reducing coupling of beta,-adrenergic receptors to adenylate cyclase in cardiac cells of duck embryos (Bobik et al. 1983) and in rat liver plasma memb~nes (Lad et al. 1979; Loh and Law 1980). Proper functioning of N-regulatory proteins, which are sensitive to changes in membrane structure (Lad et al. 1979; Sinensky et al. 1979), is essential for activation of adenylate cyclase in the beta-receptor complex (Houslay and Gordon 1983; Lefkowitz et al. 1983). Glucocorticoids and tricyclic antidepressants modulate this coupling (Mobley and Sulser 1980; Sulser et al. 1983; Pandey et al. 1985). Furthermore, glucocorticoids and glutaraldehyde have been shown to modulate beta*-adrenergic coupling to a~nyla~ cyclase via ph~~olip~-A* i~ibition (Cohen et al. 1985; Iizuka et al. 1986).

Interactions between Alpha2-Adrenergic Receptors and Phospholipase-A2

Depressed patients show (1) increased platelet alpha*-receptor number (&,,), (2) no change in alphas-receptor binding affinity (V,,), and (3) receptor sub~nsitivity that is reduced norepinephrine-induced inhibition of cyclic adenosine monophosphate (CAMP) production (Kafka and Paul 1986; Wolfe et al. 1987). Experimentally, PLA2 (1) increases receptor number (B,,&, (2) does not change receptor affinity (V,,,) in rat cerebral cortical membranes (Cohen et al. 1985), and (3) alpha2-mediated enhancement of isoproterenol- stimulated CAMP production is totally dependent on PLA, (Duman et al. 1986). Fur- thermore, Duman et al. (1986) concluded that corticol could mediate the response of this system through inhibition of PLA*.

Interactions between Phospholipase-As and Na+-K+ ATPase

In about 20 studies avowed prior to the generalized use of psycho~opic drugs, depressed patients were found to have decreased salivation. Further studies related this to decreased Na+-K+ ATPase activity. Both return to normal with recovery. Many studies show depressed patients have decreased Na+-K+ ATPase activity in a variety of tissues (plasma, RBCs, platelets) in comparison to either normal controls or their own recovered state (Glen 1968; Naylor et al. 1973; Hesketh 1976; Choi et al. 1977; Hesketh et al. 1977; Whalley et al. 1980; Numberger et al. 1982; C&row et al. 1982), but one study reports increased activity (Sengupta et al. 1980). Na’-K+ ATPase is inhibited by increased PLA, activity in beef brain microsomes (Swarm 1984) and in rat synaptosomes and brain microsomes (Taniguchi and Tonomora 1971; Lin-Shiau and Chen 1982). Swann (1984) described the dependence of two conformational forms of Na+-K+ ATPase, E, and E,,

950 BIOL PSYCHIATRY 1989:25.945-961

J.K. Hibbeln et al.

on membrane fuidity in the area of the enzyme. Increased fluidity reduced the sensitivity of the enzyme in E2 conformation and reduced cation flux. Aloia et al. (1985) reviews the role of membrane fluidity in Na’-K’ ATPase activity.

Inhibition of Ca+-MG+ ATPase by Phospholipase AZ

Ca+-Mg+ ATPase has decreased activity in manic depressive patients (Meltzer and Kassir 1983). PLAz hydrolysis inhibits Ca+-Mg + ATPase in rat skeletal muscle and sarcoplasmic reticulum (Swoboda et al. 1979).

Serotonin and Imipramine Binding

Imipramine labels the serotonin uptake site (Paul et al. 1985). Reduced serotonin uptake and decreased imipramine binding is reported in some patients with affective disorders in both platelet and autopsy brain (Meltzer et al. 1981; Potter et al. 1987). Similarly, bee venom PLA2 inhibits “H-imipramine binding in rat hippocampal membranes (Kinnier et al. 1981). Snake venom PLA2 decreases 3H-imipramine binding in mouse cerebral cortex (Retth et al. 1984). In rat brain synaptosomes, exogenous PLA2 inhibits the reuptake of 3H-serotonin and 3H-norepinephrine (Rotman 1977).

Role of Calcium and Lithium in Phospholipase-A2 Activity

Dubovsky and Franks (1983) inferred through cerebrospinal fluid (CSF) studies that depressed patients have increased intracytosolic calcium levels. Transient increases of intracytosolic calcium activate PLA*. Lithium and carbamazepine may indirectly regulate PLA2 by inhibiting phosphoinositol turnover and calcium release. Many receptors, such as 5-HT2 or alpha,-adrenergic, use the phosphoinositol second messenger system to release calcium, which stimulates PLA2 (Axelrod et al. 1988). Phospholipase-C hydrolyses phosphoinositol 4,5-bis-phosphate (PIP*) into diacylglycerol and inositol- 1,4,5-trisphosphate (1,4,5-IP3), which releases calcium from intracellular stores. This system is dependent on the availability of PIP*. Carbamazepine or lithium, at therapeutic concentrations, can inhibit the recycling of inositol components into PIP2 by inhibiting inositol- 1 -phosphatase (Allison and Blisner 1976; Hallcher and Sherman 1980; Berridge et al. 1982; Fisher and Agranoff 1987; Vadnal and Bazan 1988). Indeed, lithium alters rat cortex levels of phosphoinositols as well as phosphatidylcholine and phosphatidylethinolamine (Joseph et al. 1987). In rat synaptic membranes, chronic lithium administration causes changes in membrane fluidity and liquid composition compatible with our hypothesis (Lopez- Corcuera et al. 1988).

Electroconvulsive Shock (ECS) and Phospholipase-A2

Electroconvulsive shock is an effective antidepressant (Post et al. 1986). We postulate that ECS inhibits PLA2 for prolonged periods via the sustained release of the anticonvulsant prostaglandin-E2. Brain PLA2 is superactivated during seizures in animals (Bazan 1970; Rodriguez de Turco et al. 1976; Bazan et al. 198 1, 1982) which is consistent with increases in serum free fatty acids in humans (Schalch 1967; Ruxin et al. 1972; Stelmasiak and Curzon 1974). However, 2 hr post-ECS, there is a reduction in the release of most free fatty acids, except for increased arachidonic acid. This is due to reduced PLAZ activity

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952 BlOL PSYCHIATRY 1989;25:945- 961

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and reduced membrane tumover (Siesjo et ai. 1986). The prolonged release of a~chidonic acid may be due to phospholipase (PLC) induction during seizures (Flynn and Wecker 1987). Prolonged release of arachidonic acid and increased cyclooxygenase activity during ECS (Lysz et al. 1987) leads to increased tissue concentrations of prostaglandins, especially PCiE2 (Bazan et al. 1982; Wolfe 1982; Siesjo et al. 1986). PGE2 is a potent endogenous anticonvulsant (Rosenkranz et al. 1981; Dragunow 1986) and inhibits PLAz (Moskowitz et al. 1984). We would like to mention that our theory does not directly explain why ECS is effective in mania as well as depression, why lithium has some antidepressant properties as well as antimanic properties, or why excess cortisol can cause depression as well as euphoria. The norepinephrine (NE) or serotonin (5HT) hypotheses have similar problems.

~-Ad~~osyl~meth~onine as an Antidepressant

European and American double-blind studies have shown S-adenosyl-methionine (SAMe) to be a rapid and effective antidepressant (Agnoli et al. 1976; Kufferle and Grunberger 1982; Caruso et al. 1984; Camey et al. 1986; Janicak et al. 1988). Some patients switch from depression to mania, which suggests that methylation is involved in this process (Bunney 1978). As SAMe methylates phosphatidyle~anol~ine to form phosphatidyi- choline, it may be restoring membrane components digested by PLA;? and restoring membrane fluidity (Liu et al. 1983) (see Figure 1). Furthermore, an anticonvulsant and antimanic agent, valproate, inhibits production of phosphatidylcholine and causes endogenous accumulation of SAMe in rat brain (Carl 1985). Thus, an antidepressant, SAMe, increases phospholipid me~ylation and induces mania, whereas an ~timanic agent, valproate, decreases phospho~ipid methylation.

Tricyclic Antidepressants and Phospholipase-Az

We would postulate that effective antidepressants should inhibit PLA2. Although we could find no studies using in vivo therapeutic doses, imipramine, chlo~mipramine, and des- methy~imipramine inhibit PLA2 in vitro (Pappu and Hostetler 1989; Hostetler and Mat- suzawa 1981; Grabner 1987). Tranylcypromine inhibits PLA:! in human renal arteries (Ueda et al. 1981). Chlorpromazine, a phenothiazine found in double-blind placebo- controlled studies to be an antidepressant, inhibits PLAz in a variety of tissues and in vitro studies (Schroder et al. 198 1; Pappu and Hostetler 1984). A possible mechanism of action of PLA? inhibition comes from Tabeta et al. (1985) and Munro et al. (19861, who show in nuclear magnetic resonance (NMRf studies that imipramine-like and ami- triptyline-like antidepressants bind phosphatidylcholine tightly and induce conformational changes. PLA;? is sensitive to changes in accessibility of its cleavage site (Van den Bosch 1980) and cannot hydrolyze phosphatidylcholine. The slow accumulation of phospholipids noted by Sgaragli et al. (1983) may explain the delayed onset of therapeutic action of some antidepressants, but we hasten to add that very high doses were used, and the brain phospholipids were not assayed.

Effects of Ethanol on Membrane Fluidity

As there is an epidemiological association between alcoholism and depression, we spec- ulate that there may be a common dysfunction in depressives and alcoholics, i.e., regulation of their membrane lipid composition. The development of addiction to alcohol

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involves changes in membrane lipids (Goldstein 1984). Also, ethanol ingestion increases PLA2 activity in rats (Ramo et al. 1986) and reduces membrane control of PLA2 (Spach et al. 1979).

Transmitter Depletion

Depression may be preceded by such stress as separation or by learned helplessness. Stress increases brain NE and down-regulates beta-NE receptors. We would hypothesize that stress leads to excessive release of NE, which secondarily leads to NE depletion.

When the action potential reaches the synaptic bouton, it is hypothesized that PLA2 links the influx of Ca*+ with neurotransmitter release by allowing synaptic vesicles to fuse with the membrane and release neurotransmitters into the synaptic cleft. There is sub- stantial evidence that PLAP mediates the calcium-induced release of catecholamines in rat brain synaptosomes (Moskowitz et al. 1984). Furthermore, beta-bungarotoxin, in which PLA* is the major active component, depletes catecholamine storage in brain

synapses (Chang et al. 1973; Wernicke et al. 1974). Excessive endogenous PLA2 activity might deplete neurotransmitter stores and cause depression in much the same way that reserpine depletes neurotransmitter stores and results in depression.

Prostaglandins

Depressed patients have elevated prostaglandin-E2 (PGE2) in the CSF and serum and elevated thromboxane-AZ (TXA2) in serum (Lieb et al. 1983; Linnoila et al. 1983; Cal- abrese and Gulledge 1984). PLAz releases arachidonic acid, a precursor of series 2

prostaglandins, which include PGE2, TXA*, prostaglandin Fz,, and prostacyclin. Horrobin (1983) also found increased levels of PGF2 and PGE, in depression and postulated that this elevation caused depression. We note that aspirin and other nonsteroidal antiinflam- matory drugs inhibit prostaglandin production, but these affect neither PLA2 nor mood, whereas cortisol, which acts upstream to induce lipomodulin, decreasing PLAz and con-

sequently prostaglandin release, produces the cortisol euphoria.

Immune Function

The acute phase of depression lowers lymphocyte response to phytohemaglutinin (PHA) concanavalin-A (Con-A), and pokeweed mitogen (PWM) antigens (Stein et al. 1987). Bereavement also lowers responses to PHA, Con-A, and PWM mitogens in the first 2 months postbereavement. Free fatty acids released from PLAZ hydrolysis regulate lym-

phocyte response to Con-A, cell surface capping (Chapman et al. 1979), and lymphocyte mitogenesis (Meade and Martin 1978). PLA;! also regulates a wide variety of macrophage functions (Schmidt et al. 1984), which are central to the pathology of multiple sclerosis (Traugott et al. 1983). Macrophage digestion of myelin is dependent on PLA2 release (Trotter and Smith 1986). Woelk and Katsuyo (1974) found increased PLA2 activity in brains of multiple sclerosis patients, a disorder in which mood changes occur. Finally. release of prostaglandins by PLA2 has many regulatory effects on immune function.

Phospholipids in Patients

The most direct evidence for excess PLAz activity in depression is provided by Pettegrew et al. (1982, 1988), who showed that depressed patients had increased RBC membrane fluidity in the hydrophobic core. This increase in fluidity is consistent with excess PLAl

Lipid-Protein Interactions by Phospholipase-A2 BIOL PSYCHIATRY 955 1989;25:945-%I

activity. PLAl liberates free fatty acids, and we have shown (Mueller et al. 1970) that depressed patients have an increase in serum free fatty acids, and this increase correlated positively with the severity of depressive symptoms. To exclude the possibility of catecholamine-induced peripheral fatty acid mobilization, we measured urinary catecholamines and 17-hydroxycorticosteroids. We found these measures to be uncorrelated to free fatty acid serum levels. Using electron microscopy studies, Issidorides (1988) found increased disruption of neuronal membranes in suicide victims as compared to controls. As PLAl disrupts neuronal membranes, this finding is consistent with our hypothesis. Given that PLA2 digests phosphatidylcholine, the finding of Sengupta et al. (1981) that depressed patients had decreased platelet and RBC phosphatidylcholine is consistent with our hypothesis. For completeness, we note that serum PLAl was measured in psychiatric patients by Gattaz et al. (1987), but this is not relevant because serum PLAz measured by their technique (Thuren et al. 1985), is a different enzyme originating from the pancreas to digest fats in the intestine (Van den Bosch 1980).

Conclusion

PLAz is a major physiological regulator of lipid composition and the activity of membrane- bound receptors, enzymes, and ion pumps (Sun et al. 1983; Spector and Yorek 1985). Increased PLA2 activity could be a physiological mediator that explains a wide variety of clues to the pathogenesis of depression. This should not be taken as a single cause of depression. The regulation of membrane lipid composition and PLA2 is multifactorial and complex (Fisher et al. 1983; Scott 1984). We would postulate that a dysfunction of PLAl or one of its regulators is an inherited predisposing factor, and when coupled with stress, leads to an increased fusion of NE or 5-HT vesicles to membrane and depletion of amines, as well as changes in critical membrane-bound proteins, enzymes, and receptors. This hypothesis is highly speculative and is clearly an unproven possibility. This said, the hypothesis has heuristic value, and we think it must be stated and tested.

We are grateful to Jane Ann Retallack for her dedicated help in the preparation of this manuscript and to Raymond and Shirley Hibbeln for their generous support. We extend special thanks to Shawn Hall for graphic arts and other assistance.

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